The rise (and decline?) of biotechnology.

PubMed

Kinch, Michael S

2014-11-01

Since the 1970s, biotechnology has been a key innovator in drug development. An analysis of FDA-approved therapeutics demonstrates pharmaceutical companies outpace biotechs in terms of new approvals but biotechnology companies are now responsible for earlier-stage activities (patents, INDs or clinical development). The number of biotechnology organizations that contributed to an FDA approval began declining in the 2000s and is at a level not seen since the 1980s. Whereas early biotechnology companies had a decade from first approval until acquisition, the average acquisition of a biotechnology company now occurs months before their first FDA approval. The number of hybrid organizations that arise when pharmaceutical companies acquire biotechnology is likewise declining, raising questions about the sustainability of biotechnology. Copyright © 2014 Elsevier Ltd. All rights reserved.

78 FR 20924 - Center for Biologics Evaluation and Research eSubmitter Pilot Evaluation Program for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-08

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0248... Drug Applications AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug... sponsors of investigational new drug (IND) applications to participate in a pilot evaluation program for...

75 FR 63189 - Draft Guidance for Industry on Investigational New Drug Applications-Determining Whether Human...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-14

... obtain approval from the Office of Management and Budget (OMB) for each collection of information they... information before submitting the collection to OMB for approval. To comply with this requirement, FDA is... VIII of the draft guidance, ``Process for Addressing Inquiries Concerning the Application of the IND...

Current good manufacturing practice and investigational new drugs intended for use in clinical trials. Final rule.

PubMed

2008-07-15

The Food and Drug Administration (FDA) is amending the current good manufacturing practice (CGMP) regulations for human drugs, including biological products, to exempt most phase 1 investigational drugs from complying with the regulatory CGMP requirements. FDA will continue to exercise oversight of the manufacture of these drugs under FDA's general statutory CGMP authority and through review of the investigational new drug applications (IND). In addition, elsewhere in this issue of the Federal Register, FDA is announcing the availability of a guidance document entitled "Guidance for Industry: CGMP for Phase 1 Investigational Drugs" dated November 2007 (the companion guidance). This guidance document sets forth recommendations on approaches to compliance with statutory CGMP for the exempted phase 1 investigational drugs. FDA is taking this action to focus a manufacturer's effort on applying CGMP that is appropriate and meaningful for the manufacture of the earliest stage investigational drug products intended for use in phase 1 clinical trials while ensuring safety and quality. This action will also streamline and promote the drug development process.

Biologics as countermeasures for acute radiation syndrome: where are we now?

PubMed

Singh, Vijay K; Romaine, Patricia L P; Newman, Victoria L

2015-04-01

Despite significant scientific advances toward the development of a safe, nontoxic and effective radiation countermeasure for acute radiation syndrome (ARS) over the past six decades, no drug has been approved by the US FDA. Several biologics are currently under development as radiation countermeasures for ARS, of which three have received FDA Investigational New Drug (IND) status for clinical investigation. Presently, two of these agents, entolimod (CBLB502) and HemaMax (recombinant human IL-12) are progressing with large animal studies and clinical trials. Neupogen (G-CSF, filgrastim) has recently been recommended for approval by an FDA Advisory Committee. Filgrastim, GM-CSF (Leukine, sargramostim), and PEGylated G-CSF (Neulasta) have high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the FDA in the future. The former two biologics are available in the US Strategic National Stockpile (SNS) for use in the event of nuclear or radiological emergency. The Emergency Use Authorization (EAU) application for entolimod may be filed soon with the FDA. Biologics are attractive agents that are progressing along the path for FDA approval, to fill the unmet need for ARS countermeasures.

Probiotic (VSL#3) for Gulf War Illness

DTIC Science & Technology

2011-10-01

Probiotic (VSL#3) for Gulf War Illness 5b. GRANT NUMBER W81XWH-10-1...started the study as yet. This is due to inability to get IND (Investigational New Drug) number for the probiotic , Bifidobacterium infantis 35624 (Align...Drug Administration (FDA). We requested the Department of Defense to allow us to use another commonly used probiotic , VSL#3. The Department of

76 FR 27328 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

...--Phases 1, 2, and 3. 21 CFR 312.23(a)(7)--Chemistry, manufacturing, and control information. 21 CFR 312.23... New Drug (IND) Regulations--21 CFR Part 312--(OMB Control Number 0910-0014)--Extension FDA is... ``Investigational New Drug Application'' in part 312 (21 CFR part 312). Part 312 implements provisions of section...

Pre-clinical and Clinical Development of Low Dose Methamphetamine for the Treatment of Traumatic Brain Injury

DTIC Science & Technology

2014-12-01

Aim 3: Secure FDA approval of a phase I/II clinical trial plan and obtain an amended IND in preparation for initiating human clinical testing in TBI...Neurology 6:193–201. Raineri M, Gonzalez B, Goitia B, Garcia-Rill E, Krasnova IN, Cadet JL, Urbano FJ, Bisagno V. 2012. Modafinil abrogates

77 FR 5027 - Food and Drug Administration Transparency Initiative: Exploratory Program To Increase Access to...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2009-N-0247] Food and Drug Administration Transparency Initiative: Exploratory Program To Increase Access to the... responsible for a broad range of compliance and enforcement activities. Increasing the transparency of these...

Regulatory challenges in manufacturing of pancreatic islets.

PubMed

Linetsky, E; Ricordi, C

2008-03-01

At the present time, transplantation of pancreatic islet cells is considered an experimental therapy for a selected cohort of patients with type 1 diabetes, and is conducted under an Investigational New Drug (IND) application. Encouraging results of the Edmonton Protocol published in the year 2000 sparked a renewed interest in clinical transplantation of allogeneic islets, triggering a large number of IND applications for phase I clinical trials. Promising results reported by a number of centers since then prompted the Food and Drug Administration (FDA) to consider the possibility of licensing allogeneic islets as a therapeutic treatment for patients with type 1 diabetes. However, prior to licensure, issues such as safety, purity, efficacy, and potency of the islet product must be addressed. This is complicated by the intricate nature of pancreatic islets and limited characterization prior to transplantation. In this context, control of the manufacturing process plays a critical role in the definition of the final product. Despite significant progress made in standardization of the donor organ preservation methods, reagents used, and characterization assays performed to qualify an islet cell product, control of the isolation process remains a challenge. Within the scope of the FDA regulations, islet cells meet the definition of a biologic product, somatic cell therapy, and a drug. In addition, AABB standards that address cellular therapy products apply to manufacturing facilities accredited by this organization. Control of the source material, isolation process, and final product are critical issues that must be addressed in the context of FDA and other relevant regulations applicable to islet cell products.

DESIGNING PHASE 0 CANCER CLINICAL TRIALS

PubMed Central

Murgo, Anthony J.; Kummar, Shivaani; Rubinstein, Larry; Gutierrez, Martin; Collins, Jerry; Kinders, Robert; Parchment, Ralph E.; Ji, Jiuping; Steinberg, Seth M.; Yang, Sherry X.; Hollingshead, Melinda; Chen, Alice; Helman, Lee; Wiltrout, Robert; Tomaszewski, Joseph E.; Doroshow, James H.

2008-01-01

Phase 0 trials are designed primarily to evaluate the pharmacodynamic and/or pharmacokinetic properties of selected investigational agents prior to initiating more traditional phase 1 testing. One of the major objectives of phase 0 trials is to interrogate and refine a target or biomarker assay for drug effect in human samples implementing procedures developed and validated in preclinical models. Thus, close collaboration between laboratory scientists and clinical investigators is essential to the design and conduct of phase 0 trials. Given the relatively small number of patients and tissue samples, demonstrating a significant drug effect in phase 0 trials requires precise and reproducible assay procedures and innovative statistical methodology. Furthermore, phase 0 trials involving limited exposure of study agent administered at low doses and/or for a short period allows them to be initiated under the FDA Exploratory IND Guidance with less preclinical toxicity data than usually required for traditional first-in-human studies. Because of the very limited drug exposure, phase 0 trials offer no chance of therapeutic benefit, which can impede patient enrollment, particularly if invasive tumor biopsies are required. However, the challenges to accrual are not insurmountable, and well-designed and executed phase 0 trials are feasible and have great potential for improving the efficiency and success of subsequent trials, particularly those evaluating molecularly targeted agents. PMID:18559582

The Food and Drug Administration and pragmatic clinical trials of marketed medical products

PubMed Central

Anderson, Monique L; Griffin, Joseph; Goldkind, Sara F; Zeitler, Emily P; Wing, Liz; Al-Khatib, Sana M; Sherman, Rachel E

2015-01-01

Pragmatic clinical trials (PCTs) can help answer questions of comparative effectiveness for interventions routinely used in medical practice. PCTs may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration (FDA) is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity upon which approval of medical products are made. The FDA has broad jurisdiction over drugs and medical devices (whether or not they are approved for marketing), and as such, clinical investigations of these products are subject to applicable FDA regulations. While many PCTs will meet the criteria for an exemption from the requirements for an investigational new drug application (IND) or investigational device exemption (IDE), in general all clinical investigations of medical products that fall under FDA jurisdiction must adhere to regulations for informed consent and review by an institutional review board (IRB). We are concerned that current FDA requirements for obtaining individual informed consent may deter or delay the conduct of PCTs intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the FDA. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk PCTs. We recommend that the FDA establish a risk-based approach to obtaining informed consent in PCTs that would facilitate the conduct of PCTs without compromising the protection of enrolled individuals or the integrity of the resulting data. PMID:26374684

Tesamorelin Therapy to Enhance Axonal Regeneration, Minimize Muscle Atrophy and Improve Functional Outcomes Following Peripheral Nerve Injury and Repair

DTIC Science & Technology

2017-10-01

Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT We are currently completing the set-up phase for this study . We have hired and trained all...Hospital and University of Maryland Medical Center/Shock Trauma). The final step with regards to study set up prior to beginning recruitment will be...to receive HRPO approval. 15. SUBJECT TERMS IRB, FDA IND exemption, HRPO, study set-up phase 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

Cooperative research and development opportunities with the National Cancer Institute

NASA Technical Reports Server (NTRS)

Sybert, Kathleen

1991-01-01

The Office of Technology Development (OTD) of the National Cancer Institute (NCI) is responsible for negotiating Cooperative Research and Development Agreements (CRADAs), whereby the knowledge resulting from NCI investigators' government-sponsored research is developed in collaboration with universities and/or industry into new products of importance for the diagnosis and treatment of cancer and acquired immunodeficiency syndrome (AIDS). The NCI has recently executed a unique 'clinical trials' CRADA and is developing a model agreement based upon it for the development and commercialization of products for the diagnosis and treatment of cancer and AIDS. NCI drug screening, preclinical testing, clinical trials, and AIDS program capabilities form the basis for this new technology development/technology transfer vehicle. NCI's extensive drug screening program and 'designer foods' program serve as potential sources of investigational new drugs (INDs) and cancer preventatives. Collaborations between NCI and pharmaceutical companies having the facilities, experience, and expertise necessary to develop INDs into approved drugs available to the public are being encouraged where the companies have proprietary rights to INDs, or where NCI has proprietary rights to INDs and invites companies to respond to a collaborator announcement published in the Federal Register. The joint efforts of the NCI and the chosen collaborator are designed to generate the data necessary to obtain pharmaceutic regulatory approval from the Food and Drug Administration (FDA) to market the drugs developed, and thereby make them available to health care providers for the diagnosis and treatment of cancer and AIDS.

An integrated bioinformatics infrastructure essential for advancing pharmacogenomics and personalized medicine in the context of the FDA's Critical Path Initiative.

PubMed

Tong, Weida; Harris, Stephen C; Fang, Hong; Shi, Leming; Perkins, Roger; Goodsaid, Federico; Frueh, Felix W

2007-01-01

Pharmacogenomics (PGx) is identified in the FDA Critical Path document as a major opportunity for advancing medical product development and personalized medicine. An integrated bioinformatics infrastructure for use in FDA data review is crucial to realize the benefits of PGx for public health. We have developed an integrated bioinformatics tool, called ArrayTrack, for managing, analyzing and interpreting genomic and other biomarker data (e.g. proteomic and metabolomic data). ArrayTrack is a highly flexible and robust software platform, which allows evolving with technological advances and changing user needs. ArrayTrack is used in the routine review of genomic data submitted to the FDA; here, three hypothetical examples of its use in the Voluntary eXploratory Data Submission (VXDS) program are illustrated.: © Published by Elsevier Ltd.

Why (not) go east? Comparison of findings from FDA Investigational New Drug study site inspections performed in Central and Eastern Europe with results from the USA, Western Europe, and other parts of the world.

PubMed

Caldron, Paul H; Gavrilova, Svetlana I; Kropf, Siegfried

2012-01-01

Since the mid-1990s, investigational sites in the countries of Central and Eastern Europe (CEE) have been increasingly utilized by pharmaceutical companies because of their high productivity in terms of patient enrolment into clinical trials. Based on the FDA's publicly accessible Clinical Investigator Inspection List, we present an analysis of findings and outcome classifications from FDA inspections during Investigational New Drug (IND) studies and compare the results for the CEE region to those from Western European countries and the USA. Data from all 5531 FDA clinical trials inspections that occurred between 1994 (when the FDA first performed inspections in CEE) and the end of 2010 were entered into the database for comparative analysis. Of these, 4865 routine data audit (DA) inspections were analyzed: 401 from clinical trials performed in Western Europe, 230 in CEE, 3858 in the USA, and 376 in other countries. The average number of deficiencies per inspection ranged between 0.99 for CEE and 1.97 in Western Europe. No deficiencies were noted during 16.6%, 39.0%, and 21.5% of the inspections in Western Europe, CEE and USA, respectively. The percentages of inspections after which no follow-up action was indicated were 36.9% for Western Europe, 55.7% for CEE, and 44.3% for US sites. CEE was also the region with the lowest percentage of inspections that required official or voluntary action. On the basis of FDA inspection data, the high productivity of CEE sites appears to be accompanied by regulatory compliance as well as by data quality standards that are not inferior to those in Western regions.

Development of a PET Prostate-Specific Membrane Antigen Imaging Agent: Preclinical Translation for Future Clinical Application

DTIC Science & Technology

2016-10-01

small-molecule peptidomimetic imaging agents labeled with positron emitting fluorine- 18 . These data will enable the filing of an exploratory IND...outcome. 15. SUBJECT TERMS Prostate Cancer, Prostate Specific Membrane Antigen (PSMA), Fluorine- 18 , Molecular Imaging, Radiotracer, Automated...Synthesis, Phosphoramidate, Inhibitor, Peptide Mimic, Peptidomimetic 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a

Why (not) go east? Comparison of findings from FDA Investigational New Drug study site inspections performed in Central and Eastern Europe with results from the USA, Western Europe, and other parts of the world

PubMed Central

Caldron, Paul H; Gavrilova, Svetlana I; Kropf, Siegfried

2012-01-01

Since the mid-1990s, investigational sites in the countries of Central and Eastern Europe (CEE) have been increasingly utilized by pharmaceutical companies because of their high productivity in terms of patient enrolment into clinical trials. Based on the FDA’s publicly accessible Clinical Investigator Inspection List, we present an analysis of findings and outcome classifications from FDA inspections during Investigational New Drug (IND) studies and compare the results for the CEE region to those from Western European countries and the USA. Data from all 5531 FDA clinical trials inspections that occurred between 1994 (when the FDA first performed inspections in CEE) and the end of 2010 were entered into the database for comparative analysis. Of these, 4865 routine data audit (DA) inspections were analyzed: 401 from clinical trials performed in Western Europe, 230 in CEE, 3858 in the USA, and 376 in other countries. The average number of deficiencies per inspection ranged between 0.99 for CEE and 1.97 in Western Europe. No deficiencies were noted during 16.6%, 39.0%, and 21.5% of the inspections in Western Europe, CEE and USA, respectively. The percentages of inspections after which no follow-up action was indicated were 36.9% for Western Europe, 55.7% for CEE, and 44.3% for US sites. CEE was also the region with the lowest percentage of inspections that required official or voluntary action. On the basis of FDA inspection data, the high productivity of CEE sites appears to be accompanied by regulatory compliance as well as by data quality standards that are not inferior to those in Western regions. PMID:22563236

Proposed Industry Best Practices in Development and Marketing of Medical Foods for the Management of Chronic Conditions and Diseases while Awaiting Regulation.

PubMed

Burnett, Bruce; Levy, Robert M

Ideal therapeutics have low toxicity and can effectively manage condition(s) or disease(s). The Food & Drug Administration (FDA) marketing category of therapeutics called “medical foods” (MFs) meets such a definition. Medical foods have existed in Federal law since passage the Orphan Drug Act in 1988, which created a category of nutritional therapeutics separate from drugs. Unfortunately, MFs are not widely understood by the medical community or utilized in all patients who need them due to lack of a FDA-approval process, unclear and contradictory guidance especially with regard for need for an investigational new drug (IND) application, and no clear regulations regarding their development and marketing. The goals of this article are to propose “Best Practices” to guide the medical food industry in the development and marketing of products as well as to serve as a starting point for suggestions regarding further FDA regulation so that therapeutics which are shown to be generally recognized as safe (GRAS), provide food ingredients to meet a distinctive nutritional requirement for a specific condition/disease and are proven effective for the management for that condition/disease can be used to benefit patients who need them.

Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop.

PubMed

Lesko, Lawrence J; Salerno, Ronald A; Spear, Brian B; Anderson, Donald C; Anderson, Timothy; Brazell, Celia; Collins, Jerry; Dorner, Andrew; Essayan, David; Gomez-Mancilla, Baltazar; Hackett, Joseph; Huang, Shiew-Mei; Ide, Susan; Killinger, Joanne; Leighton, John; Mansfield, Elizabeth; Meyer, Robert; Ryan, Stephen G; Schmith, Virginia; Shaw, Peter; Sistare, Frank; Watson, Mark; Worobec, Alexandra

2003-04-01

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

Conference report: Clinical and Pharmaceutical Solutions through analysis (CPSA USA 2013): connecting patients and subject numbers through analysis.

PubMed

Needham, Shane; Premkumar, Noel; Weng, Naidong; Lee, Mike

2014-02-01

The 16th Annual Symposium on Clinical and Pharmaceutical Solutions through Analysis (CPSA) 7-10 October 2013, Sheraton Bucks County Hotel, Langhorne, PA, USA. The 2013 CPSA brought together the various US FDA regulated analytical fields affecting a 'patient' for the first time - bioanalysts supporting IND and NDAs, clinical diagnostic and pathology laboratory personnel, and clinical researchers that provide insights into new biomarkers. Although the regulatory requirements are different for each of the above disciplines, the unique analytical perspectives that affect the patient were shared - and the goal of the 2013 CPSA - 'Connecting Patients and Subject Numbers Through Analysis' was achieved.

The Development of Countermeasures for Space Radiation Induced Adverse Health Effects

NASA Astrophysics Data System (ADS)

Kennedy, Ann

The Development of Countermeasures for Space Radiation Induced Adverse Health Effects Ann R. Kennedy Department of Radiation Oncology, University of Pennsylvania School of Medicine, 195 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA, United States 19104-6072 The development of countermeasures for radiation induced adverse health effects is a lengthy process, particularly when the countermeasure/drug has not yet been evaluated in human trials. One example of a drug developed from the bench to the clinic is the soybean-derived Bowman-Birk inhibitor (BBI), which has been developed as a countermeasure for radiation induced cancer. It was originally identified as a compound/drug that could prevent the radiation induced carcinogenic process in an in vitro assay system in 1975. The first observation that BBI could inhibit carcinogenesis in animals was in 1985. BBI received Investigational New Drug (IND) Status with the U.S. Food and Drug Administration (FDA) in 1992 (after several years of negotiation with the FDA about the potential IND status of the drug), and human trials began at that time. Phase I, II and III human trials utilizing BBI have been performed under several INDs with the FDA, and an ongoing Phase III trial will be ending in the very near future. Thus, the drug has been in development for 35 years at this point, and it is still not a prescription drug on the market which is available for human use. A somewhat less time-consuming process is to evaluate compounds that are on the GRAS (Generally Recognized as Safe) list. These compounds would include some over-the-counter medications, such as antioxidant vitamins utilized in human trials at the levels for which Recommended Dietary Allowances (RDAs) have been established. To determine whether GRAS substances are able to have beneficial effects on radiation induced adverse health effects, it is still likely to be a lengthy process involving many years to potentially decades of human trial work. The human trials necessary to demonstrate "efficacy" for a beneficial effect on the long term adverse health effects of radiation, such as the development of cancer, cataracts, etc., is expected to take particularly long periods of time. To avoid the long time delay in the development of new drugs as countermeasures for radiation induced adverse health effects, the NSBRI Center for Acute Radiation Research (CARR) is currently focused on the use of drugs that have already been approved for human use by the FDA. Currently there are no approved countermeasures for external radiation exposure by the US Army or by NASA. The appropriate medications for symptoms of the Acute Radiation Syndrome (ARS) due to exposure to solar particle event (SPE) radiation are unknown, but there are medications appropriate for ARS symptoms caused by exposure to conventional ra-diation. The Armed Forces Radiobiology Research Institute (AFRRI) has medical guidelines for ARS medications (http://www.afrri.usuhs.mil/outreach/guidance.htm#policies), as does the US Dept. of Health and Human Services (the REMM (Radiation Event Medical Manage-ment) site (http://www.remm.nlm.gov). Supportive care when ARS symptoms develop include the administration of antimicrobial agents (which can include systemic antibiotics [especially those directed at gram-negative bacteria]), antiemetic agents, antidiarrheal agents, fluids, elec-trolytes, analgesic agents and topical burn creams (Waselenko, J.K. et al. Ann. Intern. Med. 140: 1037, 2004). For nausea and vomiting, serotonin receptor antagonists (5HT3 receptor antagonists) are very effective prophylaxis. There are two drugs that have been approved by the FDA (Zofran and Kytril) for radiation induced nausea and vomiting. Kytril (granisetron) is preferred by the US Army and is currently maintained in the US National Stockpile. Both of these drugs are known to stop retching and vomiting when given either before or after irradi-ation, even when vomiting and/or retching are occurring. Immune suppression can occur due to declines in white blood cells and infection is a possibility. Of particular importance is the radiation induced decline in neutrophil counts. Methods for controlling infection during the critical neutropenic phase can be used. Investigations of the CARR grant use FDA approved drugs for ARS symptoms in animals exposed to SPE radiations. ACKNOWLEDGEMENTS: The research investigations of the CARR grant are supported by the National Space Biomedical Research Institute (NSBRI) through NASA NCC 9-58.

Pharmacotherapeutics of Intranasal Scopolamine: FDA Regulations and Procedures for Clinical Applications

NASA Technical Reports Server (NTRS)

Das, H.; Daniels, V. R.; Vaksman, Z.; Boyd, J. L.; Buckey, J. C.; Locke, J. P.; Putcha, L.

2007-01-01

Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during the early flight days of a space mission. Bioavailability of oral (PO) SMS medications is often low and highly variable; additionally, physiological changes in a microgravity environment exacerbate variability and decrease bioavailability. These factors prompted NASA to develop an intranasal dosage form of scopolamine (INSCOP) suitable for the treatment of SMS. However, to assure safety and efficacy of treatment in space, NASA physicians prescribe commercially available pharmaceutical products only. Development of a pharmaceutical preparation for clinical use must follow distinct clinical phases of testing, phase I through IV to be exact, before it can be approved by the FDA for approval for clinical use. After a physician sponsored Investigative New Drug (IND) application was approved by the FDA, a phase I clinical trial of INSCOP formulation was completed in normal human subjects and results published. The current project includes three phase II clinical protocols for the assessment of pharmacokinetics and pharmacodynamics (PK/PD), efficacy, and safety of INSCOP. Three clinical protocols that were submitted to FDA to accomplish the project objectives: 1) 002-A, a FDA Phase II dose ranging study with four dose levels between 0.1 and 0.4 mg in 12 subjects to assess PK/PD, 2) 002-B, a phase II clinical efficacy study in eighteen healthy subjects to compare efficacy of 0.2 (low dose) and 0.4 mg (high dose) INSCOP for prophylactic treatment of motion-induces (off-axis vertical rotation) symptoms, and (3) 002-C, a phase II clinical study with twelve subjects to determine bioavailability and pharmacodynamics of two doses (0.2 and 0.4 mg) of INSCOP in simulated microgravity, antiorthostatic bedrest. All regulatory procedures were competed that include certification for Good laboratory Procedures by Theradex , clinical documentation, personnel training, selection of clinical research operations contractor, data capturing and management, and annual reporting of results to FDA were successfully completed. Protocol 002-A was completed and sample and data analysis is currently in progress. Protocol 002-B is currently in progress at Dartmouth Hitchcock Medical Center and Protocol 002-C has been submitted to the FDA and will be implemented at the same contractor site as 002-A. An annual report was filed as required by FDA on the results of Protocol 002-A. Once all the three Phase II protocols are completed, a New Drug Administration application will be filed with FDA for Phase III clinical assessment and approval for marketing of the formulation. A commercial vendor will be identified for this phase. This is critical for making this available for treatment of SMS in astronauts and military personnel on duty. Once approved by FDA, INSCOP can be also used by civilian population for motion sickness associated with recreational travel and other ailments that require treatment with anticholinergic drugs.

Indigenous Students' Attitudes towards Learning English through a Virtual Program: A Study in a Colombian Public University (Actitudes de estudiantes indígenas frente al aprendizaje de inglés a través de un programa virtual: un estudio en una universidad pública colombiana)

ERIC Educational Resources Information Center

Cuasialpud Canchala, Ruth Elena

2010-01-01

This article reports an exploratory study carried out at a public university in Bogotá, Colombia, with two indigenous students who took a level I virtual English-course during the second term of 2008 and the first term of 2009. The aim was to analyse their attitudes towards the learning of English through the virtual modality. Interviews,…

A rational regulatory approach for positron emission tomography imaging probes: from "first in man" to NDA approval and reimbursement.

PubMed

Barrio, Jorge R; Marcus, Carol S; Hung, Joseph C; Keppler, Jennifer S

2004-01-01

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.

Melanoma Vaccine--AVAX Technologies: DNP-VACC, M-Vax.

PubMed

2003-01-01

Adis CommentsAVAX Technologies is developing a therapeutic melanoma vaccine [M-Vax, DNP-VACC] consisting of autologous tumour cells conjugated to a highly immunogenic hapten, dinitrophenyl, which makes the cancer cells more easily recognised by the immune system. AVAX licensed the autologous cell vaccine technology (AC Vaccine) from Thomas Jefferson University in Philadelphia, USA, where it was originally developed. M-Vax was launched in Australia in the first half of 2000, but was withdrawn from this market in September 2002 due to financial constraints faced by the company and its need to focus its resources on initiatives that provide the greatest return. Although AVAX applied for Federal Government price reimbursement in Australia through the Medical Services Advisory Committee during 2001, the vaccine is not reimbursed in Australia. Obtaining Federal Government reimbursement was a step AVAX considered essential for the success of the M-Vax. AVAX has not ruled out re-entering the Australian market again at a later date. AVAX will now concentrate on gaining approval in the US and Europe. M-Vax has received orphan drug designation from the US FDA. M-Vax is in preregistration in Germany, Japan and The Netherlands for treatment of stage III melanoma. In September 1999, the company announced that it expected to market M-Vax for treatment of stage III melanoma in Germany, Japan and the Netherlands. This announcement came after AVAX's continuing dialogue with senior regulatory authorities in several pharmaceutical markets. The commercial availability of M-Vax in Germany, Japan and The Netherlands will be subject to meeting certain requirements specified by the regulatory agency in each country. Phase II data have been submitted for regulatory approval in these countries; phase III data may not be required because the vaccine contains autologous tumour cells. This was the case with the Australian approval of M-Vax, which was on the basis of data from phase II trials. Clinical development: M-Vax was in a pivotal phase III trial for treatment of stage III melanoma in the US, and a multicentre phase II trial in the US for treatment of patients with stage IV melanoma with lung metastases. However, in late March 2001, AVAX announced that the FDA had suspended these trials until the agency had further reviewed them. Subsequently, AVAX received written communication from the FDA indicating that the suspension is related to manufacturing issues. These events triggered the resignations of AVAX's executive Vice-President and Vice-President of operations, at the request of the company's board of directors. AVAX met with the FDA in October 2001 to discuss the clinical holds on M-Vax and O-Vax. AVAX's proposed improvements involving a frozen vaccine were also discussed at the meeting. Following the meeting AVAX was told by the FDA that selected characterisation work would have to be carried out on the new products, and new INDs submitted. In December 2001 AVAX announced that the development of a frozen vaccine and changes to various policies and procedures would ensure that the company complied with the FDA regulations. A new IND was submitted to the FDA for M-Vax in September 2002. In August 2002, AVAX had been unsure whether following approval of its new IND it would re-initiate clinical development for both M-Vax and O-Vax in parallel, or advance one of the agents and wait for further funding for the other. However, in September it indicated that clinical trials of both vaccines would be conducted following approval of the IND. A total of 42 patients are to be enrolled in each trial. In October 2002, AVAX announced that the US FDA had no outstanding issues regarding the IND. AVAX can now proceed with clinical trials as planned. AVAX Technologies was enrolling patients with stage III melanoma in the pivotal US phase III trial for registration of M-Vax trade ed, multicentre trial designed to compare the efficacy of the vaccine against high-dose interferon-alpha, the standard post-surgical treatment for stage III melanoma. The two end-points are rate of melanoma tumour recurrence and overall survival. The dosing regimen chosen for this study is that which was found from several clinical studies to be most effective at eliciting a positive delayed-type hypersensitivity skin response to autologous melanoma cells. The study was being conducted at more than 20 US sites. A low dose of M-Vax was also being evaluated in a phase II study at Thomas Jefferson University in the US. On 16 March 2000, AVAX announced promising interim results from this study, which revealed that 65% of 23 evaluated patients developed an immune response of the same magnitude as that observed with higher doses of M-Vax in previous studies. The study was to enroll a total of 46 patients, who were to receive seven doses of M-Vax over 7 weeks. The advantage of using a low dose of M-Vax is that it requires a smaller amount of the patient's tumour tissue to produce the vaccine (approximately half that required in previous studies) and therefore more patients would be eligible for treatment. On the basis of these results, AVAX modified the pivotal phase III trial to use the low dose of M-Vax to treat additional patients with smaller tumours. On 29 March 2000, AVAX announced that it had initiated a multicentre phase II study in the US in patients with stage IV melanoma and lung metastases. Patients were receiving seven doses of M-Vax at weekly intervals and a booster at 6 months. AVAX initiated the study because of promising results in a study of stage IV melanoma patients with lung metastases in which patients treated with M-Vax had tumour regression and prolonged survival. Commercial agreements: In June 1999, AVAX announced its first international commercialisation opportunity for M-Vax, in Australia, where the company subsequently launched the vaccine (now withdrawn) in the first half of 2000. AVAX formed a subsidiary, AVAX Australia, which was co-marketing M-Vax in Australia together with Australian Vaccine Technologies (formerly Neptunus International Holdings). Under the terms of this agreement, Australian Vaccine Technologies purchased dollars A10 million in shares, a 50% interest, in AVAX Australia. The final dollars A3 million installment was made in August 2000. AVAX had an option to purchase up to 5% of shares in Australian Vaccine Technologies. In August 2002, AVAX extended and expanded an existing production agreement with Medigene for approximately 1 year. Under the terms of the agreement, Genopoietic (Medigene) in France will process clinical samples of M-Vax. In October 2002, AVAX signed a distribution agreement with Ferrer International, SA (Grupo Ferrer) for sales and distribution of the AC Vaccines, including M-Vax and O-Vax. The agreement covers Europe, Latin America and certain Asian territories. Under the terms of the agreement AVAX will retain manufacturing rights and will sell the vaccine to Ferrer. In return, Ferrer will make payments to AVAX for the product as well as certain milestone payments for marketing and registration goals. M-Vax was manufactured in Australia by Bioenterprises, a subsidiary of Biotech Australia. However, in 2002, the manufacturer underwent an acquisition with significant changes, which resulted in its decision to discontinue manufacturing M-Vax.

[Characterization of microbial activities in marine mudflat sediment using FDA hydrolase analysis].

PubMed

Liu, Ye; Zou, Li; Liu, Lu; Gao, Dong-Mei

2013-10-01

A method based on fluorescence spectrometry was developed to detect the microbial activities in marine mudflat sediment, where is characterized by high salinity, complex organic compounds and low microbial biomass. This paper optimized the sample extracts, the detection equipment for reaction products, the pretreatment methods, and the experimental conditions. The optimal procedure is described as following. Fresh sediment was first extracted with sterilized and aged seawater, followed by the addition of Tween-80 solution, then uniformly dispersed by thorough oscillating, and kept steady for precipitation. After filtration through a sterilized membrane (1. 2 microm, sterilized in boiling water repeatedly) , the supernatant was supplemented with an appropriate amount of FDA solution and allowed to react in dark for 180 min at temperature ranged 25-30 degrees C . The reaction was terminated by the addition of acetone, and the fluorescence intensity of the reaction mixture was measured within 25 min using a molecular fluorescence photometer at an excitation wavelength of 488 nm and an emission wavelength of 530 nm, and the detection range of this method (dry weight) was 3.0 x10(3)-1. 1 x 10(5) ind.g-1. The microbial activity was reported as fluorescence content in per unit sediment mass (microg.g-1, dry weight).

Access to benznidazole for Chagas disease in the United States-Cautious optimism?

PubMed

Alpern, Jonathan D; Lopez-Velez, Rogelio; Stauffer, William M

2017-09-01

Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism.

Prevention of pneumonic plague in mice, rats, guinea pigs and non-human primates with clinical grade rV10, rV10-2 or F1-V vaccines

PubMed Central

Quenee, Lauriane E.; Ciletti, Nancy A.; Elli, Derek; Hermanas, Timothy M.; Schneewind, Olaf

2012-01-01

Yersinia pestis causes plague, a disease with high mortality in humans that can be transmitted by fleabite or aerosol. A US Food and Drug Administration (FDA)-licensed plague vaccine is currently not available. Vaccine developers have focused on two subunits of Y. pestis: LcrV, a protein at the tip of type III secretion needles, and F1, the fraction 1 pilus antigen. F1-V, a hybrid generated via translational fusion of both antigens, is being developed for licensure as a plague vaccine. The rV10 vaccine is a non-toxigenic variant of LcrV lacking residues 271–300. Here we developed Current Good Manufacturing Practice (cGMP) protocols for rV10. Comparison of clinical grade rV10 with F1-V did not reveal significant differences in plague protection in mice, guinea pigs or cynomolgus macaques. We also developed cGMP protocols for rV10-2, a variant of rV10 with an altered affinity tag. Immunization with rV10-2 adsorbed to aluminum hydroxide elicited antibodies against LcrV and conferred pneumonic plague protection in mice, rats, guinea pigs, cynomolgus macaques and African Green monkeys. The data support further development of rV10-2 for FDA Investigational New Drug (IND) authorization review and clinical testing. PMID:21763383

Provider experiences with negative-pressure wound therapy systems.

PubMed

Kaufman-Rivi, Diana; Hazlett, Antoinette C; Hardy, Mary Anne; Smith, Jacquelyn M; Seid, Heather B

2013-07-01

MedWatch, the Food and Drug Administration's (FDA's) nationwide adverse event reporting system, serves to monitor device performance after a medical device is approved or cleared for market. Through the MedWatch adverse event reporting system, the FDA receives Medical Device Reports of deaths and serious injuries with negative-pressure wound therapy (NPWT) systems, many of which are used in homes and in extended-care facilities. In response to reported events, this study was conducted to obtain additional information about device issues that healthcare professionals face in these settings, as well as challenges that caregivers might encounter using this technology at home. The study was exploratory and descriptive in nature. The FDA surveyed wound care specialists and professional home healthcare providers to learn about users' experiences with NPWT. In the first phase of the study, a semistructured questionnaire was developed for telephone interviews and self-administration. In the second phase, a web-based survey was adapted from the semistructured instrument. Respondent concerns primarily centered on issues not directly related to the NPWT devices: NPWT prescription, provider education in addition to patient training and appropriate wound management practices, notably ongoing wound assessment, and patient monitoring. Overall, respondents thought that there was a definite benefit to NPWT, regardless of the care setting, and that it was a safe therapy when prescribed and administered appropriately.

[Microdose clinical trial--impact of PET molecular imaging].

PubMed

Yano, Tsuneo; Watanabe, Yasuyoshi

2010-10-01

Microdose (MD) clinical trial and exploratory IND study including sub-therapeutic dose and therapeutic dose which are higher than microdoses are expected to bring about innovations in drug development. The outlines of guidances for microdose clinical trial and ICH-M3 (R2) issued by the MHLW in June, 2008, and February, 2010, are first explained, respectively, and some examples of their application to clinical developments of therapeutic drugs in the infection and cancer fields are introduced. Especially, thanks to the progress of molecular imaging research, a new field of drug development is explored by using imaging biomarkers for efficacy or safety evaluation which visualize biomarkers by PET imaging agents. Finally, the roadmap for drug development in infection and cancer fields utilizing PET molecular imaging is discussed.

Mechanisms underlying changes in indomethacin solubility with local anesthetics and related basic additives

NASA Astrophysics Data System (ADS)

Shimada, Yohsuke; Tateuchi, Ryo; Chatani, Hitoshi; Goto, Satoru

2018-03-01

Indomethacin (IND), an acidic nonsteroidal anti-inflammatory drug, and lidocaine (LID), a local anesthetic (LA), form a eutectic complex when mixed, with a lower melting point. The aqueous solubility of the mixture is greater than that of IND or LID alone, improving the bioavailability of IND. Therefore, IND and LID can be used to model changes in efficacy caused by physicochemical interactions between drugs. In this study, the intermolecular interactions between IND and structurally similar LAs were examined by measuring solubility and analyzing thermodynamics using differential scanning calorimetry. The results indicate that the solubility of IND (log S'IND) varies with LA hydrophobicity. Reductions in melting point resulting from mixing IND and LAs contributed to changes in IND solubility, attributable to direct intermolecular interactions between IND and the LAs. In addition, binding energy of IND-LA as in water was calculated, and the values were correlating with the solubility of IND in experiments. Understanding these interactions will help address some of the problems encountered in polypharmacy.

Positive dermal hypersensitivity and specific antibodies in workers exposed to bio-engineered enzymes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biagini, R.E.; Henningsen, G.M.; Driscoll, R.

1991-03-15

Thirty-six employees who produced industrial enzymes from bio-engineered strains of bacteria and fungi were evaluated by skin prick testing and enzyme linked immunosorbent assays for specific IgE and IgG antibodies. The workers complained of asthma- and flu-like' symptoms which generally lessened away from work. The enzymes evaluated were {alpha}-amylase from A. niger (ind-AAN), B. licheniformis (ind-AAL) and B. subtilis (ind-AAS); purified {alpha}-amylase from B. subtilis (AAS) and A. niger (AAN); alkaline protease from B. licheniformis (ind-APL) and purified alkaline protease (APL); amylase glucosidase from A. niger (ind-AGN) and purified amylase glucosidase (AGN). Significantly positive skin tests were found for APL,more » AGN and ind-AAN. Significantly elevated specific IgE results were observed for AAN, AGN, and ind-AAN; elevated specific IgGs were observed for AAN, ind-AAN, ind-AAS, ind-AAL and ind-AGN. Radioimmunoassays of air filter samples (using sera with high Ab titers) for 4 of the ind-enzymes showed only ind-AAN at extremely high environmental levels. These results indicate that occupational exposure to some ind-enzymes causes immediate onset dermal hypersensitivity reactions. The results are equivocal as to whether these reactions are IgE mediated, as IgE titers were low. Contrary to this, IgG titers were extremely high and suggest that these biomarkers can be used as indicators of both individual exposure and environmental analyses.« less

A Randomized Clinical Trial of Allopregnanolone for the Treatment of Severe Traumatic Brain Injury

DTIC Science & Technology

2010-10-01

by four outside reviewers: Kia Shahlaie, M.D., Ph.D. (University of California, San Francisco ), Anne-Marie Guerguerian, M.D. (University of Toronto...of the Pre-IND Package described below and the UC Davis IRB filing. Pre-IND Meeting Information Package and IND. Medkura Pharmaceutical and Camargo ... Camargo a Pre-IND meeting information document was developed which will serve as the basis for the IND filing that will be made after the Pre-IND meeting

Design and in vitro evaluation of self-assembled indometacin prodrug nanoparticles for sustained/controlled release and reduced normal cell toxicity

NASA Astrophysics Data System (ADS)

Lin, Jinyan; Pan, Zhou; Song, Liang; Zhang, Yanmei; Li, Yang; Hou, Zhenqing; Lin, Changjian

2017-12-01

Despite the great efficacy of indomethacin (IND) as an anti-inflammatory agent, its clinical translation has been obstructed by the water insolubility, severe side effects, and exceedingly low bioavailability. Indomethacin prodrug-based nanoparticles (NPs) combining the strengths of both nanotechnology and prodrugs that might overcome this crucial problem are presented. Here, using the carbodiimide-mediated couple reaction, IND was conjugated to clinically approved poly(ethylene glycol) (PEG) polymer via peptide linkage that was cleavaged in the presence of cathepsin B, which was significantly induced after inflammatory. The synthesized IND-PEG-IND conjugate was characterized by UV-vis, FTIR, 1H NMR, XRD, and MALDI-TOF-MS analyses. For its intrinsic amphiphilic property, the IND prodrug self-assembled into NPs in aqueous solution and served two roles-as an anti-inflammatory prodrug and a drug carrier. The constructed IND-PEG-IND NPs had naoscaled particle size of approximately 80 nm, negative surface, spherical shape, good water-dispersity, and high and fixed drug-loading content of 20.1 wt%. In addition, IND-PEG-IND NPs demonstrated sustained and cathepsin B-controlled drug release behavior. More importantly, IND-PEG-IND NPs significantly reduced the acute totoxicity agaist normal osteoblast cells and displayed the more potent anti-inflammatory effect against macrophage cells compared to the free IND. Taken together, the nanoprodrug might exhibit increased potency for nanomedicine-prospective therapeutic use in clinical treatement of implant inflammatory diseases.

Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials.

PubMed

Nathan, Brandon M; Boulware, David; Geyer, Susan; Atkinson, Mark A; Colman, Peter; Goland, Robin; Russell, William; Wentworth, John M; Wilson, Darrell M; Evans-Molina, Carmella; Wherrett, Diane; Skyler, Jay S; Moran, Antoinette; Sosenko, Jay M

2017-11-01

We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. Two cohorts were analyzed: 1 ) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2 ) baseline Index60 <1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia. The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- ( P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- ( P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- ( P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive ( P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse ( P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [ P < 0.01 for all]). The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points. © 2017 by the American Diabetes Association.

Obtaining i.v. fosfomycin through an expanded-access protocol.

PubMed

Frederick, Corey M; Burnette, Jennifer; Aragon, Laura; Gauthier, Timothy P

2016-08-15

One hospital's experience with procuring i.v. fosfomycin via an expanded-access protocol to treat a panresistant infection is described. In mid-2014, a patient at a tertiary care institution had an infection caused by a gram-negative pathogen expressing notable drug resistance. Once it was determined by the infectious diseases (ID) attending physician that i.v. fosfomycin was a possible treatment for this patient, the ID pharmacist began the process of drug procurement. The research and ID pharmacists completed an investigational new drug (IND) application, which required patient-specific details and contributions from the ID physician. After obtaining approval of the IND, an Internet search identified a product vendor in the United Kingdom, who was then contacted to begin the drug purchasing and acquisition processes. Authorization of the transaction required signatures from key senior hospital administrators, including the chief financial officer and the chief operating officer. Approximately 6 days after beginning the acquisition process, the research pharmacist arranged for the wholesaler to expedite product delivery. The ID pharmacist contacted the wholesaler's shipping company at the U.S. Customs Office, providing relevant contact information to ensure that any unexpected circumstances could be quickly addressed. The product arrived at the U.S. Customs Office 8 days after beginning the acquisition process and was held in the U.S. Customs Office for 2 days. The patient received the first dose of i.v. fosfomycin 13 days after starting the expanded-access protocol process. I.V. fosfomycin was successfully procured through an FDA expanded-access protocol by coordinating efforts among ID physicians, pharmacists, and hospital executives. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Efficacy evaluation of an anti-caries varnish: protocol for a phase II randomised controlled trial

PubMed Central

Tut, Ohnmar; Rothen, Marilynn; Mancl, Lloyd; Gallen, Marcelle; Tanzer, Jason M

2017-01-01

Introduction Dental caries (tooth decay) is a common disease in which the products of sugar metabolism by certain bacteria that populate the tooth surface induce the development and progression of lesions (cavities). This is a phase II single-centre randomised, double-blind, active-controlled, parallel-group trial to assess the efficacy of a combination povidone iodine and sodium fluoride dental varnish to determine if it is superior to a varnish containing only sodium fluoride in the prevention of new caries lesions. The objective of this report is to describe the rationale and protocol for the trial. Methods and analysis The study site is Pohnpei State, Federated States of Micronesia. The study population is 284 children 48–84 months old. The primary outcome will be the surface-level primary molar caries increment (d2-3mfs/DMFS) at 2 years post baseline. The incremental dental caries at 1 year will also be compared between the two interventions. The secondary outcome is the Facial Image Scale after the initial treatment and after the fifth treatment at 1 year that gauges the child’s response to the treatment. Ethics and dissemination The Western Institutional Review Board (designated IRB) and the Institutional Review Board of the College of Micronesia-FSM approved all study procedures. The US Food and Drug Administration (FDA) has issued IND 128835 covering this study. The study results will be published and submitted to the FDA in support of a new drug application. Trialregistration number NCT03082196. PMID:28667230

Improving the de-agglomeration and dissolution of a poorly water soluble drug by decreasing the agglomerate strength of the cohesive powder.

PubMed

Allahham, Ayman; Stewart, Peter J; Das, Shyamal C

2013-11-30

Influence of ternary, poorly water-soluble components on the agglomerate strength of cohesive indomethacin mixtures during dissolution was studied to explore the relationship between agglomerate strength and extent of de-agglomeration and dissolution of indomethacin (Ind). Dissolution profiles of Ind from 20% Ind-lactose binary mixtures, and ternary mixtures containing additional dibasic calcium phosphate (1% or 10%; DCP), calcium sulphate (10%) and talc (10%) were determined. Agglomerate strength distributions were estimated by Monte Carlo simulation of particle size, work of cohesion and packing fraction distributions. The agglomerate strength of Ind decreased from 1.19 MPa for the binary Ind mixture to 0.84 MPa for 1DCP:20Ind mixture and to 0.42 MPa for 1DCP:2Ind mixture. Both extent of de-agglomeration, demonstrated by the concentration of the dispersed indomethacin distribution, and extent of dispersion, demonstrated by the particle size of the dispersed indomethacin, were in descending order of 1DCP:2Ind>1DCP:20Ind>binary Ind. The addition of calcium sulphate dihydrate and talc also reduced the agglomerate strength and improved de-agglomeration and dispersion of indomethacin. While not definitively causal, the improved de-agglomeration and dispersion of a poorly water soluble drug by poorly water soluble components was related to the agglomerate strength of the cohesive matrix during dissolution. Copyright © 2013 Elsevier B.V. All rights reserved.

Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin.

PubMed

Ali, Hassan Refat H; Alhalaweh, Amjad; Velaga, Sitaram P

2013-05-01

Identification of optimal solid form of an active pharmaceutical ingredient and form control are very important in drug development. Thus, the structural information of these forms and in-depth insight on the modes of molecular interactions are necessary, and vibrational spectroscopic methods are well suited for this purpose. In-depth structural analysis of different solid forms of indomethacin (IND) using Raman and infrared (IR) spectroscopy is the objective. We have investigated the modes of molecular interactions in polymorphs (α and γ), amorphous and discovered cocrystals of IND with nicotinamide (NIC) and trans-cinnamic acid (CIN) coformers. The solid forms of IND have been prepared; their purity has been verified by differential scanning calorimetry and powder X-ray diffractometry and then studied in the solid-state by Raman and IR spectroscopy. The modes of the interactions were closely investigated from the vibrational data. The key vibrational features of IND solid forms have been specified. The IR (C=O) band at 1713 cm(-1) attributed to cyclic acid dimer of γ IND has disappeared in IND-NIC/CIN whilst retained in IND-SAC cocrystal. IND cocrystallizes in different conformations and crystal lattices with different coformers. The cyclic acid dimer of IND has been kept on its cocrystallization with saccharin and it could have been broken with NIC and CIN. The complementary nature of Raman and IR spectroscopy allowed unambiguous investigation of the chemical composition of pharmaceutical materials which is of particular importance in the absence of detailed structural information, as in the case of IND-NIC and IND-CIN.

77 FR 75439 - Guidances for Industry and Investigators on Safety Reporting Requirements for Investigational New...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-20

... Reporting Requirements for INDs and BA/BE Studies'' and ``Safety Reporting Requirements for INDs and BA/BE...) and bioavailability (BA) and bioequivalence (BE) studies. DATES: Submit either electronic or written... Reporting Requirements for INDs and BA/BE Studies'' and ``Safety Reporting Requirements for INDs and BA/BE...

Colonic delivery of indometacin loaded PGA-co-PDL microparticles coated with Eudragit L100-55 from fast disintegrating tablets.

PubMed

Tawfeek, Hesham M; Abdellatif, Ahmed A H; Dennison, Thomas J; Mohammed, Afzal R; Sadiq, Younis; Saleem, Imran Y

2017-10-05

The aim of this work was to investigate the efficient targeting and delivery of indometacin (IND), as a model anti-inflammatory drug to the colon for treatment of inflammatory bowel disease. We prepared fast disintegrating tablets (FDT) containing IND encapsulated within poly(glycerol-adipate-co-ɷ-pentadecalactone), PGA-co-PDL, microparticles and coated with Eudragit L100-55 at different ratios (1:1.5, 1:1, 1:0.5). Microparticles encapsulated with IND were prepared using an o/w single emulsion solvent evaporation technique and coated with Eudragit L-100-55 via spray drying. The produced coated microparticles (PGA-co-PDL-IND/Eudragit) were formulated into optimised FTD using a single station press. The loading, in vitro release, permeability and transport of IND from PGA-co-PDL-IND/Eudragit microparticles was studied in Caco-2 cell lines. IND was efficiently encapsulated (570.15±4.2μg/mg) within the PGA-co-PDL microparticles. In vitro release of PGA-co-PDL-IND/Eudragit microparticles (1:1.5) showed significantly (p<0.05, ANOVA/Tukey) lower release of IND 13.70±1.6 and 56.46±3.8% compared with 1:1 (89.61±2.5, 80.13±2.6%) and 1:0.5 (39.46±0.9 & 43.38±3.12) after 3 and 43h at pH 5.5 and 6.8, respectively. The permeability and transport studies indicated IND released from PGA-co-PDL-IND/Eudragit microparticles had a lower permeability coefficient of 13.95±0.68×10 -6 cm/s compared to free IND 23.06±3.56×10 -6 cm/s. These results indicate the possibility of targeting anti-inflammatory drugs to the colon using FDTs containing microparticles coated with Eudragit. Copyright © 2017 Elsevier B.V. All rights reserved.

Bioavailability of indomethacin-saccharin cocrystals.

PubMed

Jung, Min-Sook; Kim, Jeong-Soo; Kim, Min-Soo; Alhalaweh, Amjad; Cho, Wonkyung; Hwang, Sung-Joo; Velaga, Sitaram P

2010-11-01

Pharmaceutical cocrystals are new solid forms with physicochemical properties that appear promising for drug product development. However, the in-vivo bioavailability of cocrystals has rarely been addressed. The cocrystal of indomethacin (IND), a Biopharmaceutical Classification System class II drug, with saccharin (SAC) has been shown to have higher solubility than IND at all pH. In this study, we aimed to evaluate the in-vitro dissolution and in-vivo bioavailability of IND-SAC cocrystals in comparison with IND in a physical mixture and the marketed product Indomee. Scale-up of the cocrystals was undertaken using cooling batch crystallisation without seeding. The chemical and physical purity of the up-scaled material was verified using high-performance liquid chromatography, differential scanning calorimetry and powder X-ray diffraction. The IND-SAC cocrystals and IND plus SAC were mixed with lactose and the formulations were placed into gelatin capsules. In-vitro dissolution studies were then performed using the rotating basket dissolution method. The intrinsic dissolution rate of IND and IND-SAC cocrystals was also determined. Finally, a bioavailability study for the formulations was conducted in beagle dogs. The plasma samples were analysed using high-performance liquid chromatography and the pharmacokinetic data were analysed using standard methodologies.   The bulk cocrystals (i.e. scaled-up material) were chemically and physically pure. The in-vitro dissolution rate of the cocrystals was higher than that of IND and similar to that of Indomee at pH 7.4 and pH 1.2. The in-vivo bioavailability of the IND-SAC cocrystals in dogs was significantly higher (ANOVA, P<0.05) than that of IND but not significantly different from Indomee (ANOVA, P>0.05). The study indicates that the improved aqueous solubility of the cocrystals leads to improved bioavailability of IND. Thus, the cocrystals are a viable alternative solid form that can improve the dissolution rate and bioavailability of poorly soluble drugs. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels.

PubMed

Sun, Dajun D; Ju, Tzu-chi Rob; Lee, Ping I

2012-05-01

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH). Copyright © 2012 Elsevier B.V. All rights reserved.

Indigo Naturalis Ameliorates Oxazolone-Induced Dermatitis but Aggravates Colitis by Changing the Composition of Gut Microflora.

PubMed

Adachi, Soichiro; Hoshi, Namiko; Inoue, Jun; Yasutomi, Eiichiro; Otsuka, Takafumi; Dhakhwa, Ramesh; Wang, Zi; Koo, Yuna; Takamatsu, Toshihiro; Matsumura, Yuriko; Yamairi, Haruka; Watanabe, Daisuke; Ooi, Makoto; Tanahashi, Toshihito; Nishiumi, Shin; Yoshida, Masaru; Azuma, Takeshi

2017-01-01

Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions). © 2017 S. Karger AG, Basel.

Isolation and Characterization of Exosome from Human Embryonic Stem Cell-Derived C-Myc-Immortalized Mesenchymal Stem Cells.

PubMed

Lai, Ruenn Chai; Yeo, Ronne Wee Yeh; Padmanabhan, Jayanthi; Choo, Andre; de Kleijn, Dominique P V; Lim, Sai Kiang

2016-01-01

Mesenchymal stem cells (MSC) are currently the cell type of choice in many cell therapy trials. The number of therapeutic applications for MSCs registered as product IND submissions with the FDA and initiation of registered clinical trials has increased substantially in recent years, in particular between 2006 and 2012. However, defined mechanisms of action underpinning the therapeutic efficacy of MSCs are lacking, but they are increasingly attributed to MSC trophic secretion rather than their differentiation potential. A promising secreted therapeutic candidate is an extracellular vesicle (EV) known as the exosome. The use of exosomes instead of cells as a therapeutic agent provides several advantages. A critical advantage is the prospect of a conventional pharmaceutical manufacturing process that is highly scalable and amenable to the stringent manufacturing process. For example, MSCs used as producers of therapeutics, and not as therapeutics per se, could be immortalized to generate infinitely expansible clonal lines to enhance the reproducible production of therapeutic exosomes. In this chapter, we will describe the immortalization of MSCs, and the production, isolation, and characterization of exosomes from immortalized MSC.

First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors.

PubMed

Smith, Barry H; Parikh, Tapan; Andrada, Zoe P; Fahey, Thomas J; Berman, Nathaniel; Wiles, Madeline; Nazarian, Angelica; Thomas, Joanne; Arreglado, Anna; Akahoho, Eugene; Wolf, David J; Levine, Daniel M; Parker, Thomas S; Gazda, Lawrence S; Ocean, Allyson J

2016-01-01

Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective. Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant. RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs. The data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.

Safety of Bifidobacterium animalis subsp. lactis (B. lactis) strain BB-12-supplemented yogurt in healthy adults on antibiotics: a phase I safety study.

PubMed

Merenstein, Daniel J; Tan, Tina P; Molokin, Aleksey; Smith, Keisha Herbin; Roberts, Robert F; Shara, Nawar M; Mete, Mihriye; Sanders, Mary Ellen; Solano-Aguilar, Gloria

2015-01-01

Probiotics are live microorganisms that, when administered in sufficient doses, provide health benefits on the host. The United States Food and Drug Administration (FDA) requires phase I safety studies for probiotics when the intended use of the product is as a drug. The purpose of the study was to determine the safety of Bifidobacterium animalis subsp lactis (B. lactis) strain BB-12 (BB-12)-supplemented yogurt when consumed by a generally healthy group of adults who were prescribed a 10-day course of antibiotics for a respiratory infection. Secondary aims were to assess the ability of BB-12 to affect the expression of whole blood immune markers associated with cell activation and inflammatory response. A phase I, double-blinded, randomized controlled study was conducted in compliance with FDA guidelines for an Investigational New Drug (IND). Forty participants were randomly assigned to consume 4 ounces of either BB-12 -supplemented yogurt or non-supplemented control yogurt daily for 10 d. The primary outcome was to assess safety and tolerability, assessed by the number of reported adverse events. A total of 165 non-serious adverse events were reported, with no differences between the control and BB-12 groups. When compared to the control group, B lactis fecal levels were modestly higher in the BB-12-supplemented group. In a small subset of patients, changes in whole blood expression of genes associated with regulation and activation of immune cells were detected in the BB-12-supplemented group. BB-12-supplemented yogurt is safe and well tolerated when consumed by healthy adults concurrently taking antibiotics. This study will form the basis for future randomized clinical trials investigating the potential immunomodulatory effects of BB-12-supplemented yogurt in a variety of disease states.

An appraisal of drug development timelines in the Era of precision oncology

PubMed Central

Jardim, Denis Leonardo; Schwaederle, Maria; Hong, David S.; Kurzrock, Razelle

2016-01-01

The effects of incorporating a biomarker-based (personalized or precision) selection strategy on drug development timelines for new oncology drugs merit investigation. Here we accessed documents from the Food and Drug Administration (FDA) database for anticancer agents approved between 09/1998 and 07/2014 to compare drugs developed with and without a personalized strategy. Sixty-three drugs were included (28 [44%] personalized and 35 [56%] non-personalized). No differences in access to FDA-expedited programs were observed between personalized and non-personalized drugs. A personalized approach for drug development was associated with faster clinical development (Investigational New Drug [IND] to New Drug Application [NDA] submission; median = 58.8 months [95% CI 53.8–81.8] vs. 93.5 months [95% CI 73.9–112.9], P =.001), but a similar approval time (NDA submission to approval; median=6.0 months [95% CI 5.5–8.4] vs. 6.1 months [95% CI 5.9–8.3], P = .756) compared to a non-personalized strategy. In the multivariate model, class of drug stratified by personalized status (targeted personalized vs. targeted non-personalized vs. cytotoxic) was the only independent factor associated with faster total time of clinical drug development (clinical plus approval phase, median = 64.6 vs 87.1 vs. 112.7 months [cytotoxic], P = .038). Response rates (RR) in early trials were positively correlated with RR in registration trials (r = 0.63, P = <.001), and inversely associated with total time of drug development (r = −0.29, P = .049). In conclusion, targeted agents were developed faster than cytotoxic agents. Shorter times to approval were associated, in multivariate analysis, with a biomarker-based clinical development strategy. PMID:27419632

Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug-Polymer-Polymer Ternary Solution.

PubMed

Prasad, Dev; Chauhan, Harsh; Atef, Eman

2016-03-07

We are reporting a synergistic effect of combined Eudragit E100 and PVP K90 in precipitation inhibition of indomethacin (IND) in solutions at low polymer concentration, a phenomenon that has significant implications on the usefulness of developing novel ternary solid dispersion of poorly soluble drugs. The IND supersaturation was created by cosolvent technique, and the precipitation studies were performed in the absence and the presence of individual and combined PVP K90 and Eudragit E100. The studies were also done with PEG 8000 as a noninteracting control polymer. A continuous UV recording of the IND absorption was used to observe changes in the drug concentration over time. The polymorphic form and morphology of precipitated IND were characterized by Raman spectroscopy and scanning electron microscopy. The change in the chemical shift in solution (1)H NMR was used as novel approach to probe IND-polymer interactions. Molecular modeling was used for calculating binding energy between IND-polymer as another indication of IND-polymer interaction. Spontaneous IND precipitation was observed in the absence of polymers. Eudragit E100 showed significant inhibitory effect on nuclei formation due to stronger interaction as reflected in higher binding energy and greater change in chemical shift by NMR. PVP K90 led to significant crystal growth inhibition due to adsorption on growing IND crystals as confirmed by modified crystal habit of precipitate in the presence of PVP K90. Combination of polymers resulted in a synergistic precipitation inhibition and extended supersaturation. The NMR confirmed interaction between IND-Eudragit E100 and IND-PVP K90 in solution. The combination of polymers showed similar peak shift albeit using lower polymer concentration indicating stronger interactions. The results established the significant synergistic precipitation inhibition effect upon combining Eudragit E100 and PVP K90 due to drug-polymer interaction.

Efficacy and Safety of Indacaterol/Glycopyrronium (IND/GLY) Versus Salmeterol/Fluticasone in Chinese Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: The Chinese Cohort from the LANTERN Study.

PubMed

Zhong, Nanshan; Wang, Changzheng; Zhou, Xiangdong; Zhang, Nuofu; Humphries, Michael; Wang, Linda; Patalano, Francesco; Banerji, Donald

2016-12-01

Inhaled indacaterol/glycopyrronium fixed-dose combination (IND/GLY) is approved in over 80 countries, including the EU, Japan, Australia and Switzerland and the US. The LANTERN study evaluated the efficacy of IND/GLY compared with inhaled long-acting β 2 -agonist (LABA)/inhaled corticosteroid (ICS) or salmeterol/fluticasone (SFC) in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. Here we present the efficacy and safety of IND/GLY versus SFC in the Chinese cohort from the LANTERN study. LANTERN was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group study conducted in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. The patients were randomized (1:1) to once-daily IND/GLY (110/50 μg) or twice-daily SFC (50/500 μg). The primary endpoint was non-inferiority of IND/GLY versus SFC in terms of trough FEV 1 . Of the total 744 patients randomized in the LANTERN study, 598 (80.4%) were from Mainland China and randomized to IND/GLY (n = 298) or SFC (n = 300), and 553 (92.5%) completed the study. IND/GLY showed superiority over SFC with a statistically significant and clinically meaningful improvement in trough FEV 1 , FEV 1 AUC 0-4h , peak FEV 1 and trough forced vital capacity (FVC) change from the baseline. Annualized rate of moderate or severe COPD exacerbations was significantly lower (43%) with IND/GLY compared with SFC (rate ratio: 0.57, p = 0.015). Overall, adverse events were lower for IND/GLY (34.6%) versus SFC (43.1%). IND/GLY was superior in achieving bronchodilation versus SFC in a Chinese subgroup of patients from this study. Clinicaltrials.gov identifier: NCT01709903.

Identification of Ind transcription activation and repression domains required for dorsoventral patterning of the CNS.

PubMed

Von Ohlen, Tonia L; Moses, Cade

2009-07-01

Specification of cell fates across the dorsoventral axis of the central nervous system in Drosophila involves the subdivision of the neuroectoderm into three domains that give rise to three columns of neural precursor cells called neuroblasts. Ventral nervous system defective (Vnd), intermediate neuroblasts defective (Ind) and muscle segment homeobox (Msh) are expressed in the three columns from ventral to dorsal, respectively. The products of these genes play multiple important roles in formation and specification of the embryonic nervous system. Ind, for example, is known to play roles in two important processes. First, Ind is essential for formation of neuroblasts conjunction with SoxB class transcription factors. Sox class transcription factors are known to specify neural stem cells in vertebrates. Second, Ind plays an important role in patterning the CNS in conjunction with, vnd and msh, which is also similar to how vertebrates pattern their neural tube. This work focuses two important aspects of Ind function. First, we used multiple approaches to identify and characterize specific domains within the protein that confer repressor or activator ability. Currently, little is known about the presence of activation or repression domains within Ind. Here, we show that transcriptional repression by Ind requires multiple conserved domains within the protein, and that Ind has a transcriptional activation domain. Specifically, we have identified a novel domain, the Pst domain, that has transcriptional repression ability and appears to act independent of interaction with the co-repressor Groucho. This domain is highly conserved among insect species, but is not found in vertebrate Gsh class homeodomain proteins. Second, we show that Ind can and does repress vnd expression, but does so in a stage specific manner. We conclude from this that the function of Ind in regulating vnd expression is one of refinement and maintenance of the dorsal border.

Autophagy Contributes to the Induction of Anti-TNF Induced Macrophages

PubMed Central

Levin, Alon D.; Koelink, Pim J.; Bloemendaal, Felicia M.; Vos, Anne Christine W.; D’Haens, Geert R.; van den Brink, Gijs R.

2016-01-01

Background and Aims: Anti-tumour necrosis factor [TNF] antibodies induce regulatory macrophages which display a phenotype resembling M2 type macrophages. Anti-TNF induced macrophages [Mϕind] have immunosuppressive and wound healing properties. The factors that contribute to the induction of Mϕind remain to be explored. Autophagy has been described as a factor that is important for the induction and function of M2 type macrophages. We studied the contribution of autophagy to the induction of Mϕind. Methods: We studied the effect of autophagy on Mϕind in vitro using peripheral blood mononuclear cells. Interferon gamma [IFN-γ] induced macrophages [Mφ1] were generated by culturing monocytes in the presence of IFN-γ. Mϕind were generated by performing mixed lymphocyte reactions [MLR] in the presence of anti-TNF antibodies; 28 healthy donors were genotyped for rs_2241880 [ATG16L1]. Cells were analysed by autophagy gene array, immunofluorescence, western blot, flowcytometry, 3H-thymidine incorporation and MTS assay. Results: Mϕind had a different expression profile of autophagy related transcripts with increased expression of 33/40 altered genes compared with Mφ1. In addition, autophagic activity was increased in Mϕind compared with Mφ1. Induction of Mϕind was positively correlated to the number of wild-type alleles for the ATG16L1 T300A risk allele present in the culture. Finally, the autophagy-related protein cathepsin S was highly expressed in Mφind and inhibition resulted in decreased viability as well as decreased expression of CD206. Conclusions: Mϕind have increased levels of autophagy compared with inflammatory Mφ1, and the induction of these macrophages is impaired in donors carrying the T300A risk allele for the ATG16L1. Given the association between Mϕind and clinical response, this suggests that an intact autophagy pathway may be important for an optimal response to anti-TNF therapy in inflammatory bowel disease. PMID:26417049

Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans - a practical guide.

PubMed

Burt, Tal; John, Christy S; Ruckle, Jon L; Vuong, Le T

2017-05-01

Phase-0 studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for first-in-human (FIH) trials. Common to these approaches is the use and implied safety of limited exposures to test articles. Use of sub-pharmacological doses in phase-0/microdose studies requires sensitive analytic tools such as accelerator mass spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Areas covered: Here we present a practical guide to the range of methodologies, design options, and conduct strategies that can be used to increase the efficiency of drug development. We provide detailed examples of relevant developmental scenarios. Expert opinion: Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Applications of phase-0/microdosing approaches include study of pharmacokinetic and pharmacodynamic properties, target tissue localization, drug-drug interactions, effects in vulnerable populations (e.g. pediatric), and intra-target microdosing (ITM). Study design should take into account the advantages and disadvantages of each analytic tool. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.

Influence of PVP molecular weight on the microwave assisted in situ amorphization of indomethacin.

PubMed

Doreth, Maria; Löbmann, Korbinian; Priemel, Petra; Grohganz, Holger; Taylor, Robert; Holm, René; Lopez de Diego, Heidi; Rades, Thomas

2018-01-01

In situ amorphization is an approach that enables a phase transition of a crystalline drug to its amorphous form immediately prior to administration. In this study, three different polyvinylpyrrolidones (PVP K12, K17 and K25) were selected to investigate the influence of the molecular weight of the polymer on the degree of amorphization of the model drug indomethacin (IND) upon microwaving. Powder mixtures of crystalline IND and the respective PVP were compacted at 1:2 (w/w) IND:PVP ratios, stored at 54% RH and subsequently microwaved with a total energy input of 90 or 180kJ. After storage, all compacts had a similar moisture content (∼10% (w/w)). Upon microwaving with an energy input of 180kJ, 58±4% of IND in IND:PVP K12 compacts was amorphized, whereas 31±8% of IND was amorphized by an energy input of 90kJ. The drug stayed fully crystalline in all IND:PVP K17 and IND:PVP K25 compacts. After plasticization by moisture, PVP K12 reached a T g below ambient temperature (16±2°C) indicating that the T g of the plasticized polymer is a key factor for the success of in situ amorphization. DSC analysis showed that the amorphized drug was part of a ternary glass solution consisting of IND, PVP K12 and water. In dissolution tests, IND:PVP K12 compacts showed a delayed initial drug release due to a lack of compact disintegration, but reached a higher total drug release eventually. In summary, this study showed that the microwave assisted in situ amorphization was highly dependent on the T g of the plasticized polymer. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacological studies on proglumetacin maleate, a new non-steroidal anti-inflammatory drug (4). Mode of action on anti-inflammatory activity.

PubMed

Ono, N; Yamasaki, Y; Yamamoto, N; Sunami, A; Miyake, H

1986-11-01

The possible mechanism of the anti-inflammatory activity of proglumetacin maleate (PGM), a new indomethacin (IND) derivative interacting with arachidonic acid (AA) metabolism, was investigated to elucidate the contributions of PGM itself and its two major metabolites, desproglumideproglumetacin maleate (DPP) and IND. PGM caused much less inhibition of PGE2 formation by sheep seminal vesicle microsomes (IC50 = 310 microM) and TXB2 formation by a washed rabbit platelet suspension (IC50 = 6.3 microM) than IND. DPP also caused less inhibition of cyclooxygenase than IND. Moreover, PGM had less effect on sodium arachidonate (SAA)-induced rat platelet aggregation ex vivo and AA-induced sudden death in rabbits than IND. These results show that PGM has anti-inflammatory activity after its conversion to the active metabolite IND. However, the inhibitory effects of PGM and DPP were as strong as that of IND on SAA- or collagen-induced rabbit platelet aggregation in vitro. These activities are considered to be associated with platelet membrane interaction. Moreover, unlike IND, PGM (IC50 = 1.5 microM) and DPP (IC50 = 16.3 microM) strongly inhibited 5-HETE formation by the cytosol of guinea pig polymorphonuclear leukocytes. This unique activity of PGM on 5-lipoxygenase may contribute to its anti-inflammatory activity.

DD 21A-A Capable, Affordable, Modular 21st Century Destroyer

DTIC Science & Technology

1993-12-01

1 1.000 2 0.OOOOE+00 3 0.OOOOE+00 4 1.000 5 1.000 ARRANGEMENT OPERATION SEP SS GEN OP ARRAY = ( 2X 1) 1 2.000 2 2.000 ARRANGEMENT CG MACHY KG IND... GEN SIZE IND = GIVEN SEP SS GEN KW = 2000.00 KW SS ENGINES SS ENG SELECT IND = GIVEN SS ENG MODEL IND = DDA-501-K17 SS ENG TYPE IND = GT SS ENG SIZE...1733.6 PROPELLERS: 2 - CP - 17.0 FT DIA AREA SUMMARY - FT2 SEP GEN : 3 CT 0 2000.0 KW HULL AREA - 55529.2 SUPERSTRUCTURE AREA - 21232.1 24 HR LOAD 1858.1

TREATMENT OF ASTHMA AND FOOD ALLERGY WITH HERBAL INTERVENTIONS FROM TRADITIONAL CHINESE MEDICINE

PubMed Central

Li, Xiu-Min

2014-01-01

Prevalence of asthma and allergy has increased over the past 2–3 decades in Westernized countries. Despite increased understanding of the pathogenesis of asthma and allergic diseases, control of severe asthma is still difficult. Asthma is also associated with high prevalence of anxiety in particular adolescents. There is no effective treatment for food allergy. Food allergy is often associated with severe and recalcitrant eczema. Novel approaches for treatment of asthma and food allergy and comorbid conditions are urgently needed. Traditional Chinese medicine (TCM), used in Asia for centuries, is beginning to play a role in Western health care. There is increasing scientific evidence supporting the use of TCM for asthma treatment. This review article discusses promising TCM interventions for asthma, food allergy and comorbid conditions and explores their possible mechanisms of action. Since 2005, several controlled clinical studies of “anti-asthma” herbal remedies have been published. Among the herbal medicines, anti-asthma herbal medicine intervention (ASHMI) is the only anti-asthma TCM product that is a US FDA investigational new drug (IND) that has entered clinical trials. Research into ASHMI’s effects and mechanisms of actions in animal models is actively being pursued. Research on TCM herbal medicines for treating food allergy is rare. The herbal intervention, Food Allergy Herbal Formula-2 (FAHF-2) is the only US FDA botanical IND under investigation as a multiple food allergy therapy. Published articles and abstracts, as well as new data generated in preclinical and clinical studies of ASHMI and FAHF-2 are the bases for this review. The effect of TCM therapy on food allergy associated recalcitrant eczema, based on case review, is also included. Laboratory and clinical studies demonstrate a beneficial effect of ASHMI treatment on asthma. The possible mechanisms underlying the efficacy are multiple. Preclinical studies demonstrated the efficacy and safety of FAHF-2 for treating food allergy in a murine model. A clinical study demonstrated that FAHF-2 is safe, well tolerated, and exhibited beneficial immunomodulatory effects. A clinical report showed that TCM treatment reduced eczema scores and improved quality of life. Herbal interventions, ASHMI and FAHF-2 may be further developed as botanical drugs for treating asthma and food allergy. TCM may also be of benefit for comorbid conditions such as anxiety and recalcitrant eczema. More controlled studies are warranted. In conclusion, novel approaches for treatment of asthma and food allergy and comorbid conditions such as anxiety and eczema are urgently needed. This article discusses promising interventions for such conditions from traditional Chinese medicine (TCM) and explores their possible mechanisms of action. PMID:21913200

Derivation of Cinnamon Blocks Leukocyte Attachment by Interacting with Sialosides

PubMed Central

Lin, Wei-Ling; Guu, Shih-Yun; Tsai, Chan-Chuan; Prakash, Ekambaranellore; Viswaraman, Mohan; Chen, Hsing-Bao; Chang, Chuan-Fa

2015-01-01

Molecules derived from cinnamon have demonstrated diverse pharmacological activities against infectious pathogens, diabetes and inflammatory diseases. This study aims to evaluate the effect of the cinnamon-derived molecule IND02 on the adhesion of leukocytes to host cells. The anti-inflammatory ability of IND02, a pentameric procyanidin type A polyphenol polymer isolated from cinnamon alcohol extract, was examined. Pretreatment with IND02 significantly reduced the attachment of THP-1 cells or neutrophils to TNF-α-activated HUVECs or E-selectin/ICAM-1, respectively. IND02 also reduced the binding of E-, L- and P-selectins with sialosides. Furthermore, IND02 could agglutinate human red blood cells (RBC), and the agglutination could be disrupted by sialylated glycoprotein. Our findings demonstrate that IND02, a cinnamon-derived compound, can interact with sialosides and block the binding of selectins and leukocytes with sialic acids. PMID:26076445

Tree Classification Software

NASA Technical Reports Server (NTRS)

Buntine, Wray

1993-01-01

This paper introduces the IND Tree Package to prospective users. IND does supervised learning using classification trees. This learning task is a basic tool used in the development of diagnosis, monitoring and expert systems. The IND Tree Package was developed as part of a NASA project to semi-automate the development of data analysis and modelling algorithms using artificial intelligence techniques. The IND Tree Package integrates features from CART and C4 with newer Bayesian and minimum encoding methods for growing classification trees and graphs. The IND Tree Package also provides an experimental control suite on top. The newer features give improved probability estimates often required in diagnostic and screening tasks. The package comes with a manual, Unix 'man' entries, and a guide to tree methods and research. The IND Tree Package is implemented in C under Unix and was beta-tested at university and commercial research laboratories in the United States.

Prevalencia de síntomas depresivos e invarianza factorial de la Escala de Depresión del Centro de Estudios Epidemiológicos (CES-D) en población indígena mexicana.

PubMed

Franco-Díaz, Karen Lizbeth; Fernández-Niño, Julián Alfredo; Astudillo-García, Claudia Iveth

2018-05-01

Introducción. La versión breve de la Escala de Depresión del Centro de Estudios Epidemiológicos (CESD) es un recurso factible para la tamización de los síntomas de depresión en la población general, pero no se ha reportado la prevalencia en la población indígena, ni su invarianza factorial en Latinoamérica.Objetivo. Describir la prevalencia de los síntomas de depresión y la invarianza factorial de la versión breve de la escala CES-D en población indígena mexicana.Materiales y métodos. Se hizo un estudio transversal en una muestra representativa de 37.165 adultos mexicanos de 20 a 59 años de edad. La identidad indígena se determinó mediante el propio reporte de la persona como hablante de una lengua indígena. Se conformaron ocho grupos de análisis según el sexo, el alfabetismo y el ser indígena. Se describió la prevalencia de los síntomas depresivos en cada grupo, así como la invarianza factorial de la configuración de los perfiles mediante un análisis factorial exploratorio. Las matrices de varianza y covarianza se compararon entre pares de perfiles usando el test modificado de Mantel.Resultados. La prevalencia de síntomas depresivos en mujeres indígenas que sabían leer fue de 16,8 % (IC95%: 13,4-20,3); en mujeres indígenas que no sabían leer, de 21,3 % (IC95%: 15,5-27,1); en hombres indígenas que sabían leer de 8,5 % (IC95%: 6,0-11,1), y en hombres indígenas que no sabían leer de 10,4 % (IC95%: 5,2-15,6). No se encontraron diferencias significativas en las cargas factoriales entre los perfiles.Conclusión. Se reportó una menor prevalencia de síntomas depresivos en indígenas que en la población no indígena. La escala CES-D en su versión breve mostró invarianza factorial al emplearla en la población indígena.

21 CFR 312.305 - Requirements for all expanded access uses.

Code of Federal Regulations, 2012 CFR

2012-04-01

... contained in an existing IND if the sponsor of the existing IND grants a right of reference to the IND. (2... therapeutic options that would ordinarily be tried before resorting to the investigational drug or an...

21 CFR 312.305 - Requirements for all expanded access uses.

Code of Federal Regulations, 2011 CFR

2011-04-01

... contained in an existing IND if the sponsor of the existing IND grants a right of reference to the IND. (2... therapeutic options that would ordinarily be tried before resorting to the investigational drug or an...

21 CFR 312.305 - Requirements for all expanded access uses.

Code of Federal Regulations, 2014 CFR

2014-04-01

... contained in an existing IND if the sponsor of the existing IND grants a right of reference to the IND. (2... therapeutic options that would ordinarily be tried before resorting to the investigational drug or an...

21 CFR 312.305 - Requirements for all expanded access uses.

Code of Federal Regulations, 2013 CFR

2013-04-01

... contained in an existing IND if the sponsor of the existing IND grants a right of reference to the IND. (2... therapeutic options that would ordinarily be tried before resorting to the investigational drug or an...

Comparing Local TV News with National TV News in Cancer Coverage: An Exploratory Content Analysis

PubMed Central

Lee, Chul-joo; Long, Marilee; Slater, Michael D.; Song, Wen

2014-01-01

We compared local TV news with national TV news in terms of cancer coverage using a nationally representative sample of local nightly TV and national network TV (i.e., ABC, CBS, NBC, and CNN) cancer news stories that aired during 2002 and 2003. Compared to national TV news, local TV cancer stories were (a) much shorter in length, (b) less likely to report on cancer prevention (i.e., preventive behaviors and screening tests), and (c) less likely to reference national organizations (i.e., NCI, ACS, NIH, CDC, FDA) that have made clear recommendations about ways to prevent cancer. The implications of these findings for health communication research and cancer education were discussed. PMID:24750022

Response to Indacaterol/Glycopyrronium (IND/GLY) by Sex in Patients with COPD: A Pooled Analysis from the IGNITE Program.

PubMed

Tsiligianni, Ioanna; Mezzi, Karen; Fucile, Sebastian; Kostikas, Konstantinos; Shen, Steven; Banerji, Donald; Fogel, Robert

2017-08-01

In this pooled analysis, we compared the effect of indacaterol/glycopyrronium (IND/GLY) by sex versus other commonly used chronic obstructive pulmonary disease (COPD) treatments and placebo. Male and female patients with moderate-to-very-severe COPD who had participated in six randomized controlled trials were included in the analysis. Baseline demographics and disease characteristics were analyzed by sex, and any differences noted. The effects of IND/GLY versus salmeterol/fluticasone (SFC), glycopyrronium, tiotropium and placebo, on lung function and the patient-reported outcomes (health status, dyspnea, rescue medication use and symptoms) were assessed by sex after 26 weeks treatment. The analysis population comprised 4719 men and 1389 women. Most baseline parameters differed significantly between men and women. Nonetheless, despite these differences in baseline characteristics, IND/GLY significantly improved lung function versus placebo (p < 0.0001) and all active comparators (p < 0.01) in men and women. Overall, IND/GLY showed better improvement in dyspnea and health status compared with all other treatments in both sex. Greater reduction of rescue medication use was observed with IND/GLY versus placebo and other treatments (all p < 0.01 expect IND/GLY versus SFC). Although some variability was observed, improvements in health status, dyspnea, rescue medication use and symptoms were generally larger in women than in men. Irrespective of sex, IND/GLY provided superior efficacy to monotherapy or SFC in both men and women. Small differences in efficacy response by sex were observed, which should be evaluated further in prospective clinical studies. Nevertheless, the benefits observed with IND/GLY confirm dual bronchodilator as the preferred therapy in patients with moderate-to-very-severe COPD regardless of sex.

Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration-Approved Antibiotics, 2010-2015.

PubMed

Deak, Dalia; Outterson, Kevin; Powers, John H; Kesselheim, Aaron S

2016-09-06

A weak antibiotic pipeline and the increase in drug-resistant pathogens have led to calls for more new antibiotics. Eight new antibiotics were approved by the U.S. Food and Drug Administration (FDA) between January 2010 and December 2015: ceftaroline, fidaxomicin, bedaquiline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, and ceftazidime-avibactam. This study evaluates the development course and pivotal trials of these antibiotics for their innovativeness, development process, documented patient outcomes, and cost. Data sources were FDA approval packages and databases (January 2010 to December 2015); the Red Book (Truven Health Analytics); Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (FDA); and supplementary information from company filings, press releases, and media reports. Four antibiotics were approved for acute bacterial skin and skin-structure infection. Seven had similar mechanisms of action to those of previously approved drugs. Six were initially developed by small to midsized companies, and 7 are currently marketed by 1 of 3 large companies. The drugs spent a median of 6.2 years in clinical trials (interquartile range [IQR], 5.4 to 8.8 years) and 8 months in FDA review (IQR, 7.5 to 8 months). The median number of patients enrolled in the pivotal trials was 666 (IQR, 553 to 739 patients; full range, 44 to 1005 patients), and median trial duration was 18 months (IQR, 15 to 22 months). Seven drugs were approved on the basis of pivotal trials evaluating noninferiority. One drug demonstrated superiority on an exploratory secondary end point, 2 showed decreased efficacy in patients with renal insufficiency, and 1 showed increased mortality compared with older drugs. Seven of the drugs are substantially more expensive than their trial comparators. Limitations are that future research may show benefit to patients, new drugs from older classes may show superior effectiveness in specific patient populations, and initial U.S. prices for each new antibiotic were obtained from public sources. Recently marketed antibiotics are more expensive but have been approved without evidence of clinical superiority.

IND - THE IND DECISION TREE PACKAGE

NASA Technical Reports Server (NTRS)

Buntine, W.

1994-01-01

A common approach to supervised classification and prediction in artificial intelligence and statistical pattern recognition is the use of decision trees. A tree is "grown" from data using a recursive partitioning algorithm to create a tree which has good prediction of classes on new data. Standard algorithms are CART (by Breiman Friedman, Olshen and Stone) and ID3 and its successor C4 (by Quinlan). As well as reimplementing parts of these algorithms and offering experimental control suites, IND also introduces Bayesian and MML methods and more sophisticated search in growing trees. These produce more accurate class probability estimates that are important in applications like diagnosis. IND is applicable to most data sets consisting of independent instances, each described by a fixed length vector of attribute values. An attribute value may be a number, one of a set of attribute specific symbols, or it may be omitted. One of the attributes is delegated the "target" and IND grows trees to predict the target. Prediction can then be done on new data or the decision tree printed out for inspection. IND provides a range of features and styles with convenience for the casual user as well as fine-tuning for the advanced user or those interested in research. IND can be operated in a CART-like mode (but without regression trees, surrogate splits or multivariate splits), and in a mode like the early version of C4. Advanced features allow more extensive search, interactive control and display of tree growing, and Bayesian and MML algorithms for tree pruning and smoothing. These often produce more accurate class probability estimates at the leaves. IND also comes with a comprehensive experimental control suite. IND consists of four basic kinds of routines: data manipulation routines, tree generation routines, tree testing routines, and tree display routines. The data manipulation routines are used to partition a single large data set into smaller training and test sets. The generation routines are used to build classifiers. The test routines are used to evaluate classifiers and to classify data using a classifier. And the display routines are used to display classifiers in various formats. IND is written in C-language for Sun4 series computers. It consists of several programs with controlling shell scripts. Extensive UNIX man entries are included. IND is designed to be used on any UNIX system, although it has only been thoroughly tested on SUN platforms. The standard distribution medium for IND is a .25 inch streaming magnetic tape cartridge in UNIX tar format. An electronic copy of the documentation in PostScript format is included on the distribution medium. IND was developed in 1992.

INDES User's guide multistep input design with nonlinear rotorcraft modeling

NASA Technical Reports Server (NTRS)

1979-01-01

The INDES computer program, a multistep input design program used as part of a data processing technique for rotorcraft systems identification, is described. Flight test inputs base on INDES improve the accuracy of parameter estimates. The input design algorithm, program input, and program output are presented.

Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial).

PubMed

Anstey, Matthew H; Wibrow, Bradley; Thevathasan, Tharusan; Roberts, Brigit; Chhangani, Khushi; Ng, Pauline Yeung; Levine, Alexander; DiBiasio, Alan; Sarge, Todd; Eikermann, Matthias

2017-03-21

Patients admitted to intensive care units (ICU) are often treated with intravenous (IV) vasopressors. Persistent hypotension and dependence on IV vasopressors in otherwise resuscitated patients lead to delay in discharge from ICU. Midodrine is an oral alpha-1 adrenergic agonist approved for treatment of symptomatic orthostatic hypotension. This trial aims to evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV vasopressor treatment, and allow earlier discharge from ICU and hospital. The MIDAS trial is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial being conducted in the USA and Australia. We are targeting 120 patients. Adult patients admitted to the ICU who are resuscitated and otherwise stable on low dose IV vasopressors for at least 24 h will be considered for recruitment. Participants will be randomized to receive midodrine (20 mg) or placebo three times a day, in addition to standard care. The primary outcome is time (hours) from initiation of midodrine or placebo to discontinuation of IV vasopressors. Secondary outcomes include time (hours) from ICU admission to discharge readiness, ICU length of stay (LOS) (days), hospital LOS (days), rates of ICU readmission, and rates of adverse events related to midodrine administration. Midodrine is approved by the Food and Drug Administration (FDA) for the treatment of symptomatic orthostatic hypotension. In August 2010, FDA proposed to withdraw approval of midodrine because of lack of studies that verify the clinical benefit of the drug. We obtained Investigational New Drug (IND 113,330) approval to study its effects in critically ill patients who require IV vasopressors but are otherwise ready for discharge from the ICU. A pilot observational study in a cohort of surgical ICU patients showed that the rate of decline in vasopressor requirements increased after initiation of midodrine treatment. We hypothesize that midodrine administration is effective to wean IV vasopressors and shorten ICU and hospital LOS. This trial may have significant implications on lowering costs of hospital care and obtaining FDA approval for new indications for midodrine. This study has been registered at clinicaltrials.gov on 02/09/2012 (NCT01531959).

Composition and abundance of epibenthic-sledge catches in the South Polar Front of the Atlantic

NASA Astrophysics Data System (ADS)

Brandt, A.; Havermans, C.; Janussen, D.; Jörger, K. M.; Meyer-Löbbecke, A.; Schnurr, S.; Schüller, M.; Schwabe, E.; Brandão, S. N.; Würzberg, L.

2014-10-01

An epibenthic sledge (EBS) was deployed at seven different deep-sea stations along the South Polar Front of the Atlantic in order to explore the composition and abundance of macrofaunal organisms and to identify the most abundant taxa in this transition zone to the Southern Ocean. In total 3,130 specimens were sampled by means of the EBS on board of RV Polarstern during the expedition ANT-XXVIII/3 in the austral summer of 2012. Benthic and suprabenthic Crustacea occurred to be most frequent in the samples. Among those, copepods were by far most numerous, with 1,585 specimens followed by the peracarid taxa Isopoda (236 ind.), Amphipoda (103 ind.), Tanaidacea (78 ind.) and Cumacea (50 ind.). Annelida were represented by a high number of specimens belonging to different polychaete taxa (404 ind.). The molluscan fauna was clearly dominated by Bivalvia (255 ind.), followed in numbers of specimens by Gastropoda (47 ind.). The deep-sea benthos sampled along the Southern Polar Front occurred in surprisingly low abundances, contrasting the largely high surface productivity of the area. Numbers of specimens across different macrofaunal taxa and especially of peracarid crustaceans underscored by far those from South Ocean sites at higher latitudes in the Weddell Sea.

[The Contribution of GMP-grade Hospital Preparation to Translational Research].

PubMed

Yonezawa, Atsushi; Kajiwara, Moto; Minami, Ikuko; Omura, Tomohiro; Nakagawa, Shunsaku; Matsubara, Kazuo

2015-01-01

Translational research is important for applying the outcomes of basic research studies to practical medical treatments. In exploratory early-phase clinical trials for an innovative therapy, researchers should generally manufacture investigational agents by themselves. To provide investigational agents with safety and high quality in clinical studies, appropriate production management and quality control are essential. In the Department of Pharmacy of Kyoto University Hospital, a manufacturing facility for sterile drugs was established, independent of existing manufacturing facilities. Manuals on production management and quality control were developed according to Good Manufacturing Practices (GMP) for Investigational New Drugs (INDs). Advanced clinical research has been carried out using investigational agents manufactured in our facility. These achievements contribute to both the safety of patients and the reliability of clinical studies. In addition, we are able to do licensing-out of our technique for the manufacture of investigational drugs. In this symposium, we will introduce our GMP grade manufacturing facility for sterile drugs and discuss the role of GMP grade hospital preparation in translational research.

[When Should We Perform Surgery for N2 Lung Cancer?;Induction Chemoradiotherapy or Surgery for Local Recurrence or Residual Tumor after Definitive Chemoradiotherapy].

PubMed

Ito, Hiroyuki; Nakayama, Haruhiko

2018-04-01

Standard treatment for locally advanced clinical N2 lung cancer is definitive chemoradiotherapy, and induction chemoradiotherapy(IND-CRT) followed by surgery is an option. Most of them recurs remotely within a few years after initial therapy. Patients who received salvage surgery(SAL) after definitive chemoradiotherapy had no remote relapse for some period after definitive chemoradiotherapy, thus the outcome of SAL may be better than those of IND-CRT, but the operative risks of both procedures seem to be high. To compare the prognosis and risk of SAL and IND-CRT. From January 2001 through December 2015, 39 patients with clinical N2 primary lung cancer underwent surgery after chemoradiotherapy. Twenty-six patients received IND-CRT, and 13 underwent SAL. Perioperative factors, overall survival rates at 5 years, lung-cancer-specific mortality, relapse-free survival rates, and the rates of perioperative complications were compared between the groups. The median follow up period was 41.0 months(5~120 months). Twelve patients were women, and 27 were men. The average age was 60.2 years. The patients comprised 1.7% of the 2,330 anatomical resections performed during the same period. The radiation dose was 46.4 Gy who received IND-CRT and 61.4 Gy in those who received SAL(p<0.001). In patients who received IND-CRT, median period from the end of the initial treatment to surgery was 1.2 months in IND-CRT and 17.2 months in SAL. Lobectomy was performed in 37 patients, pneumonectomy in 2 patients. In patients who received IND-CRT, an average operation time was 236 minutes, mean bleeding volume was 135 g. In patients who underwent SAL, they were 236 minutes and 188 g(p=0.998, p=0.365). There was no perioperative and in-hospital death in either group. Postoperative complications developed in 5 of INDCRT(19.2%)and 3 in SAL(23.1%). The 5-year overall survival rate of all cases was 60.4%(IND-CRT 53.9, SAL 81.8%;p=0.737). The lung cancer-specific survival rate at 5 years was 60.4% overall, 57.5% in IND-CRT, and 90.0% in SAL(p=0.176). The 5-year relapse-free survival rate was 52.7% overall, 37.6% in IND-CRT, 57.7% in SAL(p=0.175). Although the differences were not statistically significant, SAL tended to have better outcomes. SAL did not differ significantly from IND-CRT with respect to postoperative complications or surgical invasiveness in patients with clinical N2 lung cancer and had good outcomes. SAL and IND-CRT seem to be a sufficiently meaningful treatment but should be performed by surgeons with sufficient knowledge and experience.

Intramolecular mobility of η(5)-ligands in chiral zirconocene complexes and the enantioselectivity of alkene functionalization by organoaluminum compounds.

PubMed

Parfenova, Lyudmila V; Zakirova, Irina V; Kovyazin, Pavel V; Karchevsky, Stanislav G; Istomina, Galina P; Khalilov, Leonard M; Dzhemilev, Usein M

2016-08-09

The effect of solvent nature (CD2Cl2, d8-toluene, d8-THF) on the conformational behavior of neomenthyl-substituted zirconocenes CpInd*ZrCl2 (Cp = η(5)-C5H5, Ind* = η(5)-neomenthylindenyl), CpCp'ZrCl2 (Cp = η(5)-C5H5, Cp' = η(5)-neomenthyl-4,5,6,7-tetrahydroindenyl), and Ind*2ZrCl2 (Ind* = η(5)-neomenthylindenyl) was shown by means of dynamic NMR spectroscopy, and the constants and thermodynamic parameters of conformer exchange were determined. The experimental conformational composition of the complexes was compared with structures obtained by quantum chemical modeling using the DFT methods PBE/3ζ and M06-2X/cc-pVDZ(H, C, Cl)/cc-pVDZ-PP(Zr), which predicted three rotamers in the case of both CpInd*ZrCl2 and CpCp'ZrCl2, and seven rotational isomers for Ind*2ZrCl2, three of these being C2-symmetric and the others being asymmetric. The enantioselectivity of the conformationally mobile complex Ind*2ZrCl2 in the reactions of terminal alkenes with AlR3 (R = Me, Et) was compared with that of rigid ansa-complexes, rac-p-S, p-S-[Y(η(5)-C9H10)2]ZrX2 (Y = SiMe2, C2H4; X = S-binaphtholate). Faster exchange between the conformers of Ind*2ZrCl2 in a chlorinated solvent gives the structural isomer of catalytically active sites, which affords higher substrate conversion and reaction enantioselectivity. Binding of the ligands to ansa-zirconocenes prevents the rotational isomerism of the complexes, providing the same configuration of the β-stereogenic center in the methyl- and ethylalumination products (unlike the conformationally mobile complex Ind*2ZrCl2) with an enantiomeric purity of 50-65%.

IND2, a pyrimido[1”,2”:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells

PubMed Central

Karthikeyan, Chandrabose; Lee, Crystal; Moore, Joshua; Mittal, Roopali; Suswam, Esther A.; Abbott, Kodye L; Pondugula, Satyanarayana R.; Manne, Upender; Narayanan, Narayanan K.; Trivedi, Piyush; Tiwari, Amit K.

2014-01-01

Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1”,2”:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1”,2”:1,5]pyrazolo[3,4-b]quinoline, exhibited more than tenfold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and submicromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and fivefold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer. PMID:25537531

Indacaterol/glycopyrronium versus salmeterol/fluticasone in Asian patients with COPD at a high risk of exacerbations: results from the FLAME study

PubMed Central

Wedzicha, Jadwiga A; Zhong, Nanshan; Ichinose, Masakazu; Humphries, Michael; Fogel, Robert; Thach, Chau; Patalano, Francesco; Banerji, Donald

2017-01-01

Background The FLAME study demonstrated that indacaterol/glycopyrronium (IND/GLY), the fixed-dose combination of a long-acting β2-agonist (LABA, IND) and a long-acting muscarinic antagonist (LAMA, GLY), was superior to salmeterol/fluticasone combination (SFC) in preventing exacerbations in COPD patients with a high risk of exacerbations. In this study, we report a prespecified analysis of the efficacy and safety of IND/GLY versus SFC in Asian patients from the FLAME study. Patients and methods Patients from Asian centers with moderate-to-very severe COPD and ≥1 exacerbation in the previous year from the 52-week, randomized FLAME study were included. IND/GLY was compared versus SFC for effects on exacerbations, lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), health status (St George’s Respiratory Questionnaire [SGRQ]), rescue medication use, and safety. Results A total of 510 Asian patients (IND/GLY, n=250 or SFC, n=260) were included. Compared to the overall FLAME population, the Asian cohort had more males, a shorter duration of COPD, fewer patients using inhaled corticosteroid (ICS) at screening, fewer current smokers, and more patients with very severe COPD. IND/GLY significantly reduced the rate of moderate/severe exacerbations (rate ratio: 0.75; 95% confidence interval: 0.58–0.97; P=0.027) and prolonged time to first moderate/severe exacerbation versus SFC (hazard ratio: 0.77; 95% confidence interval: 0.59–1.01; P=0.055). Predose trough FEV1 and FVC significantly improved in Asian patients (P<0.001). IND/GLY improved SGRQ for COPD (SGRQ-C score; P=0.006) and reduced rescue medication use (P=0.058) at week 52. Pneumonia incidence was 3.6% with IND/GLY and 7.7% with SFC (P=0.046). Conclusion In exacerbating Asian COPD patients, IND/GLY was more effective than SFC. PMID:28176893

Indacaterol/glycopyrronium versus salmeterol/fluticasone in Asian patients with COPD at a high risk of exacerbations: results from the FLAME study.

PubMed

Wedzicha, Jadwiga A; Zhong, Nanshan; Ichinose, Masakazu; Humphries, Michael; Fogel, Robert; Thach, Chau; Patalano, Francesco; Banerji, Donald

2017-01-01

The FLAME study demonstrated that indacaterol/glycopyrronium (IND/GLY), the fixed-dose combination of a long-acting β 2 -agonist (LABA, IND) and a long-acting muscarinic antagonist (LAMA, GLY), was superior to salmeterol/fluticasone combination (SFC) in preventing exacerbations in COPD patients with a high risk of exacerbations. In this study, we report a prespecified analysis of the efficacy and safety of IND/GLY versus SFC in Asian patients from the FLAME study. Patients from Asian centers with moderate-to-very severe COPD and ≥1 exacerbation in the previous year from the 52-week, randomized FLAME study were included. IND/GLY was compared versus SFC for effects on exacerbations, lung function (forced expiratory volume in 1 second [FEV 1 ] and forced vital capacity [FVC]), health status (St George's Respiratory Questionnaire [SGRQ]), rescue medication use, and safety. A total of 510 Asian patients (IND/GLY, n=250 or SFC, n=260) were included. Compared to the overall FLAME population, the Asian cohort had more males, a shorter duration of COPD, fewer patients using inhaled corticosteroid (ICS) at screening, fewer current smokers, and more patients with very severe COPD. IND/GLY significantly reduced the rate of moderate/severe exacerbations (rate ratio: 0.75; 95% confidence interval: 0.58-0.97; P =0.027) and prolonged time to first moderate/severe exacerbation versus SFC (hazard ratio: 0.77; 95% confidence interval: 0.59-1.01; P =0.055). Predose trough FEV 1 and FVC significantly improved in Asian patients ( P <0.001). IND/GLY improved SGRQ for COPD (SGRQ-C score; P =0.006) and reduced rescue medication use ( P =0.058) at week 52. Pneumonia incidence was 3.6% with IND/GLY and 7.7% with SFC ( P =0.046). In exacerbating Asian COPD patients, IND/GLY was more effective than SFC.

The seasonal succession of zooplankton in the Southern Ocean south of Australia, part II: The Sub-Antarctic to Polar Frontal Zones

NASA Astrophysics Data System (ADS)

Hunt, Brian P. V.; Hosie, Graham W.

2006-07-01

Between October 2001 and March 2002 six transects were completed at monthly intervals in the Sub-Antarctic Zone (SAZ) and Inter-Sub-Antarctic Front Zone (ISAFZ)/Polar Frontal Zone (PFZ) in the Southern Ocean south of Australia. Zooplankton were collected with a Continuous Plankton Recorder and NORPAC net and multivariate analysis was used to analyse the seasonal succession of communities. Despite strong, seasonally consistent, biogeographic differences between the SAZ and ISAFZ/PFZ, community structure in all zones was dominated by a suite of common taxa. These included the ubiquitous Oithona similis, foraminiferans and appendicularians (Core taxa), occurring in >97% of samples and contributing an average of 75% to total sample abundance, and Calanus simillimus, Rhincalanus gigas, Ctenocalanus citer, Clausocalanus brevipes, Clausocalanus laticeps, Oithona frigida, Limacina spp. and chaetognaths (Summer taxa), present in >57% of samples and occurring at seasonally high densities. Because of the dominance of the Core and Summer taxa, the seasonal succession was most clearly evident as a change in zooplankton densities. In October densities averaged <15 ind m -3, rising to 52 ind m -3 (max=92 ind m -3) in November, and subsequently increasing slowly through to January (ave=115 ind m -3; max=255 ind m -3). Densities peaked abruptly in February (ave=634 ind m -3; max=1593 ind m -3), and remained relatively high in March (ave=193 ind m -3; max=789 ind m -3). A latitudinal lag in seasonal development was observed with peak densities occurring first in the SAZ (February) and then in the ISAFZ/PFZ (March). The seasonal community succession was strongly influenced by species population cycles. The role of zooplankton in biogeochemical cycling in the SAZ and ISAFZ/PFZ was discussed in the light of past sediment trap data collected from the study area.

Defense.gov Special Report: Civilian Expeditionary Workforce

Science.gov Websites

TRAINING CENTER, Ind., March 10, 2011 - Civilian Expeditionary Workforce members provide a vital service to Training Center, Ind., and nearby Camp Atterbury, strive for realism to prepare civilians for service in undergo rigorous training on Muscatatuck Urban Training Center and Camp Atterbury, Ind., where they learn

Morin protects gastric mucosa from nonsteroidal anti-inflammatory drug, indomethacin induced inflammatory damage and apoptosis by modulating NF-κB pathway.

PubMed

Sinha, Krishnendu; Sadhukhan, Pritam; Saha, Sukanya; Pal, Pabitra Bikash; Sil, Parames C

2015-04-01

Deregulation in prostaglandin (PG) biosynthesis, severe oxidative stress, inflammation and apoptosis contribute to the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Unfortunately, most of the prescribed anti-ulcer drugs generate various side effects. In this scenario, we could consider morin as a safe herbal potential agent against IND-gastropathy and rationalize its action systematically. Rats were pretreated with morin for 30 min followed by IND (48 mgkg(-1)) administration for 4 h. The anti-ulcerogenic nature of morin was assessed by morphological and histological analysis. Its effects on the inflammatory (MPO, cytokines, adhesion molecules), ulcer-healing (COXs, PGE(2)), and signaling parameters (NF-κB and apoptotic signaling) were assessed by biochemical, RP-HPLC, immunoblots, IHC, RT-PCR, and ELISA at the time points of their maximal changes due to IND administration. IND induced NF-κB and apoptotic signaling in rat's gastric mucosa. These increased proinflammatory responses, but reduced the antioxidant enzymes and other protective factors. Morin reversed all the adverse effects to prevent IND-induced gastric ulceration in a PGE2 independent manner. Also, it did not affect the absorption and/or primary pharmacological activity of IND. The gastroprotective action of morin is primarily attributed to its potent antioxidant nature that also helps in controlling several IND-induced inflammatory responses. For the first time, the study reveals a mechanistic basis of morin mediated protective action against IND-induced gastropathy. As morin is a naturally abundant safe antioxidant, future detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as a gastroprotective agent. Copyright © 2015 Elsevier B.V. All rights reserved.

Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains.

PubMed

Giles, Kurt; Berry, David B; Condello, Carlo; Hawley, Ronald C; Gallardo-Godoy, Alejandra; Bryant, Clifford; Oehler, Abby; Elepano, Manuel; Bhardwaj, Sumita; Patel, Smita; Silber, B Michael; Guan, Shenheng; DeArmond, Stephen J; Renslo, Adam R; Prusiner, Stanley B

2015-10-01

Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from ∼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, β-sheet-rich "scrapie" isoform (PrP(Sc)) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrP(Sc) and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrP(Sc) accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrP(Sc) that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Effect of various enhancers on transdermal penetration of indomethacin and urea, and relationship between penetration parameters and enhancement factors.

PubMed

Ogiso, T; Iwaki, M; Paku, T

1995-04-01

The enhancing capacity of various chemicals, which are widely recognized as enhancers, for the transdermal penetration into full-thickness rat skin of a model lipophilic drug [indomethacin (IND)] and a hydrophilic permeant (urea) was estimated by an in vitro technique. In addition, the fluidity of the stratum corneum lipids, the partitioning of IND into skin, the lipid (ceramides) extraction from the stratum corneum by enhancers, and the IND solubility in enhancer vehicle were measured and related to the enhancing capacity. In vitro permeation experiments with hairless rat skin unequivocally revealed that the enhancers varied in abilities to enhance the fluxes of both agents. Laurocapram, isopropylmyristate (IPM), sodium oleate, and cineol increased fluxes of both agents to a great extent, but N-methyl-2-pyrrolidone (NMP), N,N-diethyl-m-tolamide (DEET), and oleyl oleate were less effective acclerants. Many enhancers increased the fluidity of the lipids [with a threshold of approximately 0.6-0.8 ns at 37 degrees C in the rotational correlation time (tau c)], the skin partitioning of IND, the extraction of ceramides from the cornified cells, and the thermodynamic activity of IND in vehicle (calculated from the solubility) to varying extents. A good correlation was observed between the increase in the fluidity of stratum corneum lipids and the partitioning of IND into skin, between the increase in the fluidity and the flux or the decrease in lag time for IND, between the removal of ceramides and the skin partitioning of IND, and between the removal of ceramides and the flux of urea (p < 0.05 in all cases).(ABSTRACT TRUNCATED AT 250 WORDS)

Tulsa's IndEx Program. A Business-Led Initiative for Welfare Reform and Economic Development. Connections To Work.

ERIC Educational Resources Information Center

Buck, Maria L.

In 1992, the Metropolitan Tulsa Chamber of Commerce in Oklahoma established a welfare-to-work program called Industrial Exchange, Inc. (IndEx). IndEx provides welfare recipients with a combination of education activities and work experience. By contracting with local companies to perform light manufacturing and packaging work at a central site,…

8. Photograph of post card, 'Cicotte Street Bridge, Logansport, Ind.' ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

8. Photograph of post card, 'Cicotte Street Bridge, Logansport, Ind.' Logansport News Agency, Logansport, Ind., Curteich-Chicago 'C.T. American Art' post card {Reg. U.S. Pat. Off.}, postmarked October 17, 1949. Card in the Cass County photograph file at the Indiana State Library, Indianapolis. - Cicott Street Bridge, Spanning Wabash River at State Road 25, Logansport, Cass County, IN

Performance of 1,2-indanedione and the need for sequential treatment of fingerprints.

PubMed

Mangle, Milery Figuera; Xu, Xioama; de Puit, M

2015-09-01

The use of 1,2-indanedione-ZnCl2 (IND-Zn) for the visualisation of fingermarks on porous materials has been widely accepted. The use of the reagent in comparison with others has been well described. To what extent IND or IND-Zn reacts with amino acids, in comparison to ninhydrin, has not been described to date. In this technical note we describe the analysis of amino acids with LCMS with the purpose of understanding the reactivity of ninhydrin, IND-Zn and the sequence thereof. The consumption of amino acids by these visualisation reagents is a feature we propose to use for calculations on the reactivity of these reagents. By using recently developed methods for the quantification of amino acids, we determined the consumption of these entities by visualisation reagents. We show that the differences in reactivity between IND and ninhydrin are not as big as the differences between 1,8-diazafluoren-9-one (DFO) and ninhydrin. We also show that it is of great importance to use IND-Zn and ninhydrin in sequence, in order to fully consume the amino acids present in fingermarks. Copyright © 2015 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.

Safety of Bifidobacterium animalis subsp. lactis (B. lactis) strain BB-12-supplemented yogurt in healthy adults on antibiotics: a phase I safety study

PubMed Central

Merenstein, Daniel J; Tan, Tina P; Molokin, Aleksey; Smith, Keisha Herbin; Roberts, Robert F; Shara, Nawar M; Mete, Mihriye; Sanders, Mary Ellen; Solano-Aguilar, Gloria

2015-01-01

Probiotics are live microorganisms that, when administered in sufficient doses, provide health benefits on the host. The United States Food and Drug Administration (FDA) requires phase I safety studies for probiotics when the intended use of the product is as a drug. The purpose of the study was to determine the safety of Bifidobacterium animalis subsp lactis (B. lactis) strain BB-12 (BB-12)-supplemented yogurt when consumed by a generally healthy group of adults who were prescribed a 10-day course of antibiotics for a respiratory infection. Secondary aims were to assess the ability of BB-12 to affect the expression of whole blood immune markers associated with cell activation and inflammatory response. A phase I, double-blinded, randomized controlled study was conducted in compliance with FDA guidelines for an Investigational New Drug (IND). Forty participants were randomly assigned to consume 4 ounces of either BB-12 -supplemented yogurt or non-supplemented control yogurt daily for 10 d. The primary outcome was to assess safety and tolerability, assessed by the number of reported adverse events. A total of 165 non-serious adverse events were reported, with no differences between the control and BB-12 groups. When compared to the control group, B lactis fecal levels were modestly higher in the BB-12-supplemented group. In a small subset of patients, changes in whole blood expression of genes associated with regulation and activation of immune cells were detected in the BB-12-supplemented group. BB-12-supplemented yogurt is safe and well tolerated when consumed by healthy adults concurrently taking antibiotics. This study will form the basis for future randomized clinical trials investigating the potential immunomodulatory effects of BB-12-supplemented yogurt in a variety of disease states. PMID:25569274

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

PubMed

Gauvin, David V; Zimmermann, Zachary J; Yoder, Joshua; Harter, Marci; Holdsworth, David; Kilgus, Quinn; May, Jonelle; Dalton, Jill; Baird, Theodore J

2018-05-08

Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards. For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions. Copyright © 2018. Published by Elsevier Inc.

First detection of foot-and-mouth disease virus O/ME-SA/Ind2001 in China.

PubMed

Zhu, Z; Yang, F; He, J; Li, J; Cao, W; Li, J; Xia, Y; Guo, J; Jin, Y; Zhang, K; Zheng, H; Liu, X

2018-05-09

Foot-and-mouth disease (FMD) is endemic in China and is predominantly due to foot-and-mouth disease virus (FMDV) serotype O Mya-98 lineage. In recent years, FMDV O/ME-SA/Ind2001 lineage has spread from the Indian subcontinent to South-East Asia, Middle East and Africa, which may pose potential threats for future trans-regional livestock movements. In this study, we identified the appearance of FMDV O/ME-SA/Ind2001 in China; the first time that this virus lineage has been found there. Sequencing and phylogenetic analysis of VP1 sequences revealed that this newly determined strain belongs to O/ME-SA/Ind2001 sublineage d and is closely related to strains that have caused recent outbreaks of FMD in Nepal, Myanmar, Russia and South Korea. The results suggest extensive movements of the current O/ME-SA/Ind2001 sublineage d viruses and provide essential information for an effective national FMDV control programme in China. © 2018 Blackwell Verlag GmbH.

Reproducibility of Mammography Units, Film Processing and Quality Imaging

NASA Astrophysics Data System (ADS)

Gaona, Enrique

2003-09-01

The purpose of this study was to carry out an exploratory survey of the problems of quality control in mammography and processors units as a diagnosis of the current situation of mammography facilities. Measurements of reproducibility, optical density, optical difference and gamma index are included. Breast cancer is the most frequently diagnosed cancer and is the second leading cause of cancer death among women in the Mexican Republic. Mammography is a radiographic examination specially designed for detecting breast pathology. We found that the problems of reproducibility of AEC are smaller than the problems of processors units because almost all processors fall outside of the acceptable variation limits and they can affect the mammography quality image and the dose to breast. Only four mammography units agree with the minimum score established by ACR and FDA for the phantom image.

Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin.

PubMed

ElShaer, Amr; Khan, Sheraz; Perumal, Dhaya; Hanson, Peter; Mohammed, Afzal R

2011-07-01

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

Investigation of triacetin effect on indomethacin release from poly(methyl methacrylate) microspheres: evaluation of interactions using FT-IR and NMR spectroscopies.

PubMed

Yuksel, Nilufer; Baykara, Meltem; Shirinzade, Hanif; Suzen, Sibel

2011-02-14

The purpose of this study was to form indomethacin (IND)-loaded poly(methyl methacrylate) (PMMA) microspheres having an extended drug release profile over a period of 24h. Microspheres were prepared by solvent evaporation method using sucrose stearate as a droplet stabilizer. When PMMA was used alone for the preparation of microspheres, only 44% of IND could be released at the end of 8h. Triacetin was added to PMMA, as a minor phase, and the obtained microspheres showed a high yield process with recovery of 89.82% and incorporation efficiency of 102.3%. A desired release profile lasting 24h was achieved. Differential scanning calorimetry (DSC) analysis showed that IND was found to be in an amorphous state in the microspheres. Fourier transform infrared (FT-IR) and nuclear magnetic resonance ((1)H NMR) spectra suggested that there might be a hydrogen bond present between the IND hydroxyl group and PMMA. No interaction between triacetin and IND or PMMA as the formation of secondary bonds was observed. The release enhancement of IND from microspheres was attributed to the physical plasticization effect of triacetin on PMMA and, to some extent, the amorphous state of the drug. Copyright © 2010 Elsevier B.V. All rights reserved.

Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture.

PubMed

Padrela, Luis; de Azevedo, Edmundo Gomes; Velaga, Sitaram P

2012-08-01

The solid state purity of cocrystals critically affects their performance. Thus, it is important to accurately quantify the purity of cocrystals in the final crystallization product. The aim of this study was to develop a powder X-ray diffraction (PXRD) quantification method for investigating the purity of cocrystals. The method developed was employed to study the formation of indomethacin-saccharin (IND-SAC) cocrystals by mechanochemical methods. Pure IND-SAC cocrystals were geometrically mixed with 1:1 w/w mixture of indomethacin/saccharin in various proportions. An accurately measured amount (550 mg) of the mixture was used for the PXRD measurements. The most intense, non-overlapping, characteristic diffraction peak of IND-SAC was used to construct the calibration curve in the range 0-100% (w/w). This calibration model was validated and used to monitor the formation of IND-SAC cocrystals by liquid-assisted grinding (LAG). The IND-SAC cocrystal calibration curve showed excellent linearity (R(2) = 0.9996) over the entire concentration range, displaying limit of detection (LOD) and limit of quantification (LOQ) values of 1.23% (w/w) and 3.74% (w/w), respectively. Validation results showed excellent correlations between actual and predicted concentrations of IND-SAC cocrystals (R(2) = 0.9981). The accuracy and reliability of the PXRD quantification method depend on the methods of sample preparation and handling. The crystallinity of the IND-SAC cocrystals was higher when larger amounts of methanol were used in the LAG method. The PXRD quantification method is suitable and reliable for verifying the purity of cocrystals in the final crystallization product.

Collective mechanical behavior of multilayer colloidal arrays of hollow nanoparticles.

PubMed

Yin, Jie; Retsch, Markus; Thomas, Edwin L; Boyce, Mary C

2012-04-03

The collective mechanical behavior of multilayer colloidal arrays of hollow silica nanoparticles (HSNP) is explored under spherical nanoindentation through a combination of experimental, numerical, and theoretical approaches. The effective indentation modulus E(ind) is found to decrease with an increasing number of layers in a nonlinear manner. The indentation force versus penetration depth behavior for multilayer hollow particle arrays is predicted by an approximate analytical model based on the spring stiffness of the individual particles and the multipoint, multiparticle interactions as well as force transmission between the layers. The model is in good agreement with experiments and with detailed finite element simulations. The ability to tune the effective indentation modulus, E(ind), of the multilayer arrays by manipulating particle geometry and layering is revealed through the model, where E(ind) = (0.725m(-3/2) + 0.275)E(mon) and E(mon) is the monolayer modulus and m is number of layers. E(ind) is seen to plateau with increasing m to E(ind_plateau) = 0.275E(mon) and E(mon) scales with (t/R)(2), t being the particle shell thickness and R being the particle radius. The scaling law governing the nonlinear decrease in indentation modulus with an increase in layer number (E(ind) scaling with m(-3/2)) is found to be similar to that governing the indentation modulus of thin solid films E(ind_solid) on a stiff substrate (where E(ind_solid) scales with h(-1.4) and also decreases until reaching a plateau value) which also decreases with an increase in film thickness h. However, the mechanisms underlying this trend for the colloidal array are clearly different, where discrete particle-to-particle interactions govern the colloidal array behavior in contrast to the substrate constraint on deformation, which governs the thickness dependence of the continuous thin film indentation modulus.

Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice

PubMed Central

Bell, Genevieve A.; Fadool, Debra Ann

2017-01-01

Intranasal insulin delivery is currently being used in clinical trials to test for improvement in human memory and cognition, and in particular, for lessening memory loss attributed to neurodegenerative diseases. Studies have reported the effects of short-term intranasal insulin treatment on various behaviors, but less have examined long-term effects. The olfactory bulb contains the highest density of insulin receptors in conjunction with the highest level of insulin transport within the brain. Previous research from our laboratory has demonstrated that acute insulin intranasal delivery (IND) enhanced both short- and long-term memory as well as increased two-odor discrimination in a two-choice paradigm. Herein, we investigated the behavioral and physiological effects of chronic insulin IND. Adult, male C57BL6/J mice were intranasally treated with 5 μg/μl of insulin twice daily for 30 and 60 days. Metabolic assessment indicated no change in body weight, caloric intake, or energy expenditure following chronic insulin IND, but an increase in the frequency of meal bouts selectively in the dark cycle. Unlike acute insulin IND, which has been shown to cause enhanced performance in odor habituation/dishabituation and two-odor discrimination tasks in mice, chronic insulin IND did not enhance olfactometry-based odorant discrimination or olfactory reversal learning. In an object memory recognition task, insulin IND-treated mice performed no different from controls regardless of task duration. Biochemical analyses of the olfactory bulb revealed a modest 1.3X increase in IR kinase phosphorylation but no significant increase in Kv1.3 phosphorylation. Substrate phosphorylation of IR Kinase downstream effectors (MAPK/ERK and Akt signaling) proved to be highly variable. These data indicate that chronic administration of insulin IND in mice fails to enhance olfactory ability, object memory recognition, or a majority of systems physiology metabolic factors – as reported to elicit a modulatory effect with acute administration. This leads to two alternative interpretations regarding long-term insulin IND in mice: 1) It causes an initial stage of insulin resistance to dampen the behaviors that would normally be modulated under acute insulin IND, but ability to clear a glucose challenge is still retained, or 2) There is a lack of behavioral modulation at high concentration of insulin attributed to the twice daily intervals of hyperinsulinemia caused by insulin IND administration without any insulin resistance, per se. PMID:28259806

Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice.

PubMed

Bell, Genevieve A; Fadool, Debra Ann

2017-05-15

Intranasal insulin delivery is currently being used in clinical trials to test for improvement in human memory and cognition, and in particular, for lessening memory loss attributed to neurodegenerative diseases. Studies have reported the effects of short-term intranasal insulin treatment on various behaviors, but less have examined long-term effects. The olfactory bulb contains the highest density of insulin receptors in conjunction with the highest level of insulin transport within the brain. Previous research from our laboratory has demonstrated that acute insulin intranasal delivery (IND) enhanced both short- and long-term memory as well as increased two-odor discrimination in a two-choice paradigm. Herein, we investigated the behavioral and physiological effects of chronic insulin IND. Adult, male C57BL6/J mice were intranasally treated with 5μg/μl of insulin twice daily for 30 and 60days. Metabolic assessment indicated no change in body weight, caloric intake, or energy expenditure following chronic insulin IND, but an increase in the frequency of meal bouts selectively in the dark cycle. Unlike acute insulin IND, which has been shown to cause enhanced performance in odor habituation/dishabituation and two-odor discrimination tasks in mice, chronic insulin IND did not enhance olfactometry-based odorant discrimination or olfactory reversal learning. In an object memory recognition task, insulin IND-treated mice did not perform differently than controls, regardless of task duration. Biochemical analyses of the olfactory bulb revealed a modest 1.3 fold increase in IR kinase phosphorylation but no significant increase in Kv1.3 phosphorylation. Substrate phosphorylation of IR kinase downstream effectors (MAPK/ERK and Akt signaling) proved to be highly variable. These data indicate that chronic administration of insulin IND in mice fails to enhance olfactory ability, object memory recognition, or a majority of systems physiology metabolic factors - as reported to elicit a modulatory effect with acute administration. This leads to two alternative interpretations regarding long-term insulin IND in mice: 1) It causes an initial stage of insulin resistance to dampen the behaviors that would normally be modulated under acute insulin IND, but ability to clear a glucose challenge is still retained, or 2) There is a lack of behavioral modulation at high concentration of insulin attributed to the twice daily intervals of hyperinsulinemia caused by insulin IND administration without any insulin resistance, per se. Copyright © 2017 Elsevier Inc. All rights reserved.

Report on Department of Homeland Security Sponsored Research Project at Lawrence Livermore National Laboratory on Preparation for an Improvised Nuclear Device Event

DOE Office of Scientific and Technical Information (OSTI.GOV)

A., B

2008-07-31

Following the events of September 11th, a litany of imaginable horribles was trotted out before an anxious and concerned public. To date, government agencies and academics are still grappling with how to best respond to such catastrophes, and as Senator Lieberman's quote says above, now is the time to plan and prepare for such events. One of the nation's worst fears is that terrorists might detonate an improvised nuclear device (IND) in an American city. With 9/11 serving as the catalyst, the government and many NGOs have invested money into research and development of response capabilities throughout the country. Yet,more » there is still much to learn about how to best respond to an IND event. My summer 2008 internship at Lawrence Livermore National Laboratory afforded me the opportunity to look in depth at the preparedness process and the research that has been conducted on this issue. While at the laboratory I was tasked to collect, combine, and process research on how cities and the federal government can best prepare for the horrific prospect of an IND event. Specific projects that I was involved with were meeting reports, research reviews, and a full project report. Working directly with Brooke Buddemeier and his support team at the National Atmospheric Release Advisory Center, I was able to witness first hand, preparation for meetings with response planners to inform them of the challenges that an IND event would pose to the affected communities. In addition, I supported the Homeland Security Institute team (HSI), which was looking at IND preparation and preparing a Congressional report. I participated in meetings at which local responders expressed their concerns and contributed valuable information to the response plan. I specialized in the psycho-social aspects of an IND event and served as a technical advisor to some of the research groups. Alongside attending and supporting these meetings, I worked on an independent research project which collected information from across disciplines to outline where the state of knowledge on IND response is. In addition, the report looked at meetings that were held over the summer in various cities. The meetings were attended by both federal responders and local responders. The meetings explored issues regarding IND preparation and how to mitigate the effects of an IND detonation. Looking at the research and current preparation activity the report found that the state of knowledge in responding and communicating is a mixed bag. Some aspects of an IND attack are well understood, some are not, but much is left to synthesize. The effects of an IND would be devastating, yet much can be done to mitigate those effects through education, preparation, and research. A major gap in current knowledge is how to effectively communicate with the public before an attack. Little research on the effectiveness of public education has been done, but it is likely that educating the public about the effects of an IND and how to best protect oneself could save many lives.« less

The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules in glioma cells is mediated by cell cycle regulation, differentiation, and the inhibition of survival pathways

PubMed Central

Bernardi, Andressa; Frozza, Rudimar L; Hoppe, Juliana B; Salbego, Christianne; Pohlmann, Adriana R; Battastini, Ana Maria O; Guterres, Sílvia S

2013-01-01

Despite recent advances in radiotherapy, chemotherapy, and surgical techniques, glioblastoma multiforme (GBM) prognosis remains dismal. There is an urgent need for new therapeutic strategies. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intense interest in recent years because they can provide sustained, controlled, and targeted delivery. Here, we investigate the mechanisms involved in the antiproliferative effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNC) in glioma cells. IndOH-LNC were able to reduce cell viability by inducing apoptotic cell death in C6 and U138-MG glioma cell lines. Interestingly, IndOH-LNC did not affect the viability of primary astrocytes, suggesting that this formulation selectively targeted transformed cells. Mechanistically, IndOH-LNC induced inhibition of cell growth and cell-cycle arrest to be correlated with the inactivation of AKT and β-catenin and the activation of GSK-3β. IndOH-LNC also induced G0/G1 and/or G2/M phase arrest, which was accompanied by a decrease in the levels of cyclin D1, cyclin B1, pRb, and pcdc2 and an increase in the levels of Wee1 CDK inhibitor p21WAF1. Additionally, IndOH-LNC promoted GBM cell differentiation, observed as upregulation of glial fibrillary acidic protein (GFAP) protein and downregulation of nestin and CD133. Taken together, the crosstalk among antiproliferative effects, cell-cycle arrest, apoptosis, and cell differentiation should be considered when tailoring pharmacological interventions aimed at reducing glioma growth by using formulations with multiples targets, such as IndOH-LNC. PMID:23440594

Nose and vein, speed and pain: comparing the use of intranasal diamorphine and intravenous morphine in a Scottish paediatric emergency department.

PubMed

Regan, Luke; Chapman, Andrew R; Celnik, Anna; Lumsden, Lesley; Al-Soufi, Reem; McCullough, Nicola P

2013-01-01

Urgent analgesia is essential for all children who present in severe pain, but difficulties in obtaining venous access can delay the use of adequate opiate analgesia. Intranasal diamorphine (IND) is now in use in around 60% of emergency departments and is the preferred choice of analgesia as reported by both parents and healthcare professionals. While IND has similar efficacy to intramuscular morphine in children, no study has compared its use against the current gold standard, intravenous morphine (IVM). IND was introduced to the Royal Aberdeen Children's Hospital on 24 December 2009. A retrospective case series was constructed to compare its clinical performance with its predecessor IVM. Three unexplored factors were investigated: time to opiate analgesia, the requirement for further analgesia when still in the emergency department and the effect of simple coanalgesia (eg, paracetamol/ibuprofen) on these requirements. 297 patients were eligible for the study (147 IND, 150 IVM) over a 28-month period. There was a non-significant trend to a longer median time to administration of analgesia in patients receiving IND (p=0.170). Patients who received IND were less likely to require further analgesia (p<0.001). Both groups were less likely to require further analgesia when simple coanalgesia was given (p=0.049). The authors found no significant difference in time to administration of analgesia between agents, but a learning curve has been identified. Sustained effort should be placed on the use of simple coanalgesia. The clinical performance of IND compares favourably with IVM in children with severe pain, and it remains an appropriate preferred agent.

Skill Transfer and Virtual Training for IND Response Decision-Making: Models for Government-Industry Collaboration for the Development of Game-Based Training Tools

DTIC Science & Technology

2016-05-05

Training for IND Response Decision-Making: Models for Government–Industry Collaboration for the Development of Game -Based Training Tools R.M. Seater...Skill Transfer and Virtual Training for IND Response Decision-Making: Models for Government–Industry Collaboration for the Development of Game -Based...unlimited. This page intentionally left blank. iii EXECUTIVE SUMMARY Game -based training tools, sometimes called “serious games ,” are becoming

Military Review: The Professional Journal of the U.S. Army, June 2008. Special Edition: Interagency Reader

DTIC Science & Technology

2008-06-01

Company for Mechanical Ind. - Trailers , Taji 12. Nassr State Company for Mechanical Ind. - Foundry, Taji 13. Nassr State Company for Mechanical Ind...Initiatives (oTI).44 Prior to military operations in Afghanistan and Iraq, the DG worked primarily in transitional countries that had secure, receptive ...April 2002 Zogby International survey (mentioned in the GAo report) showing that Arabs and muslims had a favorable view of American movies , television

Centella asiatica Leaf Extract Protects Against Indomethacin-Induced Gastric Mucosal Injury in Rats.

PubMed

Zheng, Hong-Mei; Choi, Myung-Joo; Kim, Jae Min; Cha, Kyung Hoi; Lee, Kye Wan; Park, Yu Hwa; Hong, Soon-Sun; Lee, Don Haeng

2016-01-01

The present study evaluated the protective effect of Centella asiatica (gotu kola) leaf extract (CAE) against indomethacin (IND)-induced gastric mucosal injury in rats. Gastric mucosal injury was induced by the oral administration of IND to the rats after a 24 h fast. CAE (50 or 250 mg/kg) or lansoprazole (a reference drug) was orally administrated 30 min before the IND administration, and 5 h later, the stomachs were removed to quantify the lesions. Orally administered CAE significantly reduced IND-induced gastric injury. The histopathological observations (hematoxylin-eosin and Periodic acid-Schiff staining) confirmed the protection against gastric mucosal injury. Also, CAE decreased the malondialdehyde content compared to the control group. Moreover, pretreatment with CAE resulted in a significant reduction in the elevated expression of tumor necrosis factor, Cyclooxygenase (COX)-2, and inducible nitric oxide synthase. These results suggested that CAE possesses gastroprotective effects against IND-induced gastric mucosal injury, which could be attributed to its ability to inhibit lipid peroxidation and stimulate gastric mucus secretion in the rat gastric mucosa.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bentz, A

While the reality of an improvised nuclear device (IND) being detonated in an American city is unlikely, its destructive power is such that the scenario must be planned for. Upon reviewing the academic literature on the effects of and response to IND events, this report looks to actual responders from around the country. The results from the meetings of public officials in the cities show where gaps exist between theoretical knowledge and actual practice. In addition to the literature, the meetings reveal areas where future research needs to be conducted. This paper recommends that local response planners: meet to discussmore » the challenges of IND events; offer education to officials, the public, and responders on IND events; incorporate 'shelter-first' into response plans; provide information to the public and responders using the 3 Cs; and engage the private sector (including media) in response plans. In addition to these recommendations for the response planners, the paper provides research questions that once answered will improve response plans around the country. By following the recommendations, both groups, response planners and researchers, can help the country better prepare for and mitigate the effects of an IND detonation.« less

Rethinking individualism and collectivism: evaluation of theoretical assumptions and meta-analyses.

PubMed

Oyserman, Daphna; Coon, Heather M; Kemmelmeier, Markus

2002-01-01

Are Americans more individualistic and less collectivistic than members of other groups? The authors summarize plausible psychological implications of individualism-collectivism (IND-COL), meta-analyze cross-national and within-United States IND-COL differences, and review evidence for effects of IND-COL on self-concept, well-being, cognition, and relationality. European Americans were found to be both more individualistic-valuing personal independence more-and less collectivistic-feeling duty to in-groups less-than others. However, European Americans were not more individualistic than African Americans, or Latinos, and not less collectivistic than Japanese or Koreans. Among Asians, only Chinese showed large effects, being both less individualistic and more collectivistic. Moderate IND-COL effects were found on self-concept and relationality, and large effects were found on attribution and cognitive style.

Characterization of Three Novel SXT/R391 Integrating Conjugative Elements ICE MfuInd1a and ICE MfuInd1b, and ICE MprChn1 Identified in the Genomes of Marinomonas fungiae JCM 18476 T and Marinomonas profundimaris Strain D104

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badhai, Jhasketan; Das, Subrata K.

The genus Marinomonas comprises Gram negative bacteria which are widespread in the marine environment and there is no report on the genomic analysis of SXT/R391 ICEs derived from this group of bacteria. This study describes the genomic features of three new SXT/R391 integrating conjugating elements (ICEs) identified in the genome of Marinomonas fungiae JCM 18476 T (ICE MfuInd1a and ICE MfuInd1b) and in Marinomonas profundimaris strain D104 (ICE MprChn1). Structural organizations of the three ICEs were similar to the typical SXT/R391 family of ICEs and showed high degree of conservation in the core genes. Sequence analysis revealed ICE MfuInd1b andmore » ICE MprChn1 were inserted into the genome at 5'-end of an typical host prfC gene, while ICE MfuInd1a was inserted at 5'-end of an atypical hipA-like gene. Despite their coexistence, the ICE MfuInd1a and ICE MfuInd1b were not present in a tandem fashion in the genome of M. fungiae. Phylogenetic analyses revealed the three ICEs either evolved independently or high degrees of recombination events had masked their evolution from a common SXT ancestor. Further, we found that the typical entry exclusion mechanism mediated by the TraG/EeX protein pair was likely defective in preventing the conjugative transfer of a second copy of the same S (SXT) group ICE into the M. fungiae genome due to mutations. Our analysis showed the presence of 16, 25, and 27 variable genes in the hotspots of ICE MfuInd1a, ICE MfuInd1b, and ICE MprChn1, respectively, many of which were not reported earlier for SXT/R391 ICEs. Sequence analysis predicted these hot spot regions were shaped by acquisition of genes through homologous recombination between the SXT and R391 related ICEs or mobile genetic elements present in disparate marine bacteria. Multidrug resistance genes which are hallmark feature of SXT/R391 ICEs were not present in either of the two ICEs from M. fungiae but were present within a transposon cassette in the HS-1 of the ICE MprChn1 from M. profundimaris. Lastly, our data provided information on the genetic diversity and predicted functions encoded by variable genes present in the hotspot regions of these new ICEs.« less

Characterization of Three Novel SXT/R391 Integrating Conjugative Elements ICE MfuInd1a and ICE MfuInd1b, and ICE MprChn1 Identified in the Genomes of Marinomonas fungiae JCM 18476 T and Marinomonas profundimaris Strain D104

DOE PAGES

Badhai, Jhasketan; Das, Subrata K.

2016-11-25

The genus Marinomonas comprises Gram negative bacteria which are widespread in the marine environment and there is no report on the genomic analysis of SXT/R391 ICEs derived from this group of bacteria. This study describes the genomic features of three new SXT/R391 integrating conjugating elements (ICEs) identified in the genome of Marinomonas fungiae JCM 18476 T (ICE MfuInd1a and ICE MfuInd1b) and in Marinomonas profundimaris strain D104 (ICE MprChn1). Structural organizations of the three ICEs were similar to the typical SXT/R391 family of ICEs and showed high degree of conservation in the core genes. Sequence analysis revealed ICE MfuInd1b andmore » ICE MprChn1 were inserted into the genome at 5'-end of an typical host prfC gene, while ICE MfuInd1a was inserted at 5'-end of an atypical hipA-like gene. Despite their coexistence, the ICE MfuInd1a and ICE MfuInd1b were not present in a tandem fashion in the genome of M. fungiae. Phylogenetic analyses revealed the three ICEs either evolved independently or high degrees of recombination events had masked their evolution from a common SXT ancestor. Further, we found that the typical entry exclusion mechanism mediated by the TraG/EeX protein pair was likely defective in preventing the conjugative transfer of a second copy of the same S (SXT) group ICE into the M. fungiae genome due to mutations. Our analysis showed the presence of 16, 25, and 27 variable genes in the hotspots of ICE MfuInd1a, ICE MfuInd1b, and ICE MprChn1, respectively, many of which were not reported earlier for SXT/R391 ICEs. Sequence analysis predicted these hot spot regions were shaped by acquisition of genes through homologous recombination between the SXT and R391 related ICEs or mobile genetic elements present in disparate marine bacteria. Multidrug resistance genes which are hallmark feature of SXT/R391 ICEs were not present in either of the two ICEs from M. fungiae but were present within a transposon cassette in the HS-1 of the ICE MprChn1 from M. profundimaris. Lastly, our data provided information on the genetic diversity and predicted functions encoded by variable genes present in the hotspot regions of these new ICEs.« less

Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

PubMed Central

Choi, Jin Huk; Croyle, Maria A.

2013-01-01

Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant-virus based vectors have been identified as potent vaccine candidates with some affording both pre- and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the United States (U.S.) Food and Drug Administration (FDA) and Phase I clinical trials initiated for two small molecule therapeutics, 1) anti-sense phosphorodiamidate morphino oligomers (PMOs: AVI-6002, AVI-6003), and 2) lipid-nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms will also be discussed. PMID:23813435

TL dosimetry for quality control of CR mammography imaging systems

NASA Astrophysics Data System (ADS)

Gaona, E.; Nieto, J. A.; Góngora, J. A. I. D.; Arreola, M.; Enríquez, J. G. F.

The aim of this work is to estimate the average glandular dose with thermoluminescent (TL) dosimetry and comparison with quality imaging in computed radiography (CR) mammography. For a measuring dose, the Food and Drug Administration (FDA) and the American College of Radiology (ACR) use a phantom, so that dose and image quality are assessed with the same test object. The mammography is a radiological image to visualize early biological manifestations of breast cancer. Digital systems have two types of image-capturing devices, full field digital mammography (FFDM) and CR mammography. In Mexico, there are several CR mammography systems in clinical use, but only one system has been approved for use by the FDA. Mammography CR uses a photostimulable phosphor detector (PSP) system. Most CR plates are made of 85% BaFBr and 15% BaFI doped with europium (Eu) commonly called barium flourohalideE We carry out an exploratory survey of six CR mammography units from three different manufacturers and six dedicated X-ray mammography units with fully automatic exposure. The results show three CR mammography units (50%) have a dose greater than 3.0 mGy without demonstrating improved image quality. The differences between doses averages from TLD system and dosimeter with ionization chamber are less than 10%. TLD system is a good option for average glandular dose measurement for X-rays with a HVL (0.35-0.38 mmAl) and kVp (24-26) used in quality control procedures with ACR Mammography Accreditation Phantom.

Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting.

PubMed

Price, David; Keininger, Dorothy; Costa-Scharplatz, Madlaina; Mezzi, Karen; Dimova, Maria; Asukai, Yumi; Ställberg, Björn

2014-12-01

Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed-dose combination of indacaterol (IND), a long-acting β2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium (IND + GLY), and with the fixed-dose combination of salmeterol/fluticasone (SFC), in a moderate-to-severe COPD population with low-exacerbation risk. The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality-adjusted life year. Assuming equal efficacy, a cost-minimisation analysis compared IND/GLY vs IND + GLY using model inputs from the double-blind, randomised SHINE trial. The double-blind, randomised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC. To consider ICS-related pneumonia events, published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used. Direct and indirect drug costs as well as drug acquisition costs (in Swedish Krona [SEK]) were derived from published Swedish sources. Cost and effects were discounted with 3%. Uncertainty was assessed by one-way and probabilistic sensitivity analyses (PSA). IND/GLY was cost-saving vs IND + GLY with incremental savings of SEK (EUR) 768 (85), and 3309 (368) per patient over one and five years. IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK (EUR) 2744 (303), 8854 (976), 13,938 (1536), 27,495 (3031) and 43,033 (4744) over one, three, five, ten years and lifetime. The PSA indicated that all iterations produced dominant results for IND/GLY. IND/GLY is cost-minimising vs IND + GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden. Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

76 FR 20588 - FDA Food Safety Modernization Act: Focus on Preventive Controls for Facilities; Public Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-13

.... FDA-2011-N-0251] FDA Food Safety Modernization Act: Focus on Preventive Controls for Facilities... comment. SUMMARY: The Food and Drug Administration (FDA) is announcing a public meeting entitled ``FDA... controls for facilities provisions of the recently enacted FDA Food Safety Modernization Act (FSMA). FDA is...

Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16(INK4a) gene in human colorectal carcinoma (Caco-2) cells.

PubMed

Naselli, Flores; Tesoriere, Luisa; Caradonna, Fabio; Bellavia, Daniele; Attanzio, Alessandro; Gentile, Carla; Livrea, Maria A

2014-07-18

Phytochemicals may exert chemo-preventive effects on cells of the gastro-intestinal tract by modulating epigenome-regulated gene expression. The effect of the aqueous extract from the edible fruit of Opuntia ficus-indica (OFI extract), and of its betalain pigment indicaxanthin (Ind), on proliferation of human colon cancer Caco-2 cells has been investigated. Whole extract and Ind caused a dose-dependent apoptosis of proliferating cells at nutritionally relevant amounts, with IC50 400±25 mg fresh pulp equivalents/mL, and 115±15 μM (n=9), respectively, without toxicity for post-confluent differentiated cells. Ind accounted for ∼80% of the effect of the whole extract. Ind did not cause oxidative stress in proliferating Caco-2 cells. Epigenomic activity of Ind was evident as de-methylation of the tumor suppressor p16(INK4a) gene promoter, reactivation of the silenced mRNA expression and accumulation of p16(INK4a), a major controller of cell cycle. As a consequence, decrease of hyper-phosphorylated, in favor of the hypo-phosphorylated retinoblastoma was observed, with unaltered level of the cycline-dependent kinase CDK4. Cell cycle showed arrest in the G2/M-phase. Dietary cactus pear fruit and Ind may have chemo-preventive potential in intestinal cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Dietary indicaxanthin from cactus pear (Opuntia ficus-indica L. Mill) fruit prevents eryptosis induced by oxysterols in a hypercholesterolaemia-relevant proportion and adhesion of human erythrocytes to endothelial cell layers.

PubMed

Tesoriere, Luisa; Attanzio, Alessandro; Allegra, Mario; Livrea, Maria A

2015-08-14

Toxic oxysterols in a hypercholesterolaemia-relevant proportion cause suicidal death of human erythrocytes or eryptosis. This process proceeds through early production of reactive oxygen species (ROS), release of prostaglandin (PGE2) and opening of PGE2-dependent Ca channels, membrane phosphatidylserine (PS) externalisation, and cell shrinkage. The present study was the first to reveal that a bioavailable phytochemical, indicaxanthin (Ind) from cactus pear fruit, in a concentration range (1.0-5.0 μM) consistent with its plasma level after a fruit meal, prevents PS externalisation and cell shrinkage in a dose-dependent manner when incubated with isolated healthy human erythrocytes exposed to an oxysterol mixture for 48 h. Dietary Ind inhibited ROS production, glutathione (GSH) depletion, PGE2 release and Ca2+ entry. Ind alone did not modify the erythrocyte redox environment or affect other parameters. Ex vivo spiking of normal human blood with the oxysterol mixture for 48 h induced eryptosis, resulting in the production of ROS and decreased levels of GSH, which was prevented by concurrent exposure to 5 μm-Ind. The adherence of eryptotic erythrocytes to the endothelium causes vascular tissue injury. Erythrocytes isolated from blood incubated with the oxysterol mixture plus 5 μm-Ind did not adhere to endothelial cell monolayers. Eryptotic erythrocytes may contribute to thrombotic complications in hypercholesterolaemia. Our findings suggest the positive effects of diets containing Ind on erythrocytes in hypercholesterolaemic subjects.

IndeCut evaluates performance of network motif discovery algorithms.

PubMed

Ansariola, Mitra; Megraw, Molly; Koslicki, David

2018-05-01

Genomic networks represent a complex map of molecular interactions which are descriptive of the biological processes occurring in living cells. Identifying the small over-represented circuitry patterns in these networks helps generate hypotheses about the functional basis of such complex processes. Network motif discovery is a systematic way of achieving this goal. However, a reliable network motif discovery outcome requires generating random background networks which are the result of a uniform and independent graph sampling method. To date, there has been no method to numerically evaluate whether any network motif discovery algorithm performs as intended on realistically sized datasets-thus it was not possible to assess the validity of resulting network motifs. In this work, we present IndeCut, the first method to date that characterizes network motif finding algorithm performance in terms of uniform sampling on realistically sized networks. We demonstrate that it is critical to use IndeCut prior to running any network motif finder for two reasons. First, IndeCut indicates the number of samples needed for a tool to produce an outcome that is both reproducible and accurate. Second, IndeCut allows users to choose the tool that generates samples in the most independent fashion for their network of interest among many available options. The open source software package is available at https://github.com/megrawlab/IndeCut. megrawm@science.oregonstate.edu or david.koslicki@math.oregonstate.edu. Supplementary data are available at Bioinformatics online.

Drugs@FDA: FDA Approved Drug Products

MedlinePlus

... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing ... Download Drugs@FDA Express for free Search by Drug Name, Active Ingredient, or Application Number Enter at ...

Seagrass species distribution, density and coverage at Panggang Island, Jakarta

NASA Astrophysics Data System (ADS)

Wahab, Iswandi; Madduppa, Hawis; Kawaroe, Mujizat

2017-01-01

This study aimed to assess species distribution, density and coverage of seagrass in Panggang Island, within Kepulauan Seribu Marine National Park, northern Jakarta. Seagrass sampling was conducted between March to April 2016 at three observation stations in the West, East, and South of Panggang Island. A total of 6 seagrass species was recorded during sampling period, including Cymodocea rotundata, C. serulata, Halodule uninervis, Syiringodium isoetifolium, Enhalus acoroides, and Thalassia hempricii. All species were observed in the South station, while in the West and East station found only three species (C. rotundata, E. acoroides, and T. hemprichii). While, C. rotundata and T. hemprichii were observed at all station. The highest density was observed for C. rotundata (520 ind/m2) and for T. hempricii (619 ind/m2) in the West station and South Station, respectively. The lowest density was observed in South Station for C. serulata (18 ind/m2), Halodule uninervis (20 ind/m2), and Syiringodium isoetifolium (15 ind/m2). Seagrass coverage of Thalassia hempricii was the highest (43.60%) and the lowest observed at Syiringodium isoetifolium (0.40%). This could be basic information for the management of seagrass ecosystem in the Kepulauan Seribu Marine National Park.

Influence of the cooling rate and the blend ratio on the physical stability of co-amorphous naproxen/indomethacin.

PubMed

Beyer, Andreas; Grohganz, Holger; Löbmann, Korbinian; Rades, Thomas; Leopold, Claudia S

2016-12-01

Co-amorphization represents a promising approach to increase the physical stability and dissolution rate of amorphous active pharmaceutical ingredients (APIs) as an alternative to polymer glass solutions. For amorphous and co-amorphous systems, it is reported that the preparation method and the blend ratio play major roles with regard to the resulting physical stability. Therefore, in the present study, co-amorphous naproxen-indomethacin (NAP/IND) was prepared by melt-quenching at three different cooling rates and at ten different NAP/IND blend ratios. The samples were analyzed using XRPD and FTIR, both directly after preparation and during storage to investigate their physical stabilities. All cooling methods led to fully amorphous samples, but with significantly different physical stabilities. Samples prepared by fast cooling had a higher degree of crystallinity after 300d of storage than samples prepared by intermediate cooling and slow cooling. Intermediate cooling was subsequently used to prepare co-amorphous NAP/IND at different blend ratios. In a previous study, it was postulated that the equimolar (0.5:0.5) co-amorphous blend of NAP/IND is most stable. However, in the present study the physically most stable blend was found for a NAP/IND ratio of 0.6:0.4, which also represents the eutectic composition of the crystalline NAP/γ-IND system. This indicates that the eutectic point may be of major importance for the stability of binary co-amorphous systems. Slight deviations from the optimal naproxen molar fraction led to significant recrystallization during storage. Either naproxen or γ-indomethacin recrystallized until a naproxen molar fraction of about 0.6 in the residual co-amorphous phase was reached again. In conclusion, the physical stability of co-amorphous NAP/IND may be significantly improved, if suitable preparation conditions and the optimal phase composition are chosen. Copyright © 2016 Elsevier B.V. All rights reserved.

21 CFR 312.22 - General principles of the IND submission.

Code of Federal Regulations, 2014 CFR

2014-04-01

... other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting...-investigator who uses, as a research tool, an investigational new drug that is already subject to a...

21 CFR 312.22 - General principles of the IND submission.

Code of Federal Regulations, 2013 CFR

2013-04-01

... other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting...-investigator who uses, as a research tool, an investigational new drug that is already subject to a...

21 CFR 312.22 - General principles of the IND submission.

Code of Federal Regulations, 2011 CFR

2011-04-01

... other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting...-investigator who uses, as a research tool, an investigational new drug that is already subject to a...

21 CFR 312.22 - General principles of the IND submission.

Code of Federal Regulations, 2012 CFR

2012-04-01

... other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting...-investigator who uses, as a research tool, an investigational new drug that is already subject to a...

One-step continuous extrusion process for the manufacturing of solid dispersions.

PubMed

Maniruzzaman, M; Nair, A; Scoutaris, N; Bradley, Michael S A; Snowden, M J; Douroumis, D

2015-12-30

The purpose of this study was to evaluate the performance of synthetic magnesium aluminometasilicate (MAS) as a novel inorganic carrier in hot melt extrusion (HME) processing of indomethacin (IND) for the development of solid dispersions. A continuous extrusion process at various IND/excipient blend ratios (20%, 30% and 40%) was performed using a twin-screw extruder. Physicochemical characterization carried out by SEM, DSC, and XRPD demonstrated the presence of IND in amorphous nature within the porous network of the inorganic material for all extruded formulations. Further, AFM and FTIR studies revealed a single-phase amorphous system and intermolecular H-bonding formation. The IND/MAS extrudates showed enhanced INM dissolution rates within 100% been released within 1h. Stability studies under accelerated conditions (40°C, RH 75%) showed that MAS retained the physical stability of the amorphous solid dispersions even at high drug loadings for 12 months. Copyright © 2015 Elsevier B.V. All rights reserved.

[Effects of eutrophication on distribution and population density of Corbicula fluminea and Bellamya sp. in Chaohu Lake].

PubMed

Deng, Daogui; Li, Hongyuan; Hu, Wanming; Zhou, Qiong; Guo, Longgen

2005-08-01

The investigation on the distribution an d population density of C. fluminea and Bellamya sp. in Chaohu Lake during September 2001 and September 2002 showed that in the west region of the lake where was seriously eutrophic, the density and biomass of C. fluminea were 5.1 ind. x m(-2) and 17.87 g x m(-2) in 2001, and 8.8 ind. x m(-2) and 47.29 g x m(-2) in 2002, while those of Bellamya sp. were 13.3 ind. x m(-2) and 45.45 g x m(-2) in 2001, and 3.8 ind. x m(-2) and 12.56 g x m(-2) in 2002, respectively. In the east region of the lake where was eutrophic, the density and biomass of C. fluminea were 23.8 ind. x m(-2) and 67.86 g x m(-2) in 2001, and 29.2 ind. x m(-2) and 96.18 g x m(-2) in 2002, while those of Bellamya sp. were 10.1 ind. x m(-2) and 32.00 g x m(-2) in 2001, and 9.4 ind. x m(-2) and 31.21 g x m(-2) in 2002, respectively. The density and biomass of C. fluminea and Bellamya sp. were declined with increasing eutrophication. In hypertrophic region, C. fluminea and Bellamya sp. were absent. The density and biomass of the two species were obviously higher in littoral than in pelagic region. The distribution type of C. fluminea was core-model, while that of Bellamya sp. was random. The correlation between the density and biomass of C. fluminea and Bellamya sp. and water depth was not significant (P > 0.05). The biomass of Bellamya sp. was negatively correlated with water TN (P < 0.01), NO3-N (P < 0.05), TP(P < 0.01) and PO4-P (P < 0.05), while that of C. fluminea only had a significantly negative correlation with PO4-P(P < 0.05). Compared with 1981, there was fewer C. fluminea in the lake nowadays. The effects of other environmental factors on the population distribution and growth of C. fluminea and Bellamya sp. were also discussed.

78 FR 19715 - Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-02

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-1153] Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish Pilot Projects and...: The Food and Drug Administration (FDA) is extending the comment period for the notice entitled...

Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects.

PubMed

Prasad, Dev; Chauhan, Harsh; Atef, Eman

2014-11-01

The purpose of this study was to understand the combined effect of two polymers showing drug-polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%-40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug-polymer interaction offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Amorphization within the tablet: Using microwave irradiation to form a glass solution in situ.

PubMed

Doreth, Maria; Hussein, Murtadha Abdul; Priemel, Petra A; Grohganz, Holger; Holm, René; Lopez de Diego, Heidi; Rades, Thomas; Löbmann, Korbinian

2017-03-15

In situ amorphization is a concept that allows to amorphize a given drug in its final dosage form right before administration. Hence, this approach can potentially be used to circumvent recrystallization issues that other amorphous formulation approaches are facing during storage. In this study, the feasibility of microwave irradiation to prepare amorphous solid dispersions (glass solutions) in situ was investigated. Indomethacin (IND) and polyvinylpyrrolidone K12 (PVP) were tableted at a 1:2 (w/w) ratio. In order to study the influence of moisture content and energy input on the degree of amorphization, tablet formulations were stored at different relative humidity (32, 43 and 54% RH) and subsequently microwaved using nine different power-time combinations up to a maximum energy input of 90kJ. XRPD results showed that up to 80% (w/w) of IND could be amorphized within the tablet. mDSC measurements revealed that with increasing microwaving power and time, the fractions of crystalline IND and amorphous PVP reduced, whereas the amount of in situ formed IND-PVP glass solution increased. Intrinsic dissolution showed that the dissolution rate of the microwaved solid dispersion was similar to that of a quench cooled, fully amorphous glass solution even though the microwaved samples contained residual crystalline IND. Copyright © 2017 Elsevier B.V. All rights reserved.

Low-Dose Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-Resistant or Contraindicated Preterm Infants: Three Cases Reports.

PubMed

Matsumura, Shun; Oshima, Ayumi; Fujinuma, Sumie; Tanaka, Kosuke; Nagano, Nobuhiko; Miyake, Fuyu; Masutani, Satoshi; Tamura, Masanori; Ueda, Keiko; Namba, Fumihiko

2017-10-01

Background  Although indomethacin (IND) is the standard treatment for hemodynamically significant patent ductus arteriosus (hsPDA) in Japan, it may be associated with renal impairment and gastrointestinal complications. The use of paracetamol for hsPDA closure has recently increased. Unlike IND, paracetamol does not have a peripheral vasoconstrictive effect and can be given to infants with contraindications to IND. Based on limited data available from randomized trials, paracetamol and IND seem to have similar effects. However, there have been no reports of the use of paracetamol for hsPDA in Japan. Cases  Our drug administration protocol was approved by the institutional ethics committee after purchasing a clinical trial insurance. In three premature infants in whom IND was contraindicated or ineffective, a 7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days after obtaining parental consents. A temporary hsPDA closure was observed in two of the three infants. However, all three infants eventually needed surgical closure. No side effects, such as hepatic and renal dysfunctions, and adverse events were reported. Conclusion  The intravenous administration of paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials with optimized dose and timing of administration are needed.

77 FR 14404 - Guidance for the Public, Food and Drug Administration (FDA) Advisory Committee Members, and FDA...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2002-D-0094; (formerly Docket No. 02D-0049)] Guidance for the Public, Food and Drug Administration (FDA) Advisory... Food and Drug Administration (FDA) is announcing the availability of a guidance for the public, FDA...

78 FR 950 - Medical Devices; Availability of Safety and Effectiveness Summaries for Premarket Approval...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-07

..., FDA- 2012-M-0965, FDA-2012-M-0968, FDA-2012-M-1011, and FDA-2012-M-1013] Medical Devices; Availability...\\ February 16, 2011. Adjustable Gastric Banding System. P100049, FDA-2012-M-0893....... Torax Medical, Inc.... Trabecular Micro- Bypass Stent and Inserter. P110007, FDA-2012-M-0734....... Abbott Medical Healon[supreg...

75 FR 76992 - Guidance for the Public, FDA Advisory Committee Members, and FDA Staff: The Open Public Hearing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-10

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2005-D-0072] (formerly Docket No. 2005D-0042) Guidance for the Public, FDA Advisory Committee Members, and FDA Staff: The Open Public Hearing at FDA Advisory Committee Meetings; Availability AGENCY: Food and Drug...

78 FR 14309 - Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-05

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-1153] Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish Pilot Projects and... information. SUMMARY: In September 2011, the Food and Drug Administration (FDA or the Agency) asked the...

Perceptions of the Food and Drug Administration as a Tobacco Regulator

PubMed Central

Jarman, Kristen L.; Ranney, Leah M.; Baker, Hannah M.; Vallejos, Quirina M.; Goldstein, Adam O.

2017-01-01

Objectives The U. S. Food and Drug Administration (FDA) now has regulatory authority over all tobacco products. Little is known about public awareness and perceptions of FDA in their new role as a tobacco regulator. This research utilizes focus groups to examine perceptions of FDA as a tobacco regulator so that FDA can better communicate with the public about this role. Methods We conducted 6 focus groups in 2014 among a diverse sample of smokers and non-smokers. Participants were asked if they had heard of FDA, what they knew about FDA, if they associated FDA with tobacco, and their thoughts about this FDA role. Results A total of 41 individuals participated. Although nearly all participants had heard of FDA, most were not aware of FDA’s regulatory authority over tobacco products, did not associate the role of FDA with tobacco, and some drew comparisons between FDA’s work in tobacco and their work regulating food and drugs. Conclusion Data suggest that although public awareness of FDA regulatory authority over tobacco is low, with proper public education, the public may find FDA to be a trustworthy source of tobacco regulation. PMID:29051917

Cost-effectiveness of indacaterol/glycopyrronium in comparison with salmeterol/fluticasone combination for patients with moderate-to-severe chronic obstructive pulmonary disease: a LANTERN population analysis from Singapore.

PubMed

Tee, Augustine; Chow, Wai Leng; Burke, Colin; Basavarajaiah, Guruprasad

2018-03-16

In light of the growing evidence base for better clinical results with the use of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) over inhaled corticosteroid-containing salmeterol/fluticasone combination (SFC), this study aimed to evaluate the cost-effectiveness of IND/GLY over SFC in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who are at low risk of exacerbations in the Singapore healthcare setting. A previously published patient-level simulation model was adapted for use in Singapore by applying local unit costs. The model was populated with clinical data from the LANTERN and ECLIPSE studies. Both costs and health outcomes were predicted for the lifetime horizon from a payer's perspective and were discounted at 3% per annum. Costs were expressed in 2015 USD. Uncertainty was assessed through probabilistic sensitivity analysis. Compared to SFC, use of IND/GLY increased mean life expectancy by 0.316 years and mean quality-adjusted life-years (QALYs) by 0.246 years, and decreased mean total treatment costs (drug costs and management of associated events) by USD 1,474 over the entire lifetime horizon. IND/GLY was considered to be 100% cost-effective at a threshold of 1 × gross domestic product per capita. The probabilistic sensitivity analysis results showed that IND/GLY was 100% cost-effective at a threshold of USD 2,000 when compared to SFC. IND/GLY was estimated to be highly cost-effective compared to SFC in patients with moderate-to-severe COPD who are not at high risk of exacerbations in the Singapore healthcare setting.

Central and peripheral haemodynamic effects of non-steroidal anti-inflammatory drugs in man.

PubMed

Wennmalm, A; Carlsson, I; Edlund, A; Eriksson, S; Kaijser, L; Nowak, J

1984-01-01

The haemodynamic effects of non-steroidal anti-inflammatory (NSAI) drugs can be attributed either to their common property of inhibiting the formation of prostaglandins (PG) in the cardiovascular system, or to direct actions on the tone and sensitivity of the resistance vessels in various regions. Indomethacin (IND) is the most frequently studied NSAI drug, in animals and in man. Its cardiovascular effects differ somewhat from those of other NSAI, due to the fact that, besides inhibiting PG formation, IND acts as a direct vasoconstrictor. The stimulatory effect of IND in vascular smooth muscle results in an increased systemic vascular resistance which, although partially compensated by a decreased cardiac output, gives rise to a moderate increase in systemic blood pressure. The vasoconstrictor effect of IND is of particular interest in patients with ischemic heart disease, since it lowers their already decreased coronary flow, and may thereby accentuate the risk of myocardial infarction. Administration of IND also leads to a decreased blood flow in the splanchnic region, the kidneys, and the brain. The cerebral blood flow is lowered by 25-35%; in addition, IND almost entirely erases the hyperemic flow response to hypercapnia. Of other NSAI drugs, at least aspirin and naproxen are completely devoid of such actions on the cerebral circulation. A common vascular effect of all NSAI drugs is a diminution of reactive hyperemia, the local hyperemia that develops in a tissue subjected to a short period of arterial occlusion. Part of this hyperemic response is dependent on an intact vascular PG formation and consequently it is inhibited when PG formation is blocked. In contrast, NSAI drugs do not affect the functional increase in the blood flow in working skeletal muscle.

Anti-inflammatory polymersomes of redox-responsive polyprodrug amphiphiles with inflammation-triggered indomethacin release characteristics.

PubMed

Tan, Jiajia; Deng, Zhengyu; Liu, Guhuan; Hu, Jinming; Liu, Shiyong

2018-03-21

Inflammation serves as a natural defense mechanism to protect living organisms from infectious diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) can help relieve inflammatory reactions and are clinically used to treat pain, fever, and inflammation, whereas long-term use of NSAIDs may lead to severe side effects including gastrointestinal damage and cardiovascular toxicity. Therefore, it is of increasing importance to configure new dosing strategies and alleviate the side effects of NSAIDs. Towards this goal, glutathione (GSH)-responsive disulfide bonds and hydrogen peroxide (H 2 O 2 )-reactive phenylboronic ester linkages were utilized as triggering moieties in this work to design redox-responsive prodrug monomers and polyprodrug amphiphiles based on indomethacin (IND) drug. Note that IND is a widely prescribed NSAID in the clinic. Starting from three types of redox-reactive IND prodrug monomers, redox-responsive polyprodrug amphiphiles were synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerizations of prodrug monomers using poly(ethylene oxide) (PEO)-based macroRAFT agent. The resultant polyprodrug amphiphiles with high IND loading contents (>33 wt%) could self-assemble into polymersomes with PEO shielding coronas and redox-responsive bilayer membranes composed of IND prodrugs. Upon incubation with GSH or H 2 O 2 , controlled release of intact IND in the active form from polyprodrug polymersomes was actuated by GSH-mediated disulfide cleavage reaction and H 2 O 2 -mediated oxidation of phenylboronic ester moieties, respectively, followed by self-immolative degradation events. Furthermore, in vitro studies at the cellular level revealed that redox-responsive polymersomes could efficiently relieve inflammatory responses induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells. Copyright © 2018. Published by Elsevier Ltd.

21 CFR 312.140 - Address for correspondence.

Code of Federal Regulations, 2012 CFR

2012-04-01

... biological products regulated by CBER. Send the IND submission to the Document Control Center (HFM-99... North VII, 7620 Standish Pl., Rockville, MD 20855. (2) For biological products regulated by CDER. Send the IND submission to the CDER Therapeutic Biological Products Document Room, Center for Drug...

21 CFR 312.140 - Address for correspondence.

Code of Federal Regulations, 2013 CFR

2013-04-01

... biological products regulated by CBER. Send the IND submission to the Document Control Center (HFM-99... North VII, 7620 Standish Pl., Rockville, MD 20855. (2) For biological products regulated by CDER. Send the IND submission to the CDER Therapeutic Biological Products Document Room, Center for Drug...

Targeted Nanodiamonds as Phenotype Specific Photoacoustic Contrast Agents for Breast Cancer

PubMed Central

Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

2015-01-01

Aim The aim is to develop irradiated nanodiamonds (INDs) as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. Materials & Methods The surface of acid treated radiation-damaged nanodiamonds was grafted with polyethylene glycol (PEG) to improve its stability and circulation time in blood, followed by conjugation to an anti-Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) with a final nanoparticle size of ca. 92 nm. Immunocompetent mice bearing orthotopic HER2 positive or negative tumors were administered INDs and PA imaged using an 820-nm near infrared laser. Results PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 hours. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are non-toxic. Conclusions PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype specific monitoring of cancer growth. PMID:25723091

Latent fingermark development on a range of porous substrates using ninhydrin analogs--a comparison with ninhydrin and 1,8-diazofluoren.

PubMed

Berdejo, Stephanie; Rowe, Mark; Bond, John W

2012-03-01

Three relatively new reagents for developing latent fingermarks on porous substrates, 1,2-indandione (IND), 5-methylthioninhydrin (5-MTN), and lawsone, are compared with the more widely used ninhydrin and 1,8-diazofluoren (DFO). Developed latent fingermark visualization on 10 different substrates comprising colored papers, cardboard, and cellophane rather than conventional printer and writing/notepad paper is assessed using latent fingermark deposits from 48 donors. Results show improved fluorescent fingermark visualization using IND compared with DFO on a range of colored cardboards and thick white paper, thus extending the range of substrates known to yield improved visualization with IND. Adding zinc chloride to IND failed to yield any further improvement in fluorescent fingermark visualization. 5-MTN (with and without zinc chloride posttreatment) showed no improvement in visualization compared with ninhydrin and DFO although visible fingermarks were developed. Lawsone produced fluorescent visible fingermarks only with white substrates, which were inferior to those produced with DFO. © 2011 American Academy of Forensic Sciences.

Distribution of the planktonic shrimp Lucifer (Thompson, 1829) (Decapoda, Sergestoidea) off the Amazon.

PubMed

Melo, N F A C; Neumann-Leitão, S; Gusmão, L M O; Martins-Neto, F E; Palheta, G D A

2014-08-01

Lucifer faxoni (BORRADAILE, 1915) and L. typus (EDWARDS, 1837) are species first identified in the neritic and oceanic waters off the Amazon. Samplings were made aboard the vessel "Antares" at 22 stations in July and August, 2001 with a bongo net (500-µm mesh size). Hydrological data were taken simultaneously for comparative purposes. L. faxoni was present at thirteen of the fourteen neritic stations analysed, as well as at five of the eight oceanic stations. L. typus was present at three of the fourteen neritic stations and in one of the eight oceanic stations. The highest density of L. faxoni in the neritic province was 7,000 ind.m(-3) (St. 82) and 159 ind.m(-3) (St. 75) in the oceanic area. For L. typus, the highest density observed was 41 ind.m(-3) (St. 64) in the neritic province. In the oceanic province, the highest single density value was recorded at station 75 (5 ind.m(-3)). Overall, L. faxoni typically presented the highest densities.

Assembled nanomedicines as efficient and safe therapeutics for articular inflammation.

PubMed

Che, Ling; Zhou, Jianzhi; Li, Shuhui; He, Hongmei; Zhu, Yuxuan; Zhou, Xing; Jia, Yi; Liu, Yao; Zhang, Jianxiang; Li, Xiaohui

2012-12-15

Highly efficient nanomedicines were successfully fabricated by the indomethacin (IND) directed self-assembly of β-cyclodextrin (β-CD)-conjugated polyethyleneimine (PEI-CD), taking advantage of the multiple interactions between drug and polymer. These nanoscaled assemblies exhibited spherical shape and positively charged surface. Compared with the commercial tablet, the relative oral bioavailability of IND-nanomedicines was significantly enhanced. Evaluation based on either carrageenan-induced paw edema or complete Freund's adjuvant (CFA)-induced arthritis suggested the newly developed nanomedicines were more effective than raw IND or IND tablet in terms of prophylactic effect and therapeutic activity. Even the low dose of nanomedicines offered the comparable results to those of control groups at the high dosage in most cases. Moreover, the nanoformulation exhibited ameliorated gastrointestinal stimulation. All these positive results indicated that this type of nanomedicines might serve as a highly efficient and effective delivery nanoplatform for the oral delivery of water-insoluble therapeutics. Copyright © 2012 Elsevier B.V. All rights reserved.

Imperfect duplicate insertions type of mutations in plasmepsin V modulates binding properties of PEXEL motifs of export proteins in Indian Plasmodium vivax.

PubMed

Rawat, Manmeet; Vijay, Sonam; Gupta, Yash; Tiwari, Pramod Kumar; Sharma, Arun

2013-01-01

Plasmepsin V (PM-V) have functionally conserved orthologues across the Plasmodium genus who's binding and antigenic processing at the PEXEL motifs for export about 200-300 essential proteins is important for the virulence and viability of the causative Plasmodium species. This study was undertaken to determine P. vivax plasmepsin V Ind (PvPM-V-Ind) PEXEL motif export pathway for pathogenicity-related proteins/antigens export thereby altering plasmodium exportome during erythrocytic stages. We identify and characterize Plasmodium vivax plasmepsin-V-Ind (mutant) gene by cloning, sequence analysis, in silico bioinformatic protocols and structural modeling predictions based on docking studies on binding capacity with PEXEL motifs processing in terms of binding and accessibility of export proteins. Cloning and sequence analysis for genetic diversity demonstrates PvPM-V-Ind (mutant) gene is highly conserved among all isolates from different geographical regions of India. Imperfect duplicate insertion types of mutations (SVSE from 246-249 AA and SLSE from 266-269 AA) were identified among all Indian isolates in comparison to P.vivax Sal-1 (PvPM-V-Sal 1) isolate. In silico bioinformatics interaction studies of PEXEL peptide and active enzyme reveal that PvPM-V-Ind (mutant) is only active in endoplasmic reticulum lumen and membrane embedding is essential for activation of plasmepsin V. Structural modeling predictions based on docking studies with PEXEL motif show significant variation in substrate protein binding of these imperfect mutations with data mined PEXEL sequences. The predicted variation in the docking score and interacting amino acids of PvPM-V-Ind (mutant) proteins with PEXEL and lopinavir suggests a modulation in the activity of PvPM-V in terms of binding and accessibility at these sites. Our functional modeled validation of PvPM-V-Ind (mutant) imperfect duplicate insertions with data mined PEXEL sequences leading to altered binding and substrate accessibility of the enzyme makes it a plausible target to investigate export mechanisms for in silico virtual screening and novel pharmacophore designing.

Imperfect Duplicate Insertions Type of Mutations in Plasmepsin V Modulates Binding Properties of PEXEL Motifs of Export Proteins in Indian Plasmodium vivax

PubMed Central

Rawat, Manmeet; Vijay, Sonam; Gupta, Yash; Tiwari, Pramod Kumar; Sharma, Arun

2013-01-01

Introduction Plasmepsin V (PM-V) have functionally conserved orthologues across the Plasmodium genus who's binding and antigenic processing at the PEXEL motifs for export about 200–300 essential proteins is important for the virulence and viability of the causative Plasmodium species. This study was undertaken to determine P. vivax plasmepsin V Ind (PvPM-V-Ind) PEXEL motif export pathway for pathogenicity-related proteins/antigens export thereby altering plasmodium exportome during erythrocytic stages. Method We identify and characterize Plasmodium vivax plasmepsin-V-Ind (mutant) gene by cloning, sequence analysis, in silico bioinformatic protocols and structural modeling predictions based on docking studies on binding capacity with PEXEL motifs processing in terms of binding and accessibility of export proteins. Results Cloning and sequence analysis for genetic diversity demonstrates PvPM-V-Ind (mutant) gene is highly conserved among all isolates from different geographical regions of India. Imperfect duplicate insertion types of mutations (SVSE from 246–249 AA and SLSE from 266–269 AA) were identified among all Indian isolates in comparison to P.vivax Sal-1 (PvPM-V-Sal 1) isolate. In silico bioinformatics interaction studies of PEXEL peptide and active enzyme reveal that PvPM-V-Ind (mutant) is only active in endoplasmic reticulum lumen and membrane embedding is essential for activation of plasmepsin V. Structural modeling predictions based on docking studies with PEXEL motif show significant variation in substrate protein binding of these imperfect mutations with data mined PEXEL sequences. The predicted variation in the docking score and interacting amino acids of PvPM-V-Ind (mutant) proteins with PEXEL and lopinavir suggests a modulation in the activity of PvPM-V in terms of binding and accessibility at these sites. Conclusion/Significance Our functional modeled validation of PvPM-V-Ind (mutant) imperfect duplicate insertions with data mined PEXEL sequences leading to altered binding and substrate accessibility of the enzyme makes it a plausible target to investigate export mechanisms for in silico virtual screening and novel pharmacophore designing. PMID:23555891

Targeting human prostate cancer with 111In-labeled D2B IgG, F(ab')2 and Fab fragments in nude mice with PSMA-expressing xenografts.

PubMed

Lütje, Susanne; van Rij, Catharina M; Franssen, Gerben M; Fracasso, Giulio; Helfrich, Wijnand; Eek, Annemarie; Oyen, Wim J; Colombatti, Marco; Boerman, Otto C

2015-01-01

D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab')2 and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing subcutaneous prostate cancer xenografts. The optimal time point for imaging was determined in biodistribution and microSPECT imaging studies with (111)In-D2B IgG, (111)In-capromab pendetide, (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments in mice with PSMA-expressing LNCaP and PSMA-negative PC3 tumors at several time points after injection. All (111)In-labeled antibody formats specifically accumulated in the LNCaP tumors, with highest uptake of (111)In-D2B IgG and (111)In-capromab pendetide at 168 h p.i. (94.8 ± 19.2% injected dose per gram (ID/g) and 16.7 ± 2.2% ID/g, respectively), whereas uptake of (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments peaked at 24 h p.i. (12.1 ± 3.0% ID/g and 15.1 ± 2.9% ID/g, respectively). Maximum LNCaP tumor-to-blood ratios were 13.0 ± 2.3 (168 h p.i.), 6.2 ± 0.7 (24 h p.i.), 23.0 ± 4.0 (24 h p.i.) and 4.5 ± 0.6 (168 h p.i.) for (111)In-D2B IgG, (111)In-F(ab')2, (111)In-Fab and (111)In-capromab pendetide, respectively. LNCaP tumors were clearly visualized with microSPECT with all antibody formats. This study demonstrates the feasibility of D2B IgG, F(ab')2 and Fab fragments for targeting PSMA-expressing prostate cancer xenografts. Copyright © 2014 John Wiley & Sons, Ltd.

Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers.

PubMed

Borad, Mitesh J; Egan, Jan B; Condjella, Rachel M; Liang, Winnie S; Fonseca, Rafael; Ritacca, Nicole R; McCullough, Ann E; Barrett, Michael T; Hunt, Katherine S; Champion, Mia D; Patel, Maitray D; Young, Scott W; Silva, Alvin C; Ho, Thai H; Halfdanarson, Thorvardur R; McWilliams, Robert R; Lazaridis, Konstantinos N; Ramanathan, Ramesh K; Baker, Angela; Aldrich, Jessica; Kurdoglu, Ahmet; Izatt, Tyler; Christoforides, Alexis; Cherni, Irene; Nasser, Sara; Reiman, Rebecca; Cuyugan, Lori; McDonald, Jacquelyn; Adkins, Jonathan; Mastrian, Stephen D; Valdez, Riccardo; Jaroszewski, Dawn E; Von Hoff, Daniel D; Craig, David W; Stewart, A Keith; Carpten, John D; Bryce, Alan H

2016-12-23

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1-3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.

21 CFR 314.102 - Communications between FDA and applicants.

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2012-04-01

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Implementation of transmission NIR as a PAT tool for monitoring drug transformation during HME processing.

PubMed

Islam, Muhammad T; Scoutaris, Nikolaos; Maniruzzaman, Mohammed; Moradiya, Hiren G; Halsey, Sheelagh A; Bradley, Michael S A; Chowdhry, Babur Z; Snowden, Martin J; Douroumis, Dennis

2015-10-01

The aim of the work reported herein was to implement process analytical technology (PAT) tools during hot melt extrusion (HME) in order to obtain a better understanding of the relationship between HME processing parameters and the extruded formulations. For the first time two in-line NIR probes (transmission and reflectance) have been coupled with HME to monitor the extrusion of the water insoluble drug indomethacin (IND) in the presence of Soluplus (SOL) or Kollidon VA64 hydrophilic polymers. In-line extrusion monitoring of sheets, produced via a specially designed die, was conducted at various drug/polymer ratios and processing parameters. Characterisation of the extruded transparent sheets was also undertaken by using DSC, XRPD and Raman mapping. Analysis of the experimental findings revealed the production of molecular solutions where IND is homogeneously blended (ascertained by Raman mapping) in the polymer matrices, as it acts as a plasticizer for both hydrophilic polymers. PCA analysis of the recorded NIR signals showed that the screw speed used in HME affects the recorded spectra but not the homogeneity of the embedded drug in the polymer sheets. The IND/VA64 and IND/SOL extruded sheets displayed rapid dissolution rates with 80% and 30% of the IND being released, respectively within the first 20min. Copyright © 2015 Elsevier B.V. All rights reserved.

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2010-04-01

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21 CFR 14.15 - Committees working under a contract with FDA.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

21 CFR 14.15 - Committees working under a contract with FDA.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

77 FR 52036 - Privacy Act of 1974; Report of a New System of Records; FDA Records Related to Research...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-28

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0253] Privacy Act of 1974; Report of a New System of Records; FDA Records Related to Research Misconduct... Drug Administration's (FDA's) regulations for the protection of privacy, FDA is publishing notice of a...

21 CFR 14.15 - Committees working under a contract with FDA.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

21 CFR 60.34 - FDA action on petitions.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

21 CFR 60.34 - FDA action on petitions.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

21 CFR 60.34 - FDA action on petitions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

21 CFR 60.34 - FDA action on petitions.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

21 CFR 14.15 - Committees working under a contract with FDA.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

21 CFR 14.15 - Committees working under a contract with FDA.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Committees working under a contract with FDA. 14... under a contract with FDA. (a) FDA may enter into contracts with independent scientific or technical... contract initially executed with FDA after July 1, 1975, but which is determined not to be an advisory...

21 CFR 830.220 - Termination of FDA service as an issuing agency.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Termination of FDA service as an issuing agency... SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA as an Issuing Agency § 830.220 Termination of FDA service as an issuing agency. (a) FDA may end our services as an issuing agency if we...

21 CFR 60.34 - FDA action on petitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the Federal...

FDA Warns About Stem Cell Therapies

MedlinePlus

... For Consumers Consumer Updates FDA Warns About Stem Cell Therapies Share Tweet Linkedin Pin it More sharing ... the boxed section below for more advice. Stem Cell Uses and FDA Regulation The FDA has the ...

Protocol Coordinator | Center for Cancer Research

Cancer.gov

PROGRAM DESCRIPTION Within the Leidos Biomedical Research Inc.’s Clinical Research Directorate, the Clinical Monitoring Research Program (CMRP) provides high-quality comprehensive and strategic operational support to the high-profile domestic and international clinical research initiatives of the National Cancer Institute (NCI), National Institute of Allergy and Infectious Diseases (NIAID), Clinical Center (CC), National Heart, Lung and Blood Institute (NHLBI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Center for Advancing Translational Sciences (NCATS), National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Mental Health (NIMH). Since its inception in 2001, CMRP’s ability to provide rapid responses, high-quality solutions, and to recruit and retain experts with a variety of backgrounds to meet the growing research portfolios of NCI, NIAID, CC, NHLBI, NIAMS, NCATS, NINDS, and NIMH has led to the considerable expansion of the program and its repertoire of support services. CMRP’s support services are strategically aligned with the program’s mission to provide comprehensive, dedicated support to assist National Institutes of Health researchers in providing the highest quality of clinical research in compliance with applicable regulations and guidelines, maintaining data integrity, and protecting human subjects. For the scientific advancement of clinical research, CMRP services include comprehensive clinical trials, regulatory, pharmacovigilance, protocol navigation and development, and programmatic and project management support for facilitating the conduct of 400+ Phase I, II, and III domestic and international trials on a yearly basis. These trials investigate the prevention, diagnosis, treatment of, and therapies for cancer, influenza, HIV, and other infectious diseases and viruses such as hepatitis C, tuberculosis, malaria, and Ebola virus; heart, lung, and blood diseases and conditions; parasitic infections; rheumatic and inflammatory diseases; and rare and neglected diseases. CMRP’s collaborative approach to clinical research and the expertise and dedication of staff to the continuation and success of the program’s mission has contributed to improving the overall standards of public health on a global scale. KEY ROLES/RESPONSIBILITIES The Protocol Coordinator II: Provides comprehensive clinical and administrative support to the Brain Tumor Trial Collaborative, Neuro-Oncology Branch, NCI, National Institutes of Health Serves as a liaison with Principal Investigators (PIs), the associated study teams and a variety of offices associated with protocol development and approvals Orchestrates meetings with investigators and other key medical staff to identify required support Coordinates the writing and regulatory review processes that occur in tandem, facilitates the bi-directional dialogue and feedback between various teams, and assists investigators and medical writers on the production/revision of clinical research protocols Assists research staff in coordinating/navigating requirements for special circumstances and facilitates access to necessary services Facilitates initiation of intramural research by providing assistance in obtaining required approvals Coordinates with investigators and medical writers to ensure Institutional Review Board (IRB) and Food and Drug Administration (FDA) stipulations are appropriately addressed in a timely manner Provides consultation and assistance for all aspects of the protocol lifecycle including initial Investigational New Drug (IND) submission, IRB submission, continuing review applications, protocol amendments, annual reports, and protocol inactivation with IRB and FDA Tracks a portfolio of protocols through each lifecycle step; processes and tracks appropriate approvals (e.g., IRB, Data and Safety Monitoring Board, Radiation Safety, Office of Protocol Services, etc.) Provides administrative support to Scientific Review Committees (SRC), reviews proposed protocol documents to ensure they are complete, distributes to reviewers, documents meeting minutes, enters data into the IRIS database, facilitates processes to obtain approval to initiate and continue clinical research Creates, maintains and queries an IRB database of approved amendment descriptions Maintains records of the current protocol(s) version, current Informed Consent document(s), FDA Safe to Proceed designation, etc. for each IND Provides expertise in data management including data collection and analysis Develops procedural manuals for clinical trials protocols Participates in quality improvement and assurance involving International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines This position is located at the National Institutes of Health (NIH) in Bethesda, Maryland.

Environmental Impact Analysis Process. Environmental Assessment for Defense Satellite Communications System III With Integrated Apogee Boost System

DTIC Science & Technology

1995-07-01

spectabilis Royal fern C FDA n/o Remirea maritima Beach star E FDA, FNAI o Scaevola plumeria Scaevola T FDA o Tillandsia simulata Wildpine; air plant...unnamed) T FDA n/o Tillandsia utriculata Giant wildpine; giant air plant C FDA o 1 E = Endangered; T = Threatened; T(S/A) = Threatened due to

21 CFR 1.393 - What information must FDA include in the detention order?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

21 CFR 1.393 - What information must FDA include in the detention order?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

45 CFR 73a.735-201 - Control activity employees formerly associated with organizations subject to FDA regulation.

Code of Federal Regulations, 2014 CFR

2014-10-01

... with organizations subject to FDA regulation. 73a.735-201 Section 73a.735-201 Public Welfare Department... with organizations subject to FDA regulation. (a) For a period of 1 year after FDA appointment, or... employed in a regulated organization within 1 year before FDA employment shall not participate in any...

21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false What expedited procedures apply when FDA initiates... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a... under this subpart, FDA will send the seizure recommendation to the Department of Justice (DOJ) within 4...

21 CFR 1.393 - What information must FDA include in the detention order?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

21 CFR 830.210 - Eligibility for use of FDA as an issuing agency.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Eligibility for use of FDA as an issuing agency... SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA as an Issuing Agency § 830.210 Eligibility for use of FDA as an issuing agency. When FDA acts as an issuing agency, any labeler will be...

21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What expedited procedures apply when FDA initiates... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a... under this subpart, FDA will send the seizure recommendation to the Department of Justice (DOJ) within 4...

21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false What expedited procedures apply when FDA initiates... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a... under this subpart, FDA will send the seizure recommendation to the Department of Justice (DOJ) within 4...

21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false What expedited procedures apply when FDA initiates... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a... under this subpart, FDA will send the seizure recommendation to the Department of Justice (DOJ) within 4...

45 CFR 73a.735-201 - Control activity employees formerly associated with organizations subject to FDA regulation.

Code of Federal Regulations, 2013 CFR

2013-10-01

... with organizations subject to FDA regulation. 73a.735-201 Section 73a.735-201 Public Welfare DEPARTMENT... with organizations subject to FDA regulation. (a) For a period of 1 year after FDA appointment, or... employed in a regulated organization within 1 year before FDA employment shall not participate in any...

21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false What expedited procedures apply when FDA initiates... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a... under this subpart, FDA will send the seizure recommendation to the Department of Justice (DOJ) within 4...

21 CFR 1.393 - What information must FDA include in the detention order?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

45 CFR 73a.735-201 - Control activity employees formerly associated with organizations subject to FDA regulation.

Code of Federal Regulations, 2012 CFR

2012-10-01

... with organizations subject to FDA regulation. 73a.735-201 Section 73a.735-201 Public Welfare DEPARTMENT... with organizations subject to FDA regulation. (a) For a period of 1 year after FDA appointment, or... employed in a regulated organization within 1 year before FDA employment shall not participate in any...

45 CFR 73a.735-201 - Control activity employees formerly associated with organizations subject to FDA regulation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... with organizations subject to FDA regulation. 73a.735-201 Section 73a.735-201 Public Welfare DEPARTMENT... with organizations subject to FDA regulation. (a) For a period of 1 year after FDA appointment, or... employed in a regulated organization within 1 year before FDA employment shall not participate in any...

45 CFR 73a.735-201 - Control activity employees formerly associated with organizations subject to FDA regulation.

Code of Federal Regulations, 2011 CFR

2011-10-01

... with organizations subject to FDA regulation. 73a.735-201 Section 73a.735-201 Public Welfare DEPARTMENT... with organizations subject to FDA regulation. (a) For a period of 1 year after FDA appointment, or... employed in a regulated organization within 1 year before FDA employment shall not participate in any...

21 CFR 1.393 - What information must FDA include in the detention order?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed and...

33 CFR 117.441 - D'Inde Bayou.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false D'Inde Bayou. 117.441 Section 117.441 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE... railroad bridge, mile 4.3, shall open on signal if at least 72 hours notice is given to the Defense Plant...

33 CFR 117.441 - D'Inde Bayou.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false D'Inde Bayou. 117.441 Section 117.441 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE... railroad bridge, mile 4.3, shall open on signal if at least 72 hours notice is given to the Defense Plant...

33 CFR 117.441 - D'Inde Bayou.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false D'Inde Bayou. 117.441 Section 117.441 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE... railroad bridge, mile 4.3, shall open on signal if at least 72 hours notice is given to the Defense Plant...

33 CFR 117.441 - D'Inde Bayou.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false D'Inde Bayou. 117.441 Section 117.441 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE... railroad bridge, mile 4.3, shall open on signal if at least 72 hours notice is given to the Defense Plant...

33 CFR 117.441 - D'Inde Bayou.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false D'Inde Bayou. 117.441 Section 117.441 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE... railroad bridge, mile 4.3, shall open on signal if at least 72 hours notice is given to the Defense Plant...

78 FR 55262 - Guidance for Clinical Investigators, Sponsors, and Institutional Review Boards on Investigational...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-10

... Applications--Determining Whether Human Research Studies Can Be Conducted Without an Investigational New Drug...)--Determining Whether Human Research Studies Can Be Conducted Without an IND.'' The guidance is intended to... research studies must be conducted under an IND. The guidance describes the basic criteria for determining...

76 FR 81508 - Communications and Activities Related to Off-Label Uses of Marketed Products and Use of Products...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-28

... derived from clinical investigations and presented as part of a marketing application. The marketing... product is safe and effective for its intended uses, as reflected in the marketing application, it... general principles underlying the IND submission and the general requirements for an IND's content and...

21 CFR 312.320 - Treatment IND or treatment protocol.

Code of Federal Regulations, 2010 CFR

2010-04-01

... clinical trial under an IND designed to support a marketing application for the expanded access use, or (ii) All clinical trials of the drug have been completed; and (2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access use with due diligence; and (3) Evidence...

21 CFR 312.32 - IND safety reporting.

Code of Federal Regulations, 2014 CFR

2014-04-01

... testing. The sponsor must report any findings from animal or in vitro testing, whether or not conducted by... 21 Food and Drugs 5 2014-04-01 2014-04-01 false IND safety reporting. 312.32 Section 312.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR...

Non-Ionizing Radiation Used in Microwave Ovens

MedlinePlus

... Human Services (HHS), U.S. Food and Drug Administration (FDA) FDA's Center for Devices and Radiological Health (CDRH) sets ... public health. These standards can be viewed on FDA's Code of Federal Regulations on Microwave Ovens . FDA ...

[Interspecific interaction between Moina mongolica and Brachionus plicatilis].

PubMed

Chen, Taoying; Wang, Yan; Huang, Changzhi; Hu, Shiheng; Zhang, Jun

2004-07-01

In a laboratory experiment, Moina mongolica and Brachionus plicatilis were polycultured at four relatively inoculating densities, i.e., 0.06/0.30, 0.10/0.30, 0.30/0.30 and 0.60/0.30 (ind x ml(-1)/ind x ml(-1)), while M. mongolica monocultured at 0.06, 0.10, 0.30 and 0.60 ind x ml(-1) and B. plicatilis at 0.30 ind x ml(-1) were used as the control. Interspecific interference did exist between M. mongolica and B. plicatilis when these two species coexisted in a microcosm. In the polycultured microcosms, depressed population density of M. mongolica resulted from the coexistence of B. plicatilis, and M. mongolica maintained at extremely low density. In opposite, M. mongolica had negligibly negative influence on the population of B. plicatilis. Further experiment showed that the mortality of M. mongolica deprived of food for 120 h was 100%, while 90% of B. plicatilis survived after 144 h of food deprivation. The relatively strong capacity of B. plicatilis in tolerating starvation may be one of the important reasons for it wins the competition against M. mongolica.

Breeding signatures of rice improvement revealed by a genomic variation map from a large germplasm collection

PubMed Central

Xie, Weibo; Wang, Gongwei; Yuan, Meng; Yao, Wen; Lyu, Kai; Zhao, Hu; Yang, Meng; Li, Pingbo; Zhang, Xing; Yuan, Jing; Wang, Quanxiu; Liu, Fang; Dong, Huaxia; Zhang, Lejing; Li, Xinglei; Meng, Xiangzhou; Zhang, Wan; Xiong, Lizhong; He, Yuqing; Wang, Shiping; Yu, Sibin; Xu, Caiguo; Luo, Jie; Li, Xianghua; Xiao, Jinghua; Lian, Xingming; Zhang, Qifa

2015-01-01

Intensive rice breeding over the past 50 y has dramatically increased productivity especially in the indica subspecies, but our knowledge of the genomic changes associated with such improvement has been limited. In this study, we analyzed low-coverage sequencing data of 1,479 rice accessions from 73 countries, including landraces and modern cultivars. We identified two major subpopulations, indica I (IndI) and indica II (IndII), in the indica subspecies, which corresponded to the two putative heterotic groups resulting from independent breeding efforts. We detected 200 regions spanning 7.8% of the rice genome that had been differentially selected between IndI and IndII, and thus referred to as breeding signatures. These regions included large numbers of known functional genes and loci associated with important agronomic traits revealed by genome-wide association studies. Grain yield was positively correlated with the number of breeding signatures in a variety, suggesting that the number of breeding signatures in a line may be useful for predicting agronomic potential and the selected loci may provide targets for rice improvement. PMID:26358652

The effect of feeding native warm season grasses in the stocker phase on the carcass quality, meat quality, and sensory attributes of beef loin steaks from grain-finished steers.

PubMed

Kurve, V P; Joseph, P; Williams, J B; Kim, T J; Boland, H; Smith, T; Schilling, M W

2016-02-01

The objective of this study was to evaluate the effect of feeding native warm season grass (NWSG) to beef cattle during the stocker phase (110days) on carcass and meat quality. Treatments included Bermudagrass (BER), Indiangrass monoculture (IND), and a mixture of NWSG including Big Bluestem, Little Bluestem, and Indiangrass (MIX). Cattle were finished on grain (180days) in a commercial feedlot and carcass data were collected after harvest. The percentages of 'choice' carcasses were 100, 95.8, and 87 within MIX, BER, and IND treatments, respectively. Steaks from BER had greater (P<0.05) fat content, and lower (P<0.05) protein and moisture percentages when compared to steaks from IND and MIX treatments. However, steaks from the MIX and IND treatments had less (P<0.05) lipid oxidation than steaks from BER after 6days of refrigerated storage. Results indicate that NWSG could be effectively incorporated into forage systems for stocker cattle without compromising carcass and meat quality. Copyright © 2015 Elsevier Ltd. All rights reserved.

A tale of tails: Sialidase is key to success in a model of phage therapy against K1-capsulated Escherichia coli.

PubMed

Bull, J J; Vimr, E R; Molineux, I J

2010-03-01

Prior studies treating mice infected with Escherichia coli O18:K1:H7 observed that phages requiring the K1 capsule for infection (K1-dep) were superior to capsule-independent (K1-ind) phages. We show that three K1-ind phages all have low fitness when grown on cells in serum whereas fitnesses of four K1-dep phages were high. The difference is serum-specific, as fitnesses in broth overlapped. Sialidase activity was associated with all K1-dep virions tested but no K1-ind virions, a phenotype supported by sequence analyses. Adding endosialidase to cells infected with K1-ind phage increased fitness in serum by enhancing productive infection after adsorption. We propose that virion sialidase activity is the primary determinant of high fitness on cells grown in serum, and thus in a mammalian host. Although the benefit of sialidase is specific to K1-capsulated bacteria, this study may provide a scientific rationale for selecting phages for therapeutic use in many systemic infections. Copyright 2009 Elsevier Inc. All rights reserved.

Indacaterol and glycopyrronium versus indacaterol on body plethysmography measurements in COPD-a randomised controlled study.

PubMed

Salomon, Joerg; Stolz, Daiana; Domenighetti, Guido; Frey, Jean-Georges; Turk, Alexander J; Azzola, Andrea; Sigrist, Thomas; Fitting, Jean-William; Schmidt, Ulrich; Geiser, Thomas; Wild, Corinne; Kostikas, Konstantinos; Clemens, Andreas; Brutsche, Martin

2017-01-11

Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. This multicentre, randomised, double-blind, single-dose, cross-over, placebo-controlled study evaluated efficacy and safety of the free combination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) versus IND alone on spirometric and body plethysmography parameters, including inspiratory capacity (IC), forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), total lung capacity (TLC) and airway resistance (Raw) in moderate-to-severe COPD patients. Seventy-eight patients with FEV 1 % pred. (mean ± SD) 56 ± 13% were randomised. The combination of IND + GLY versus IND presented a numerically higher peak-IC (Δ = 0.076 L, 95% confidence interval [CI]: -0.010 - 0.161 L; p = 0.083), with a statistically significant difference in mean IC over 4 h (Δ = 0.054 L, 95%CI 0.022 - 0.086 L; p = 0.001). FEV 1 , FVC and Raw, but not TLC, were consistently significantly improved by IND + GLY compared to IND alone. Safety profiles of both treatments were comparable. The free combination of IND + GLY improved lung function parameters as evaluated by spirometry and body plethysmography, with a similar safety profile compared to IND alone. NCT01699685.

Pitfalls and challenges when assessing the depth of hypnosis during general anaesthesia by clinical signs and electronic indices.

PubMed

Jensen, E W; Litvan, H; Struys, M; Martinez Vazquez, P

2004-11-01

The objective of this article was to review the present methods used for validating the depth of hypnosis. We introduce three concepts, the real depth of hypnosis (DHreal), the observed depth of hypnosis (DHobs), and the electronic indices of depth of hypnosis (DHel-ind). The DHreal is the real state of hypnosis that the patient has in a given moment during the general anaesthesia. The DHobs is the subjective assessment of the anaesthesiologist based on clinical signs. The DHel-ind is any estimation of the depth of hypnosis given by an electronic device. The three entities DHreal, DHobs and DHel-ind should in the ideal situation be identical. However, this is rarely the case. The correlation between the DHobs and the DHel-ind can be affected by a number of factors such as the stimuli used for the assessment of the level of consciousness or the administration of analgesic agents or neuro muscular blocking agents. Opioids, for example, can block the response to tactile and noxious stimuli, and even the response to verbal command could vanish, hence deeming the patient in a lower depth of hypnosis than the real patient state. The DHel-ind can be disturbed by the presence of facial muscular activity. In conclusion, although several monitors and clinical scoring scales are available to assess the depth of hypnosis during general anaesthesia, care should be taken when interpreting their results.

OpenFDA: an innovative platform providing access to a wealth of FDA's publicly available data.

PubMed

Kass-Hout, Taha A; Xu, Zhiheng; Mohebbi, Matthew; Nelsen, Hans; Baker, Adam; Levine, Jonathan; Johanson, Elaine; Bright, Roselie A

2016-05-01

The objective of openFDA is to facilitate access and use of big important Food and Drug Administration public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Using cutting-edge technologies deployed on FDA's new public cloud computing infrastructure, openFDA provides open data for easier, faster (over 300 requests per second per process), and better access to FDA datasets; open source code and documentation shared on GitHub for open community contributions of examples, apps and ideas; and infrastructure that can be adopted for other public health big data challenges. Since its launch on June 2, 2014, openFDA has developed four APIs for drug and device adverse events, recall information for all FDA-regulated products, and drug labeling. There have been more than 20 million API calls (more than half from outside the United States), 6000 registered users, 20,000 connected Internet Protocol addresses, and dozens of new software (mobile or web) apps developed. A case study demonstrates a use of openFDA data to understand an apparent association of a drug with an adverse event. With easier and faster access to these datasets, consumers worldwide can learn more about FDA-regulated products. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved.

21 CFR 1.391 - Who approves a detention order?

Code of Federal Regulations, 2013 CFR

2013-04-01

... Fda Order A Detention? § 1.391 Who approves a detention order? An authorized FDA representative, i.e., the FDA District Director in whose district the article of food involved is located or an FDA official...

FDA Issues Final Guidance Clarifying FDA and EPA Jurisdiction over Mosquito-Related Products

EPA Pesticide Factsheets

FDA finalized guidance to provide information on FDA and EPA jurisdiction over the regulation of mosquito-related products intended to function as pesticides, including those products intended to function as pesticides

21 CFR 1.391 - Who approves a detention order?

Code of Federal Regulations, 2011 CFR

2011-04-01

... Fda Order A Detention? § 1.391 Who approves a detention order? An authorized FDA representative, i.e., the FDA District Director in whose district the article of food involved is located or an FDA official...

21 CFR 1.391 - Who approves a detention order?

Code of Federal Regulations, 2010 CFR

2010-04-01

... Fda Order A Detention? § 1.391 Who approves a detention order? An authorized FDA representative, i.e., the FDA District Director in whose district the article of food involved is located or an FDA official...

21 CFR 1.391 - Who approves a detention order?

Code of Federal Regulations, 2012 CFR

2012-04-01

... Fda Order A Detention? § 1.391 Who approves a detention order? An authorized FDA representative, i.e., the FDA District Director in whose district the article of food involved is located or an FDA official...

Indicaxanthin inhibits NADPH oxidase (NOX)-1 activation and NF-κB-dependent release of inflammatory mediators and prevents the increase of epithelial permeability in IL-1β-exposed Caco-2 cells.

PubMed

Tesoriere, L; Attanzio, A; Allegra, M; Gentile, C; Livrea, M A

2014-02-01

Dietary redox-active/antioxidant phytochemicals may help control or mitigate the inflammatory response in chronic inflammatory bowel disease (IBD). In the present study, the anti-inflammatory activity of indicaxanthin (Ind), a pigment from the edible fruit of cactus pear (Opuntia ficus-indica, L.), was shown in an IBD model consisting of a human intestinal epithelial cell line (Caco-2 cells) stimulated by IL-1β, a cytokine known to play a major role in the initiation and amplification of inflammatory activity in IBD. The exposure of Caco-2 cells to IL-1β brought about the activation of NADPH oxidase (NOX-1) and the generation of reactive oxygen species (ROS) to activate intracellular signalling leading to the activation of NF-κB, with the over-expression of inflammatory enzymes and release of pro-inflammatory mediators. The co-incubation of the cells with Ind, at a nutritionally relevant concentration (5-25 μM), and IL-1β prevented the release of the pro-inflammatory cytokines IL-6 and IL-8, PGE2 and NO, the formation of ROS and the loss of thiols in a dose-dependent manner. The co-incubation of the cells with Ind and IL-1β also prevented the IL-1β-induced increase of epithelial permeability. It was also shown that the activation of NOX-1 and NF-κB was prevented by Ind and the expression of COX-2 and inducible NO synthase was reduced. The uptake of Ind in Caco-2 cell monolayers appeared to be unaffected by the inflamed state of the cells. In conclusion, our findings suggest that the dietary pigment Ind may have the potential to modulate inflammatory processes at the intestinal level.

Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells.

PubMed

Flores-Santana, Wilmarie; Moody, Terry; Chen, Weibin; Gorczynski, Michael J; Shoman, Mai E; Velázquez, Carlos; Thetford, Angela; Mitchell, James B; Cherukuri, Murali K; King, S Bruce; Wink, David A

2012-02-01

Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO-indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549. We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E(2) (PGE(2) ) and leukotriene B(4) (LTB(4) ). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo. MTD were: TEMPO (140 mg·kg(-1) ), ASA (100 mg·kg(-1) ), indomethacin (5 mg·kg(-1) ), TEMPO-ASA (100 mg·kg(-1) ) and TEMPO-IND (40 mg·kg(-1) ). While TEMPO-ASA was as well tolerated as ASA, TEMPO-IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE(2) and LTB(4) in A549 cells with maximum effects at 100 µg·mL(-1) or 10 µg·mL(-1) respectively. The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16{sup INK4a} gene in human colorectal carcinoma (Caco-2) cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naselli, Flores; Tesoriere, Luisa; Caradonna, Fabio

Highlights: • Cactus pear fruit extract and indicaxanthin cause apoptosis of colon cancer cells. • Indicaxanthin does not cause ROS formation, but affects epigenoma in Caco-2 cells. • Indicaxanthin reverses methylation of oncosuppressor p16{sup INK4a} gene in Caco-2 cells. • Indicaxanthin reactivates retinoblastoma in Caco-2 cells. • Bioavailable indicaxanthin may have chemopreventive activity in colon cancer. - Abstract: Phytochemicals may exert chemo-preventive effects on cells of the gastro-intestinal tract by modulating epigenome-regulated gene expression. The effect of the aqueous extract from the edible fruit of Opuntia ficus-indica (OFI extract), and of its betalain pigment indicaxanthin (Ind), on proliferation of humanmore » colon cancer Caco-2 cells has been investigated. Whole extract and Ind caused a dose-dependent apoptosis of proliferating cells at nutritionally relevant amounts, with IC{sub 50} 400 ± 25 mg fresh pulp equivalents/mL, and 115 ± 15 μM (n = 9), respectively, without toxicity for post-confluent differentiated cells. Ind accounted for ∼80% of the effect of the whole extract. Ind did not cause oxidative stress in proliferating Caco-2 cells. Epigenomic activity of Ind was evident as de-methylation of the tumor suppressor p16{sup INK4a} gene promoter, reactivation of the silenced mRNA expression and accumulation of p16{sup INK4a}, a major controller of cell cycle. As a consequence, decrease of hyper-phosphorylated, in favor of the hypo-phosphorylated retinoblastoma was observed, with unaltered level of the cycline-dependent kinase CDK4. Cell cycle showed arrest in the G2/M-phase. Dietary cactus pear fruit and Ind may have chemo-preventive potential in intestinal cells.« less

Cost Effectiveness of the Long-Acting β2-Adrenergic Agonist (LABA)/Long-Acting Muscarinic Antagonist Dual Bronchodilator Indacaterol/Glycopyrronium Versus the LABA/Inhaled Corticosteroid Combination Salmeterol/Fluticasone in Patients with Chronic Obstructive Pulmonary Disease: Analyses Conducted for Canada, France, Italy, and Portugal.

PubMed

Reza Maleki-Yazdi, M; Molimard, Mathieu; Keininger, Dorothy L; Gruenberger, Jean-Bernard; Carrasco, Joao; Pitotti, Claudia; Sauvage, Elsa; Chehab, Sara; Price, David

2016-10-01

The objective of this study was to assess the cost effectiveness of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) compared with salmeterol/fluticasone combination (SFC) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who had a history of one or no exacerbations in the previous year, in Canada, France, Italy, and Portugal. A patient-level simulation was developed to compare the costs and outcomes of IND/GLY versus SFC based on data from the LANTERN trial (NCT01709903). Monte-Carlo simulation methods were employed to follow individual patients over various time horizons. Population and efficacy inputs were derived from the LANTERN trial. Considering the payers' perspective, only direct costs were included. Costs and health outcomes were discounted annually at 3.0 % for all countries. Unit costs were taken from publically available sources with all costs converted to euros (€). The cost base year was 2015. Deterministic and probabilistic sensitivity analyses were undertaken to test the robustness of the model results. IND/GLY was found to be the dominant (more effective and less costly) treatment option compared with SFC in all four countries. The use of IND/GLY was associated with mean total cost savings per patient over a lifetime of €6202, €1974, €1611, and €220 in Canada, France, Italy, and Portugal, respectively. Sensitivity analysis showed that exacerbation rates had the largest impact on incremental costs and quality-adjusted life-years (QALYs). The probability of IND/GLY being cost effective was estimated to be >95 % for thresholds above €5000/QALY. In patients with moderate to severe COPD, IND/GLY is likely to be a cost-effective treatment alternative compared with SFC.

Genetic divergence of Chikungunya viruses in India (1963-2006) with special reference to the 2005-2006 explosive epidemic.

PubMed

Arankalle, Vidya A; Shrivastava, Shubham; Cherian, Sarah; Gunjikar, Rashmi S; Walimbe, Atul M; Jadhav, Santosh M; Sudeep, A B; Mishra, Akhilesh C

2007-07-01

Re-emergence of Chikungunya (CHIK), caused by CHIK virus, was recorded in India during 2005-2006 after a gap of 32 years, causing 1.3 million cases in 13 states. Several islands of the Indian Ocean reported similar outbreaks in the same period. These outbreaks were attributed to the African genotype of CHIK virus. To examine relatedness of the Indian isolates (IND-06) with Reunion Island isolates (RU), full-genome sequences of five CHIK virus isolates representative of different Indian states were determined. In addition, an isolate obtained from mosquitoes in the year 2000 (Yawat-2000), identified as being of the African genotype, and two older strains isolated in 1963 and 1973 (of the Asian genotype), were sequenced. The IND-06 isolates shared 99.9 % nucleotide identity with RU isolates, confirming involvement of the same strain in these outbreaks. The IND-06 isolates shared 98.2 % identity with the Yawat-2000 isolate. Of two crucial substitutions reported for RU isolates in the E1 region, M269V was noted in the Yawat-2000 and IND-06 isolates, whereas D284E was seen only in the IND-06 isolates. The A226V shift observed with the progression of the epidemic in Reunion Island, probably associated with adaptation to the mosquito vector, was absent in all of the Indian isolates. Three unique substitutions were noted in the IND-06 isolates: two (T128K and T376M) in the Nsp1 region and one (P23S) in the capsid protein. The two Asian strains showed 99.4 % nucleotide identity to each other, indicating relative stability of the virus. No evidence of recombination of the Asian and African genotypes, or of positive selection was observed. The results may help in understanding the association, if any, of the unique mutations with the explosive nature of the CHIK outbreak.

Selection of Metastatic Breast Cancer Cells Based on Adaptability of Their Metabolic State

PubMed Central

Singh, Balraj; Tai, Karen; Madan, Simran; Raythatha, Milan R.; Cady, Amanda M.; Braunlin, Megan; Irving, LaTashia R.; Bajaj, Ankur; Lucci, Anthony

2012-01-01

A small subpopulation of highly adaptable breast cancer cells within a vastly heterogeneous population drives cancer metastasis. Here we describe a function-based strategy for selecting rare cancer cells that are highly adaptable and drive malignancy. Although cancer cells are dependent on certain nutrients, e.g., glucose and glutamine, we hypothesized that the adaptable cancer cells that drive malignancy must possess an adaptable metabolic state and that such cells could be identified using a robust selection strategy. As expected, more than 99.99% of cells died upon glutamine withdrawal from the aggressive breast cancer cell line SUM149. The rare cells that survived and proliferated without glutamine were highly adaptable, as judged by additional robust adaptability assays involving prolonged cell culture without glucose or serum. We were successful in isolating rare metabolically plastic glutamine-independent (Gln-ind) variants from several aggressive breast cancer cell lines that we tested. The Gln-ind cells overexpressed cyclooxygenase-2, an indicator of tumor aggressiveness, and they were able to adjust their glutaminase level to suit glutamine availability. The Gln-ind cells were anchorage-independent, resistant to chemotherapeutic drugs doxorubicin and paclitaxel, and resistant to a high concentration of a COX-2 inhibitor celecoxib. The number of cells being able to adapt to non-availability of glutamine increased upon prior selection of cells for resistance to chemotherapy drugs or resistance to celecoxib, further supporting a linkage between cellular adaptability and therapeutic resistance. Gln-ind cells showed indications of oxidative stress, and they produced cadherin11 and vimentin, indicators of mesenchymal phenotype. Gln-ind cells were more tumorigenic and more metastatic in nude mice than the parental cell line as judged by incidence and time of occurrence. As we decreased the number of cancer cells in xenografts, lung metastasis and then primary tumor growth was impaired in mice injected with parental cell line, but not in mice injected with Gln-ind cells. PMID:22570721

21 CFR 1.379 - How long may FDA detain an article of food?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

21 CFR 1.379 - How long may FDA detain an article of food?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

21 CFR 1.379 - How long may FDA detain an article of food?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

21 CFR 1.379 - How long may FDA detain an article of food?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

21 CFR 1.379 - How long may FDA detain an article of food?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional 10...

The influence of ultra-pasteurization by indirect heating versus direct steam injection on skim and 2% fat milks.

PubMed

Lee, A P; Barbano, D M; Drake, M A

2017-03-01

Fluid milk is traditionally pasteurized by high temperature, short time (HTST) pasteurization, which requires heating to at least 72°C for 15 s. Ultra-pasteurization (UP) extends milk shelf life and is defined as heating to at least 138°C for 2 s. The UP process can be done by indirect heating (IND) or by direct steam injection (DSI). The influence of these 2 UP methods on milk flavor has not been widely investigated. The objective of this study was to compare the effect of HTST, IND-UP, and DSI-UP on sensory perception of fluid milk. Raw skim and standardized 2% milks were pasteurized at 140°C for 2.3 s by IND or DSI or by HTST (78°C, 15 s) and homogenized at 20.7 MPa. The processed milks were stored in light-shielded opaque high-density polyethylene containers at 4°C and examined by descriptive analysis and microbial analysis on d 3, 7, and 14. Furosine and serum protein denaturation analyses were performed on d 0 and 14 as an indicator of heat treatment. Last, consumer acceptance testing was conducted at d 10, with adults (n = 250) and children (ages 8 to13 y, n = 100) who were self-reported consumers of skim or 2% milk; consumers only received samples for either skim or 2% milk. The entire experiment was repeated in triplicate. Milks treated by HTST had lower cooked flavor than either UP milk. Milks heated by DSI-UP were characterized by sulfur or eggy and cooked flavors, whereas IND-UP milks had higher sweet aromatic and sweet taste compared with DSI-UP milk. Aromatic flavor intensities of all milks decreased across 14 d of storage. Furosine concentrations and serum protein denaturation were highest for the IND treatments, followed by DSI and HTST. Furosine content in both skim and 2% milk increased with time, but the increase was faster in IND-UP skim milk. Adult and child consumers preferred HTST milk over either UP milk, regardless of fat content. Ultra-pasteurization by IND or DSI did not affect consumer acceptance at 10 d postprocessing, but traditional HTST milks were preferred by consumers of all ages. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

[Density, size structure and reproductive activity of the pink conch Eustrombus gigas (Mesogastropoda: Strombidae) in Banco Chinchorro, Mexico].

PubMed

Cala, Yuself R; Navarrete, Alberto de Jesús; Ocaña, Frank A; Rivera, José Oliva

2013-12-01

The pink conch Eustrombus gigas is an important fisheries resource. At the regional level in the Caribbean, over-exploitation and habitat destruction have caused a decrease in the abundance of this resource. In order to provide necessary information for the species management in Mexico, this work aimed to analyze the total density, adult density, size structure and reproductive behavior of pink conch population at Banco Chinchorro during 2009-2010. Data from three seasons were obtained (rainy, dry and cold fronts periods) in three areas: Norte (North), Centro (Center) and Sur (South). The organisms were separated into two groups: (a) the criteria based upon legal harvest in Mexico: legal size conchs (siphonal length > 200 mm) and illegal size conchs (siphonal length < 200 mm), and (b) the criteria based upon sexual maturity using the 15 mm lip thickness standard: lip < 15 mm as juvenile conch and lip > or = 15 mm as adult conch. Copulation, spawning, egg masses and aggregations were evaluated as reproductive evidences. The highest total density was observed during the dry season with 384ind./ha, and the lowest during the rainy season with 127ind./ha. The highest density was reported at Sur (385ind./ha) and the lowest at Norte (198ind./ ha). The highest adult density was observed during the rainy season (8.33ind./ha), and the lowest occurred in the dry season (6.1 ind./ha). Adult density values were 5.55, 7.05 and 8.33ind./ha for Centro, Sur and Norte areas, respectively. Adult densities were lower than the threshold needed for reproduction, and 42% of the population may be vulnerable to fishing, as they had the minimum size for catch (Lsi 200 mm). Furthermore, only 2.2% of the population reached a Gl > 15 mm as sexual maturity indicator. During the study period, only six evidences of reproductive activity were observed. The smaller densities reported at Banco Chinchorro may cause reproduction events to be almost absent which in turn is sufficient evidence to show that the Allee Effect is acting on the queen conch population and there is an urgent need of fishery closure. Three important points were proposed for management of queen conch at Banco Chinchorro: total closure of fishing, systematic assessment of the conch population and the implementation of conch fishing refuge.

Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms.

PubMed

Zhang, Jian-Liang; Yu, Hui; Hou, Ying-Wei; Wang, Ke; Bi, Wen-Shan; Zhang, Liang; Wang, Qian; Li, Pan; Yu, Man-Li; Zhao, Xian-Xian

2018-04-01

Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K + level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K + level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K + level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090)  mmol/L vs. 0.029 (95% CI: 0.006-0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

The Food and Drug Administration advisory committees and panels: how they are applied to the drug regulatory process.

PubMed

Ciociola, Arthur A; Karlstadt, Robyn G; Pambianco, Daniel J; Woods, Karen L; Ehrenpreis, Eli D

2014-10-01

Food and Drug Administration (FDA) advisory panels and committees play a critical role in advising the FDA on the safety and efficacy of medical devices and drugs marketed in the US. Advisory panel recommendations are used by the FDA to make decisions regarding medical products. Currently, the FDA utilizes over 50 advisory panels that serve the three major FDA centers, including the Centers for Biologics, Drugs and Device Products. Members of an advisory panel typically include academicians, clinicians, consumers, patients, and industry representatives. The FDA establishes the schedules for advisory panel meetings on an annual basis and a panel usually meets several times a year for two consecutive days in Washington, DC. Typically, the advisory panel discusses issues highlighted by the FDA and is then asked to vote a response to the questions posed in advance by the FDA. Advisory panel recommendations have a strong influence on FDA's decision to approve a product, as evidenced by the 214 Advisory Panels FDA convened between January 2008 to November 2012, during which advisory panel members voted to approve the product (or use of the product) ∼74% of the time, with FDA ultimately approving the medical product (or use of the product) ∼79% of the time. The ACG membership are encouraged to consider serving the public's interest by participating in an FDA advisory panel utilizing their expertise for the evaluation of a new drug or medical device, and providing advice about whether the product should be sold in the US.

Patient Experience Data in US Food and Drug Administration (FDA) Regulatory Decision Making:: A Policy Process Perspective.

PubMed

Kuehn, Carrie M

2018-01-01

The influence of patient advocates on FDA regulatory decision making has increased. Despite enhanced engagement with FDA, there remain challenges to achieving the regulatory goals of patients within FDA's regulatory framework. Gaps exist between patient advocates' knowledge of the agency's processes and FDA's need for rigorous, clinically meaningful patient experience data. This study examined the policy process in which patient experience data are collected by patient advocates and provided to FDA for regulatory decision making. Semistructured, narrative interviews were conducted with 14 professionals working in patient advocacy or at FDA. The purpose was to examine, in depth, participants' perceptions and experiences regarding this new regulatory process. Interviews were coded and examined for themes. The use of patient experience data by FDA is an evolving regulatory process. Participants identified a number of barriers and contributors to regulatory success. Well-organized and sophisticated patient advocacy groups with access to scientific and policy expertise are more likely to find success meeting FDA's patient experience data requirements. A conceptual model of this regulatory process was developed. Use of patient experience data by FDA has the potential to positively influence the regulation of medical products in the United States. Success within this new regulatory process will depend on clear guidance from FDA regarding the collection, analysis, and use of patient experience data. Patient advocacy groups must enhance internal capacity and expertise while engaging in substantive collaborations with FDA and other stakeholders in order to meaningfully contribute to the regulatory review of new therapeutics.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bentz, A; Buddemeier, B; Dombroski, M

Following the events of September 11, a litany of imaginable horribles was trotted out before an anxious and concerned public. To date, government agencies and academics are still grappling with how to best respond to such catastrophes, and as Senator Lieberman's quote says above, now is the time to plan and prepare for such events. One of the nation's worst fears is that terrorists might detonate an improvised nuclear device (IND) in an American city. With 9/11 serving as the catalyst, the government and many NGOs have invested money into research and development of response capabilities throughout the country. Yet,more » there is still much to learn about how to best respond to an IND event. Understanding the state of knowledge, identifying gaps, and making recommendations for how to fill those gaps, this paper will provide a framework under which past findings can be understood and future research can fit. The risk of an improvised nuclear device (IND) detonation may seem unlikely; and while this is hopefully true, due to its destructive capability, IND events must be prepared for. Many people still live under the Cold War mentality that if a city is attacked with a nuclear weapon, there is little chance of survival. This assumption, while perhaps true in the case of multiple, thermonuclear weapons exchanges, does not hold for the current threat. If a single IND were detonated in the United States, there would be many casualties at the point of impact; however, there would also be many survivors and the initial response by two major groups will mean the difference between life and death for many people. These groups are the first responders and the public. Understanding how these two groups prepare, react and interact will improve response to nuclear terrorism. Figure 1 provides a visualization of the response timeline of an IND event. For the purposes of this assessment, it is assumed that to accurately inform the public, three functions need to be fulfilled by response personnel, namely planning, developing situational awareness, and developing a public message. Planning varies widely from city to city, and to date no comprehensive study has been completed to assess how individual cities are progressing with preparation plans. Developing situational awareness about an IND detonation has been well researched over the years, yet it is far from fully understood. While messaging is an integral component to response, it is one that suffers from a dearth of knowledge. The public will have a certain level of education and preparation. After the detonation the public will respond naturally and upon receiving the responders message will react to the message and may modify their behavior accordingly. Reviewing the nodes under both headings, responders and public will help better prepare the country to meet the challenges of an IND attack.« less

Differences in recovery between deep-sea hydrothermal vent and vent-proximate communities after a volcanic eruption

NASA Astrophysics Data System (ADS)

Gollner, Sabine; Govenar, Breea; Arbizu, Pedro Martinez; Mills, Susan; Le Bris, Nadine; Weinbauer, Markus; Shank, Timothy M.; Bright, Monika

2015-12-01

Deep-sea hydrothermal vents and the surrounding basalt seafloor are subject to major natural disturbance events such as volcanic eruptions. In the near future, anthropogenic disturbance in the form of deep-sea mining could also significantly affect the faunal communities of hydrothermal vents. In this study, we monitor and compare the recovery of insular, highly productive vent communities and vent-proximate basalt communities following a volcanic eruption that destroyed almost all existing communities at the East Pacific Rise, 9°50‧N in 2006. To study the recovery patterns of the benthic communities, we placed settlement substrates at vent sites and their proximate basalt areas and measured the prokaryotic abundance and compared the meio- and macrofaunal species richness and composition at one, two and four years after the eruption. In addition, we collected samples from the overlying water column with a pelagic pump, at one and two years after the volcanic eruption, to determine the abundance of potential meiofauna colonisers. One year after eruption, mean meio- and macrofaunal abundances were not significantly different from pre-eruption values in vent habitats (meio: 8-1838 ind. 64 cm-2 in 2006; 3-6246 ind. 64 cm-2 in 2001/02; macro: 95-1600 ind. 64 cm-2 in 2006; 205-4577 ind. 64 cm-2 in 2001/02) and on non-vent basalt habitats (meio: 10-1922 ind. 64 cm-2 in 2006; 8-328 ind. 64 cm-2 in 2003/04; macro: 14-3351 ind. 64 cm-2 in 2006; 2-63 ind. 64 cm-2 in 2003/04), but species recovery patterns differed between the two habitat types. In the vent habitat, the initial community recovery was relatively quick but incomplete four years after eruption, which may be due to the good dispersal capabilities of vent endemic macrofauna and vent endemic dirivultid copepods. At vents, 42% of the pre-eruption meio- and 39% of macrofaunal species had returned. In addition, some new species not evident prior to the eruption were found. At the tubeworm site Tica, a total of 26 meio- and 19 macrofaunal species were found in 2009, which contrasts with the 24 meio- and 29 macrofauna species detected at the site in 2001/02. In the basalt habitat, community recovery of meiofauna was slower with only 28% of the original 64 species present four years after eruption. The more limited dispersal capabilities of meiofauna basalt specialists such as nematodes or harpacticoid copepods probably caused this pattern. In contrast, 67% of the original 27 macrofaunal species had recolonized the basalt by 2009. Our results suggest that not only vent communities, but also species-rich communities of vent-proximate habitats require attention in conservation efforts.

Fluorescein Diacetate Microplate Assay in Cell Viability Detection.

PubMed

Chen, Xi; Yang, Xiu-Ying; Fang, Lian-Hua; DU, Guan-Hua

2016-12-20

Objective To investigate the application of the fluorescein diacetate (FDA) microplate assay in cell viability detection. Methods Cells were seeded in a 96-well culture plate until detection. After incubated with FDA,the plate was detected by fluorescence microplate analyzer. The effects of FDA incubation duration,concentration,and other factors on the assay's accuracy and stability were assessed. We also compared the results of FDA with methyl thiazolyl(MTT) in terms of cell numbers and H 2 O 2 injury. Results Within 0-30 minutes,the fluorescence-cell number coefficient of FDA assay increased with duration and reached 0.99 in 27-30 minutes. The optimum concentration of final FDA in this study was 10-30 μg/ml. On cell viability detection,the result of FDA method was equivalent to MTT method. As to H 2 O 2 injury assay,the sensitivity of FDA method was superior to MTT on the higher concentration H 2 O 2 treatment due to a relative shorter duration for detection. Conclusion As a stable and reliable method,FDA is feasible for cell variability detection under varied conditions.

76 FR 1180 - FDA Transparency Initiative: Improving Transparency to Regulated Industry

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-07

...] FDA Transparency Initiative: Improving Transparency to Regulated Industry AGENCY: Food and Drug... the Transparency Initiative, the Food and Drug Administration (FDA) is announcing the availability of a report entitled ``FDA Transparency Initiative: Improving Transparency to Regulated Industry.'' The...

77 FR 70955 - FDA Actions Related to Nicotine Replacement Therapies and Smoking-Cessation Products; Report to...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-28

.... FDA-2012-N-1148] FDA Actions Related to Nicotine Replacement Therapies and Smoking-Cessation Products... comments. SUMMARY: The Food and Drug Administration (FDA) is announcing a 1-day public hearing to obtain...

Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

DTIC Science & Technology

2016-10-01

consensus meeting, with input from investigators in the Prostate Cancer Clinical Trials Consortium, FDA Office of Oncology Drug Products, FDA Study...Cancer Clinical Trials Consortium, FDA Office of Oncology Drug Products, FDA Study Endpoint and Label Development Team, and FDA Division of...Abstract. American Society of Clinical Oncology . Chicago IL, June 1-5, 2013. INVENTIONS, PATENTS AND LICENSES None 11 REPORTABLE OUTCOMES

First detection of foot-and-mouth disease virus O/Ind-2001d in Vietnam

USDA-ARS?s Scientific Manuscript database

In recent years, foot-and-mouth disease virus (FMDV) serotype O, lineage Ind2001d has spread to the Middle East, North Africa, and Southeast Asia. In the current report, we describe the first detection of this lineage in Vietnam in May, 2015 in Dak Nong province which borders Cambodia. Three subsequ...

21 CFR 312.130 - Availability for public disclosure of data and information in an IND.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Availability for public disclosure of data and... Miscellaneous § 312.130 Availability for public disclosure of data and information in an IND. (a) The existence... publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information...

21 CFR 312.130 - Availability for public disclosure of data and information in an IND.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Availability for public disclosure of data and... Miscellaneous § 312.130 Availability for public disclosure of data and information in an IND. (a) The existence... publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information...

21 CFR 312.130 - Availability for public disclosure of data and information in an IND.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Availability for public disclosure of data and... Miscellaneous § 312.130 Availability for public disclosure of data and information in an IND. (a) The existence... publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information...

21 CFR 312.130 - Availability for public disclosure of data and information in an IND.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Availability for public disclosure of data and... Miscellaneous § 312.130 Availability for public disclosure of data and information in an IND. (a) The existence... publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information...

21 CFR 312.130 - Availability for public disclosure of data and information in an IND.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Availability for public disclosure of data and... Miscellaneous § 312.130 Availability for public disclosure of data and information in an IND. (a) The existence... publicly disclosed or acknowledged. (b) The availability for public disclosure of all data and information...

78 FR 67215 - Norfolk Southern Railway Company-Abandonment Exemption-in Fayette and Wayne Counties, Ind.; C&NC...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-08

... Wayne Counties, Ind.; C&NC Railroad Corporation-- Discontinuance of Service Exemption--in Fayette and...-Exempt Abandonments and Discontinuances of Service for NSR to abandon, and for CNUR to discontinue service over, approximately 0.61 miles of rail line between milepost CB 4.80 (near East County Road 450N...

21 CFR 316.10 - Content and format of a request for written recommendations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... approval of a marketing application shall be submitted in the form and contain the information required in... indication or indications for use for such disease or condition. (7) Current regulatory and marketing status... marketing application (if the product is the subject of an IND or a marketing application, the IND or...

75 FR 16177 - Notice of Lodging of Material Modification to Consent Decree Under the Clean Water Act

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-31

... the State of Indiana v. City of Anderson, Indiana, Civil Action No. IP 02- 1103 C M/S (S.D. Ind.) was... Anderson, Indiana, Civil Action No. IP 02-1103 C M/S (S.D. Ind.) and D.J. Ref. No. 90-5-2-1-07043/2. The...

Santa Claus, Ga./Ind.

NASA Image and Video Library

2002-12-23

The towns of Santa Claus, Ga., (top) and Santa Claus, Ind. (bottom), are shown in these two images from the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) instrument on NASA's Terra satellite. They are the only two Santa Claus towns in the United States with post offices and zip codes, although there are 11 towns with this name in the United States. Santa Claus, Ga. is located in Toombs County, and has a population of 237. Santa Claus, Ind. is located in Spencer County, and has a population of 2,041. Its name was accepted by the United States Postal Service in 1856. The images were acquired on July 3, 2000 (top) and June 16, 2001 (bottom), respectively. http://photojournal.jpl.nasa.gov/catalog/PIA03891

Functional exploratory data analysis for high-resolution measurements of urban particulate matter.

PubMed

Ranalli, M Giovanna; Rocco, Giorgia; Jona Lasinio, Giovanna; Moroni, Beatrice; Castellini, Silvia; Crocchianti, Stefano; Cappelletti, David

2016-09-01

In this work we propose the use of functional data analysis (FDA) to deal with a very large dataset of atmospheric aerosol size distribution resolved in both space and time. Data come from a mobile measurement platform in the town of Perugia (Central Italy). An OPC (Optical Particle Counter) is integrated on a cabin of the Minimetrò, an urban transportation system, that moves along a monorail on a line transect of the town. The OPC takes a sample of air every six seconds and counts the number of particles of urban aerosols with a diameter between 0.28 μm and 10 μm and classifies such particles into 21 size bins according to their diameter. Here, we adopt a 2D functional data representation for each of the 21 spatiotemporal series. In fact, space is unidimensional since it is measured as the distance on the monorail from the base station of the Minimetrò. FDA allows for a reduction of the dimensionality of each dataset and accounts for the high space-time resolution of the data. Functional cluster analysis is then performed to search for similarities among the 21 size channels in terms of their spatiotemporal pattern. Results provide a good classification of the 21 size bins into a relatively small number of groups (between three and four) according to the season of the year. Groups including coarser particles have more similar patterns, while those including finer particles show a more different behavior according to the period of the year. Such features are consistent with the physics of atmospheric aerosol and the highlighted patterns provide a very useful ground for prospective model-based studies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biomonitoring of persistent organic pollutants (POPs) in child populations living near contaminated sites in Mexico.

PubMed

Flores-Ramírez, R; Pérez-Vázquez, F J; Rodríguez-Aguilar, M; Medellín-Garibay, S E; Van Brussel, E; Cubillas-Tejeda, A C; Carrizales-Yáñez, L; Díaz-Barriga, F

2017-02-01

The aim of this study was to conduct a POP biomonitoring programme for children in high-risk areas. We evaluated 247 serum samples from children between the ages of 6 and 12years old from two zones in Mexico: (1) indigenous zones, which included Cuatlamayan (CUA), Tocoy (TOC), and Santa Maria Picula (SAM); and (2) industrial zones, which included Tercera Chica (TC), Industrial San Luis (IND) and Rincon de San Jose (SJR); Mundo Nuevo (MN); and Alpuyeca (ALP). Our results showed that α-endosulfan was similar to CUA, TOC, SAM, TC and MN (178.6-306.9ng/g lipid). β-Endosulfan levels were higher in ALP (901.5ng/g lipid), followed by CUA (139.9ng/g lipid) and TOC, SAM, TC and MN, which had similar levels (55.4-64.5ng/g lipid). For endosulfan sulfate, the ALP community had the highest concentration levels (1096.4ng/g lipid), whereas CUA and TOC (212.3 and 289ng/g lipid, respectively) had concentrations similar to those found in SAM and TC (99.5 and 119.1ng/g lipid, respectively). DDE levels were found in malaria-endemic areas of SAM, CUA and TOC (1782.2, 1358.3 and 57.0ng/g lipid), followed by MN (35.1ng/g lipid). HCB concentration levels were found to be higher in MN and SJR (691.8 and 575.4ng/g lipid, respectively), followed by CUA and TC (363.9 and 269.1ng/g lipid, respectively), with levels similar to those found in TOC and SAM (191.8 and 181.9ng/g lipid, respectively). Finally, PCB 101 concentration levels were found to be the highest in ALP (1032.7ng/g lipid), followed by similar levels of SJR and IND (567.5 and 327.3ng/g lipid, respectively) and TC and MN, with 109.1 and 144.5ng/g lipid, respectively. The evidence provided by this exploratory study indicates that the evaluation of the health risks posed to children living in contaminated areas is a high priority health issue. Copyright © 2016 Elsevier B.V. All rights reserved.

Food and Drug Administration criteria for the diagnosis of drug-induced valvular heart disease in patients previously exposed to benfluorex: a prospective multicentre study.

PubMed

Maréchaux, Sylvestre; Rusinaru, Dan; Jobic, Yannick; Ederhy, Stéphane; Donal, Erwan; Réant, Patricia; Arnalsteen, Elise; Boulanger, Jacques; Garban, Thierry; Ennezat, Pierre-Vladimir; Jeu, Antoine; Szymanski, Catherine; Tribouilloy, Christophe

2015-02-01

The Food and Drug Administration (FDA) criteria for diagnosis of drug-induced valvular heart disease (DIVHD) are only based on the observation of aortic regurgitation ≥ mild and/or mitral regurgitation ≥ moderate. We sought to evaluate the diagnostic value of FDA criteria in a cohort of control patients and in a cohort of patients exposed to a drug (benfluorex) known to induce VHD. This prospective, multicentre study included 376 diabetic control patients not exposed to valvulopathic drugs and 1000 subjects previously exposed to benfluorex. Diagnosis of mitral or aortic DIVHD was based on a combined functional and morphological echocardiographic analysis of cardiac valves. Patients were classified according to the FDA criteria [mitral or aortic-FDA(+) and mitral or aortic-FDA(-)]. Among the 376 control patients, 2 were wrongly classified as mitral-FDA(+) and 17 as aortic-FDA(+) (0.53 and 4.5% of false positives, respectively). Of those exposed to benfluorex, 48 of 58 with a diagnosis of mitral DIVHD (83%) were classified as mitral-FDA(-), and 901 of the 910 patients (99%) without a diagnosis of the mitral DIVHD group were classified as mitral-FDA(-). All 40 patients with a diagnosis of aortic DIVHD were classified as aortic-FDA(+), and 105 of the 910 patients without a diagnosis of aortic DIVHD (12%) were classified aortic-FDA(+). Older age and lower BMI were independent predictors of disagreement between FDA criteria and the diagnosis of DIVHD in patients exposed to benfluorex (both P ≤ 0.001). FDA criteria solely based on the Doppler detection of cardiac valve regurgitation underestimate for the mitral valve and overestimate for the aortic valve the frequency of DIVHD. Therefore, the diagnosis of DIVHD must be based on a combined echocardiographic and Doppler morphological and functional analysis of cardiac valves. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

21 CFR 314.103 - Dispute resolution.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.103 Dispute resolution. (a) General. FDA is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications or abbreviated...

21 CFR 314.103 - Dispute resolution.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.103 Dispute resolution. (a) General. FDA is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications or abbreviated...

21 CFR 314.103 - Dispute resolution.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.103 Dispute resolution. (a) General. FDA is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications or abbreviated...

21 CFR 314.103 - Dispute resolution.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.103 Dispute resolution. (a) General. FDA is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications or abbreviated...

21 CFR 314.103 - Dispute resolution.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.103 Dispute resolution. (a) General. FDA is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications or abbreviated...

Investigation of the interfacial reaction between metal and fluorine-contained polyimides

NASA Astrophysics Data System (ADS)

Yang, Ching-Yu; Chen, J. S.; Hsu, S. L. C.

2005-07-01

In this work, thin metal films (Cr and Ta) were deposited on fluorine-contained polyimides, 6FDA-BisAAF, and 6FDA-PPD. The chemical states of the metal/polyimide samples were characterized by using x-ray photoelectron spectroscopy (XPS). XPS analysis reveals that metal-C, C-O, and metal-O bondings are present in metallized 6FDA-BisAAF and 6FDA-PPD. C-F bonds are observed in bare 6FDA-BisAAF and 6FDA-PPD however, they are not seen in the metallized samples. Disappearance of the C-F bonding is attributed to the disruption of CF3 side groups from the main chains of 6FDA-BisAAF and 6FDA-PPD when the chains are exposed to the plasma during the metal deposition. Nevertheless, the disruption of CF3 side groups also creates sites for the formation of metal-C or C-O bondings, which provide a positive adhesion strength at the metal/polyimide interface, as revealed by the tape test.

Reflections on the US FDA's Warning on Direct-to-Consumer Genetic Testing.

PubMed

Yim, Seon-Hee; Chung, Yeun-Jun

2014-12-01

In November 2013, the US Food and Drug Administration (FDA) sent a warning letter to 23andMe, Inc. and ordered the company to discontinue marketing of the 23andMe Personal Genome Service (PGS) until it receives FDA marketing authorization for the device. The FDA considers the PGS as an unclassified medical device, which requires premarket approval or de novo classification. Opponents of the FDA's action expressed their concerns, saying that the FDA is overcautious and paternalistic, which violates consumers' rights and might stifle the consumer genomics field itself, and insisted that the agency should not restrict direct-to-consumer (DTC) genomic testing without empirical evidence of harm. Proponents support the agency's action as protection of consumers from potentially invalid and almost useless information. This action was also significant, since it reflected the FDA's attitude towards medical application of next-generation sequencing techniques. In this review, we followed up on the FDA-23andMe incident and evaluated the problems and prospects for DTC genetic testing.

The history and contemporary challenges of the US Food and Drug Administration.

PubMed

Borchers, Andrea T; Hagie, Frank; Keen, Carl L; Gershwin, M Eric

2007-01-01

The year 2006 marks the 100th anniversary of the regulatory agency now known as the US Food and Drug Administration (FDA), the first consumer protection agency of the federal government and arguably the most influential regulatory agency in the world. The FDA thus plays an integral role in the use of pharmaceuticals, not only in the United States but worldwide. The goal of this review was to present an overview of the FDA and place its current role in the perspectives of history and contemporary needs. Relevant materials for this review were identified through a search of the English-language literature indexed on MEDLINE (through 2006) using the main search terms United States Food and Drug Administration, FDA, history of the FDA, drug approvals, drug legislation, and FDA legislation. Results from the initial searches were then explored further. The statute that created the bureau which later became the FDA established this agency to prohibit interstate commerce of adulterated foods, drinks, and drugs. The Food, Drug, and Cosmetic Act that replaced it in 1938, and subsequent food and drug laws and amendments, expanded the FDA's responsibilities to cosmetics, medical devices, biological products, and radiation-emitting products. These amendments have also established the FDA as a mainly preventive regulatory agency that relies chiefly on pre-market control. As such, the FDA has played an important role in shaping the modern pharmaceutical industry by making the scientific approach and the clinical trial process the standard for establishing safety and efficacy and by making rigorous scientific analysis the predominant component of the process for pharmaceutical regulation. As shown in this review, the evolution of the FDA can be described as a series of "crisis-legislation-adaptation" cycles: a public health crisis promoted the passage of congressional legislation, which was then followed by implementation of the law by the FDA. However, the crises the FDA faces currently are likely to be overcome only under strong and permanent leadership willing to redefine the role and procedures of the FDA with an open mind.

Current FDA directives for promoting public health

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayes, A.H. Jr.

1982-03-01

The current directions of the FDA are outlined. The underlying philosophy of the FDA under the Reagan Administration is that both the private sector and the government must address the responsibilities to which they are best suited for the health-care system to work more efficiently. To facilitate this, FDA is conducting comprehensive reviews of FDA regulations and the drug-evaluation process. There are many dimensions to promoting public health, and the FDA alone cannot assure an adequate supply of safe and effective drugs. Innovative science and technology are needed to develop new drugs, followed by maximum potentiation (maximum good and leastmore » harm) after FDA approval. Hospital pharmacists have a role in maximizing the potential benefits of drugs through pharmacy and therapeutics committees. The current status of the pilot program for patient package inserts is described. The response at a recent hearing on the program indicates that the responsibility to protect the public health is shared by the government, health professions, industry, and the public. The FDA's campaign on sodium is based on that shared responsibility. By improving communication and building upon their common objections, both pharmacy and the FDA can do their jobs successfully.« less

OpenVigil FDA - Inspection of U.S. American Adverse Drug Events Pharmacovigilance Data and Novel Clinical Applications.

PubMed

Böhm, Ruwen; von Hehn, Leocadie; Herdegen, Thomas; Klein, Hans-Joachim; Bruhn, Oliver; Petri, Holger; Höcker, Jan

2016-01-01

Pharmacovigilance contributes to health care. However, direct access to the underlying data for academic institutions and individual physicians or pharmacists is intricate, and easily employable analysis modes for everyday clinical situations are missing. This underlines the need for a tool to bring pharmacovigilance to the clinics. To address these issues, we have developed OpenVigil FDA, a novel web-based pharmacovigilance analysis tool which uses the openFDA online interface of the Food and Drug Administration (FDA) to access U.S. American and international pharmacovigilance data from the Adverse Event Reporting System (AERS). OpenVigil FDA provides disproportionality analyses to (i) identify the drug most likely evoking a new adverse event, (ii) compare two drugs concerning their safety profile, (iii) check arbitrary combinations of two drugs for unknown drug-drug interactions and (iv) enhance the relevance of results by identifying confounding factors and eliminating them using background correction. We present examples for these applications and discuss the promises and limits of pharmacovigilance, openFDA and OpenVigil FDA. OpenVigil FDA is the first public available tool to apply pharmacovigilance findings directly to real-life clinical problems. OpenVigil FDA does not require special licenses or statistical programs.

76 FR 38184 - Agency Information Collection Activities; Proposed Collection; Comment Request; FDA Recall...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-29

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0439] Agency Information Collection Activities; Proposed Collection; Comment Request; FDA Recall Regulations AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA...

Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis.

PubMed

Wang, Bo; Franklin, Jessica M; Eddings, Wesley; Landon, Joan; Kesselheim, Aaron S

2016-01-01

Following Food and Drug Administration (FDA) approval, many drugs are prescribed for non-FDA-approved ("off-label") uses. If substantial evidence supports the efficacy and safety of off-label indications, manufacturers can pursue formal FDA approval through supplemental new drug applications (sNDAs). We evaluated the effect of FDA determinations on pediatric sNDAs for antipsychotic drugs on prescribing of these products in children. Retrospective, segmented time-series analysis using new prescription claims during 2003-2012 for three atypical antipsychotics (olanzapine, quetiapine, ziprasidone). FDA approved the sNDAs for pediatric use of olanzapine and quetiapine in December 2009, but did not approve the sNDA for pediatric use of ziprasidone. During the months before FDA approval of its pediatric sNDA, new prescriptions of olanzapine decreased for both children and adults. After FDA approval, the increase in prescribing trends was similar for both age groups (P = 0.47 for schizophrenia and bipolar disorder; P = 0.37 for other indications). Comparable decreases in use of quetiapine were observed between pediatrics and adults following FDA approval of its pediatric sNDA (P = 0.88; P = 0.63). Prescribing of ziprasidone decreased similarly for pediatric and adult patients after FDA non-approval of its pediatric sNDA (P = 0.61; P = 0.79). The FDA's sNDA determinations relating to use of antipsychotics in children did not result in changes in use that favored the approved sNDAs and disfavored the unapproved sNDA. Improved communication may help translate the agency's expert judgments to clinical practice.

78 FR 67216 - Norfolk Southern Railway Company-Abandonment Exemption-in Lake County, Ind.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-08

... Junction Avenue in the City of Schererville, Ind.) and milepost MQ 283.10 (near the line's crossing of E... 14, 2014, or 10 days after service of a decision granting the petition for exemption, whichever occurs sooner. Each OFA must be accompanied by a $1,600 filing fee. See 49 CFR 1002.2(f)(25). All...

Genome sequence of foot-and-mouth disease virus serotype O lineage ind-2001d collected in Vietnam in 2015

USDA-ARS?s Scientific Manuscript database

Foot-and-mouth disease (FMD) is endemic in several countries in Asia and Africa and is considered one of the most important livestock diseases worldwide. Three serotypes of FMD virus (A, O and Asia1) contribute to endemicity in mainland Southeast Asia. In 2015, FMDV lineage Ind-2001 was detected for...

21 CFR 312.86 - Focused FDA regulatory research.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

21 CFR 312.86 - Focused FDA regulatory research.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

21 CFR 312.86 - Focused FDA regulatory research.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

21 CFR 312.86 - Focused FDA regulatory research.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

76 FR 61709 - Agency Information Collection Activities; Proposed Collection; Comment Request; FDA Form 3728...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-05

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0708] Agency Information Collection Activities; Proposed Collection; Comment Request; FDA Form 3728, Animal...: The Food and Drug Administration (FDA) is announcing an opportunity for public comment on the proposed...

21 CFR 830.120 - Responsibilities of an FDA-accredited issuing agency.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Responsibilities of an FDA-accredited issuing... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA Accreditation of an Issuing Agency § 830.120 Responsibilities of an FDA-accredited issuing agency. To maintain its accreditation, an...

21 CFR 314.80 - Postmarketing reporting of adverse drug experiences.

Code of Federal Regulations, 2011 CFR

2011-04-01

... SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications... resubmit to FDA adverse drug experience reports forwarded to the applicant by FDA; however, applicants must submit all followup information on such reports to FDA. Any person subject to the reporting requirements...

21 CFR 812.30 - FDA action on applications.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

21 CFR 314.108 - New drug product exclusivity.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and... investigation means that before or during the investigation, the applicant was named in Form FDA-1571 filed with FDA as the sponsor of the investigational new drug application under which the investigation was...

77 FR 51949 - Privacy Act, Exempt Record System

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-28

.... FDA-2011-N-0252] Office of the Secretary 45 CFR Part 5b Privacy Act, Exempt Record System AGENCY... Drug Administration (FDA) of the Department of Health and Human Services (HHS) will be implementing a new system of records, 09-10-0020, ``FDA Records Related to Research Misconduct Proceedings, HHS/FDA...

21 CFR 314.96 - Amendments to an unapproved abbreviated application.

Code of Federal Regulations, 2011 CFR

2011-04-01

... SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Abbreviated... applicant on the same drug product formulation, unless the information has previously been submitted to FDA... and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may...

21 CFR 812.30 - FDA action on applications.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

Internet Database Review: The FDA BBS.

ERIC Educational Resources Information Center

Tomaiuolo, Nicholas G.

1993-01-01

Describes the electronic bulletin board system (BBS) of the Food and Drug Administration (FDA) that is accessible through the Internet. Highlights include how to gain access; the menu-driven software; other electronic sources of FDA information; and adding value. Examples of the FDA BBS menu and the help screen are included. (LRW)

21 CFR 312.86 - Focused FDA regulatory research.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

10 CFR 35.7 - FDA, other Federal, and State requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

10 CFR 35.7 - FDA, other Federal, and State requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

10 CFR 35.7 - FDA, other Federal, and State requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

77 FR 14401 - Draft Guidance on Drug Safety Information-FDA's Communication to the Public; Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2005-D-0339] Draft Guidance on Drug Safety Information--FDA's Communication to the Public; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is...

21 CFR 314.80 - Postmarketing reporting of adverse drug experiences.

Code of Federal Regulations, 2013 CFR

2013-04-01

... SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications... resubmit to FDA adverse drug experience reports forwarded to the applicant by FDA; however, applicants must submit all followup information on such reports to FDA. Any person subject to the reporting requirements...

21 CFR 314.80 - Postmarketing reporting of adverse drug experiences.

Code of Federal Regulations, 2012 CFR

2012-04-01

... SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications... resubmit to FDA adverse drug experience reports forwarded to the applicant by FDA; however, applicants must submit all followup information on such reports to FDA. Any person subject to the reporting requirements...

78 FR 36194 - Draft Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-17

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2009-D-0490] Draft Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally... Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the...

10 CFR 35.7 - FDA, other Federal, and State requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

21 CFR 812.30 - FDA action on applications.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

21 CFR 812.30 - FDA action on applications.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

10 CFR 35.7 - FDA, other Federal, and State requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false FDA, other Federal, and State requirements. 35.7 Section....7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee from complying with applicable FDA, other Federal, and State requirements governing radioactive drugs or devices. ...

21 CFR 812.30 - FDA action on applications.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the date...

21 CFR 314.96 - Amendments to an unapproved abbreviated application.

Code of Federal Regulations, 2012 CFR

2012-04-01

... SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Abbreviated... applicant on the same drug product formulation, unless the information has previously been submitted to FDA... and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may...

Preparation and Characterization of Ion-Irradiated Nanodiamonds as Photoacoustic Contrast Agents.

PubMed

Fang, Chia-Yi; Chang, Cheng-Chun; Mou, Chung-Yuan; Chang, Huan-Cheng

2015-02-01

Highly radiation-damaged or irradiated nanodiamonds (INDs) are a new type of nanomaterial developed recently as a potential photoacoustic (PA) contrast agent for deep-tissue imaging. This work characterized in detail the photophysical properties of these materials prepared by ion irradiation of natural diamond powders using various spectroscopic methods. For 40-nm NDs irradiated with 40-keV He+ at a dose of 3 x 10(15) ions/cm2, an average molar extinction coefficient of 4.2 M-1 cm-1 per carbon atom was measured at 1064 nm. Compared with gold nanorods of similar dimensions (10 nm x 67 nm), the INDs have a substantially smaller (by > 4 orders of magnitude) molar extinction coefficient per particle. However, the deficit is readily compensated by the much higher thermal stability, stronger hydrophilic interaction with water, and a lower nanobubble formation threshold (~30 mJ/cm2) of the sp3-carbon-based nanomaterial. No sign of photodamage was detected after high-energy (>100 mJ/cm2) illumination of the INDs for hours. Cell viability assays at the IND concentration of up to 100 µg/mL showed that the nanomaterial is non-cytotoxic and potentially useful for long-term PA bioimaging applications.

[Effects of population density and culture volume on the growth and reproduction of Moina irrasa].

PubMed

Chen, Li-Na; Li, Yu-Ying; Deng, Dao-Gui; Jin, Xian-Wen; Ge, Qian; Wang, Shao-Qin

2012-07-01

A laboratory experiment was conducted to study the effects of different population density (D1 : 100 ind x L(-1), D2 : 150 ind x L(-1), D3 : 300 ind x L(-1)) and culture volume (V1: 50 mL, V2 : 100 mL, V3 : 400 mL) on the growth and reproduction of Moina irrasa at 25 degrees C. At the same culture density, the body length of the M. irrasa females at their first pregnancy, the first brood, and the total offsprings per female decreased with the increase of culture volumes, while the sex ratio (male/female) of the offsprings was in adverse. At the same culture volumes, the total offsprings per female decreased with the increase of culture density. At D1 V1, the body length of the females at their first pregnancy (0.95 +/- 0.10 mm) and the total offsprings (171.3 +/- 19.8 ind) per female were the maximum. At D3V2, the sex ratio was the maximum (0.54 +/- 0.05). Culture density, culture volume, and their interactions significantly affected the total offsprings per female and the sex ratio (P < 0.001).

Conditions of Decapods Infraorders in Dead Coral Pocillopora sp. at Pemuteran, Bali: Study Case 2011 and 2016

NASA Astrophysics Data System (ADS)

Kholilah, Nenik; Malik, Muhammad Danie Al; Kurniasih, Eka Maya; Sembiring, Andrianus; Ambariyanto, Ambariyanto; Mayer, Christopher

2018-02-01

Decapods are marine organism which have burrowing-life characteristic and tend to live in the hard coral, such as Pocillopora sp. Pemuteran district is located in West Bali with high marine biodiversity. In 2016 almost all of the coral reefs in this area have bleached. This research investigates the condition of decapods before and after coral bleaching in Pemuteran. Dead corals, Pocillopora sp., were taken from 8-12 meters depth in 2016. All organisms within those corals were collected and identified until infraorder and family level. Comparison was done with data collected in 2011. This study found 12 families with a total of 5 infraorder which are equal to the previous data. The number of individual has increased from 88 into 214 individual. The mean presence increased from 6.2875 ind/fam to 15.2875 ind/fam. While the density also increased from 23.68 ind/L to 42.09 ind/L. Uniformity and dominance indices for all infraorder is low. These results show that there is an increase of the density of decapods after coral bleaching event, but the diversity of decapods was slightly changed.

Agenda: EDRN FDA Education Workshop — EDRN Public Portal

Cancer.gov

The purpose of this workshop was to open dialogue between FDA staff that provide oversight for review of in vitro diagnostic applications and EDRN scientists currently performing clinical validation studies on cancer biomarkers. Issues related to FDA review of diagnostic tests were presented by FDA personnel. Representatives from EDRN provided details on supporting data of their validation studies and the resources developed within EDRN to facilitate such research for FDA compliance. The agenda provided here provides links to the presentations by each speaker.

Broadband 0.25-um Gallium Nitride (GaN) Power Amplifier Designs

DTIC Science & Technology

2017-08-14

CP pF RES ID=R1 R=RP Ohm PORT P=1 Z=50 Ohm RP=87.5ohm/mm... CP =-0.31pF/mm For 1.75mm, RP=50ohms, CP =0.54pf CP = 0.31 * size size=1.75 RP = 87.5 / size CAP ID=C1 C=CP1 pF RES ID=R1 R=RP Ohm IND ID=L1 L=LP1 nH CAP...ID=C2 C=Cser2 pF IND ID=L2 L=Lser2 nH IND ID=L3 L=LP1 nH CAP ID=C3 C=CP1 pF PORT P=1 Z=50 Ohm PORT P=2 Z=50 Ohm size=1.75 RP = 87.5 / size CP =

The debate on FDA reform: a view from the U.S. Senate. Food and Drug Administration.

PubMed

Baker, R

1995-09-01

The recently released concept paper on Food and Drug Administration (FDA) reform from Republican Senator, Nancy Kassebaum, is reviewed. Senator Kassebaum chairs the Senate Committee on Labor and Human Resources that will influence the Senate's action on FDA reform. The paper outlines the Senator's priorities for Congressional legislation on FDA reform in the following areas: the FDA mission and its accountability; creation of a Performance Review Panel and Industry Advisory Council; approval and access of products for seriously ill patients; the FDA's responsibility for good manufacturing practices; establishment of an Ombudsman Office for resolving disputes; dissemination of information on unapproved uses of approved products; and approval standards for new drugs.

Use of data mining at the Food and Drug Administration.

PubMed

Duggirala, Hesha J; Tonning, Joseph M; Smith, Ella; Bright, Roselie A; Baker, John D; Ball, Robert; Bell, Carlos; Bright-Ponte, Susan J; Botsis, Taxiarchis; Bouri, Khaled; Boyer, Marc; Burkhart, Keith; Condrey, G Steven; Chen, James J; Chirtel, Stuart; Filice, Ross W; Francis, Henry; Jiang, Hongying; Levine, Jonathan; Martin, David; Oladipo, Taiye; O'Neill, Rene; Palmer, Lee Anne M; Paredes, Antonio; Rochester, George; Sholtes, Deborah; Szarfman, Ana; Wong, Hui-Lee; Xu, Zhiheng; Kass-Hout, Taha

2016-03-01

This article summarizes past and current data mining activities at the United States Food and Drug Administration (FDA). We address data miners in all sectors, anyone interested in the safety of products regulated by the FDA (predominantly medical products, food, veterinary products and nutrition, and tobacco products), and those interested in FDA activities. Topics include routine and developmental data mining activities, short descriptions of mined FDA data, advantages and challenges of data mining at the FDA, and future directions of data mining at the FDA. Published by Oxford University Press on behalf of the American Medical Informatics Association 2015. This work is written by US Government employees and is in the public domain in the US.

A review of the FDA draft guidance document for software validation: guidance for industry.

PubMed

Keatley, K L

1999-01-01

A Draft Guidance Document (Version 1.1) was issued by the United States Food and Drug Administration (FDA) to address the software validation requirement of the Quality System Regulation, 21 CFR Part 820, effective June 1, 1997. The guidance document outlines validation considerations that the FDA regards as applicable to both medical device software and software used to "design, develop or manufacture" medical devices. The Draft Guidance is available at the FDA web site http:@www.fda.gov/cdrh/comps/swareval++ +.html. Presented here is a review of the main features of the FDA document for Quality System Regulation (QSR), and some guidance for its implementation in industry.

21 CFR 316.34 - FDA recognition of exclusive approval.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

21 CFR 807.100 - FDA action on a premarket notification.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

21 CFR 812.42 - FDA and IRB approval.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

21 CFR 316.34 - FDA recognition of exclusive approval.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 316.34 - FDA recognition of exclusive approval.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

21 CFR 812.42 - FDA and IRB approval.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

21 CFR 314.125 - Refusal to approve an application.

Code of Federal Regulations, 2014 CFR

2014-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... the application under section 505(d) of the act, if: (1) FDA sends the applicant a complete response... question of whether the application is approvable; and (3) FDA finds that any of the reasons given in...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

76 FR 31615 - Draft Guidance for Industry and FDA Staff: Commercially Distributed In Vitro Diagnostic Products...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0305] Draft Guidance for Industry and FDA Staff: Commercially Distributed In Vitro Diagnostic Products Labeled...: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is...

21 CFR 60.10 - FDA assistance on eligibility.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

21 CFR 60.10 - FDA assistance on eligibility.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

21 CFR 314.110 - Complete response letter to the applicant.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... response letter. FDA will send the applicant a complete response letter if the agency determines that we...) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in...

21 CFR 314.110 - Complete response letter to the applicant.

Code of Federal Regulations, 2012 CFR

2012-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... response letter. FDA will send the applicant a complete response letter if the agency determines that we...) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in...

77 FR 11553 - Draft Guidance on Food and Drug Administration Oversight of Positron Emission Tomography Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-27

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0080... Food and Drug Administration (FDA) is announcing the availability of a draft guidance entitled ``FDA... that address nearly all aspects of the FDA approval and surveillance processes, including application...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 807.100 - FDA action on a premarket notification.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

21 CFR 807.100 - FDA action on a premarket notification.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

21 CFR 812.42 - FDA and IRB approval.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

21 CFR 314.125 - Refusal to approve an application.

Code of Federal Regulations, 2013 CFR

2013-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... the application under section 505(d) of the act, if: (1) FDA sends the applicant a complete response... question of whether the application is approvable; and (3) FDA finds that any of the reasons given in...

21 CFR 830.110 - Application for accreditation as an issuing agency.

Code of Federal Regulations, 2014 CFR

2014-04-01

... SERVICES (CONTINUED) MEDICAL DEVICES UNIQUE DEVICE IDENTIFICATION FDA Accreditation of an Issuing Agency.... (1) An applicant seeking initial FDA accreditation as an issuing agency shall notify FDA of its desire to be accredited by sending a notification by email to [email protected]fda.hhs.gov, or by correspondence to...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 314.110 - Complete response letter to the applicant.

Code of Federal Regulations, 2013 CFR

2013-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... response letter. FDA will send the applicant a complete response letter if the agency determines that we...) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in...

29 CFR 1987.108 - Role of Federal agencies.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) PROCEDURES FOR HANDLING RETALIATION COMPLAINTS UNDER SECTION 402 OF THE FDA FOOD SAFETY...) The FDA, if interested in a proceeding, may participate as amicus curiae at any time in the proceeding, at the FDA's discretion. At the request of the FDA, copies of all documents in a case must be sent to...

21 CFR 314.125 - Refusal to approve an application.

Code of Federal Regulations, 2012 CFR

2012-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... the application under section 505(d) of the act, if: (1) FDA sends the applicant a complete response... question of whether the application is approvable; and (3) FDA finds that any of the reasons given in...

21 CFR 807.100 - FDA action on a premarket notification.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

21 CFR 314.110 - Complete response letter to the applicant.

Code of Federal Regulations, 2014 CFR

2014-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... response letter. FDA will send the applicant a complete response letter if the agency determines that we...) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in...

76 FR 32367 - Draft Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-1999-D-0742 (formerly Docket No. 1999D-4396)] Draft Guidance for Clinical Investigators, Industry, and FDA Staff...: Notice; correction. SUMMARY: The Food and Drug Administration (FDA) is correcting a notice that appeared...

78 FR 29141 - Center for Devices and Radiological Health Appeals Processes; Guidance for Industry and FDA Staff...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-17

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0893] Center for Devices and Radiological Health Appeals Processes; Guidance for Industry and FDA Staff... Administration (FDA) is announcing the availability of the guidance entitled ``Center for Devices and...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 801.57 - Discontinuation of legacy FDA identification numbers assigned to devices.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Discontinuation of legacy FDA identification... Device Identification § 801.57 Discontinuation of legacy FDA identification numbers assigned to devices... been assigned an FDA labeler code to facilitate use of NHRIC or NDC numbers may continue to use that...

78 FR 19492 - Draft Guidance for Industry on Formal Meetings Between FDA and Biosimilar Biological Product...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-D-0286] Draft Guidance for Industry on Formal Meetings Between FDA and Biosimilar Biological Product Sponsors or... Drug Administration (FDA) is announcing the availability of a draft guidance for industry entitled...

21 CFR 60.10 - FDA assistance on eligibility.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

21 CFR 316.34 - FDA recognition of exclusive approval.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

21 CFR 314.125 - Refusal to approve an application.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... the application under section 505(d) of the act, if: (1) FDA sends the applicant a complete response... question of whether the application is approvable; and (3) FDA finds that any of the reasons given in...

21 CFR 316.34 - FDA recognition of exclusive approval.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely...

75 FR 11893 - Food and Drug Administration Transparency Task Force; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2009-N-0247... Administration, HHS. ACTION: Notice; request for comments. SUMMARY: The Food and Drug Administration (FDA) is soliciting comments from interested persons on ways in which FDA can increase transparency between FDA and...

77 FR 71803 - Guidance on Food and Drug Administration Oversight of Positron Emission Tomography Drug Products...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-04

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0080... and Drug Administration (FDA) is announcing the availability of a guidance entitled ``FDA Oversight of... nearly all aspects of the FDA approval and surveillance processes, including application submission...

21 CFR 314.110 - Complete response letter to the applicant.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... response letter. FDA will send the applicant a complete response letter if the agency determines that we...) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in...

21 CFR 812.42 - FDA and IRB approval.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

21 CFR 812.42 - FDA and IRB approval.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both...

21 CFR 314.125 - Refusal to approve an application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications... the application under section 505(d) of the act, if: (1) FDA sends the applicant a complete response... question of whether the application is approvable; and (3) FDA finds that any of the reasons given in...

21 CFR 807.100 - FDA action on a premarket notification.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA action on a premarket notification. 807.100... IMPORTERS OF DEVICES Premarket Notification Procedures § 807.100 FDA action on a premarket notification. (a) After review of a premarket notification, FDA will: (1) Issue an order declaring the device to be...

21 CFR 60.10 - FDA assistance on eligibility.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA assistance on eligibility. 60.10 Section 60.10... TERM RESTORATION Eligibility Assistance § 60.10 FDA assistance on eligibility. (a) Upon written request from the U.S. Patent and Trademark Office, FDA will assist the U.S. Patent and Trademark Office in...

76 FR 41506 - Draft Guidance for Industry and FDA Staff on In Vitro Companion Diagnostic Devices; Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-14

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0215] Draft Guidance for Industry and FDA Staff on In Vitro Companion Diagnostic Devices; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is...

76 FR 56205 - Request for Notification From Industry Organizations Interested in Participating in the Selection...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-12

... Products Scientific Advisory Committee, notify FDA in writing. FDA is also requesting nominations for... letters stating interest in participating in the selection process to FDA by October 12, 2011 (see... candidates should be sent to FDA by October 12, 2011. ADDRESSES: All letters of interest and nominations...

Regulating (for the benefit of) future persons: a different perspective on the FDA's jurisdiction to regulate human reproductive cloning.

PubMed

Javitt, Gail H; Hudson, Kathy

2003-01-01

The Food and Drug Administration (FDA) has taken the position that human reproductive cloning falls within its regulatory jurisdiction. This position has been subject to criticism on both procedural and substantive grounds. Some have contended that the FDA has failed to follow administrative law principles in asserting its jurisdiction, while others claim the FDA is ill suited to the task of addressing the ethical and social implications of human cloning. This Article argues, that, notwithstanding these criticisms, the FDA could plausibly assert jurisdiction over human cloning as a form of human gene therapy, an area in which the FDA is already regarded as having primary regulatory authority. Such an assertion would require that the FDA's jurisdiction extend to products affecting future persons, i.e., those not yet born. This Article demonstrates, for the first time, that such jurisdiction was implicit in the enactment of the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act and that the FDA has historically relied on such authority in promulgating regulations for drugs and devices.

EBOLA and FDA: reviewing the response to the 2014 outbreak, to find lessons for the future

PubMed Central

Largent, Emily A.

2016-01-01

Abstract In 2014, West Africa confronted the most severe outbreak of Ebola virus disease (EVD) in history. At the onset of the outbreak—as now—there were no therapies approved by the U.S. Food and Drug Administration (FDA) for prevention of, post-exposure prophylaxis against, or treatment of EVD. As a result, the outbreak spurred interest in developing novel treatments, sparked calls to use experimental interventions in the field, and highlighted challenges to the standard approach to FDA approval of new drugs. Although the outbreak was geographically centered in West Africa, it showcased FDA's global role in drug development, approval, and access. FDA's response to EVD highlights the panoply of agency powers and demonstrates the flexibility of FDA's regulatory framework. This paper evaluates the strengths and weaknesses of FDA's response and makes policy recommendations regarding how FDA should respond to new and re-emerging public health threats. In particular, it argues that greater emphasis should be placed on drug development in interoutbreak periods and on assuring access to approved products. The current pandemic of Zika virus infection is but one example of an emerging health threat that will require FDA involvement in order to achieve a successful response. PMID:28852537

A Critical Review of Methods to Evaluate the Impact of FDA Regulatory Actions

PubMed Central

Briesacher, Becky A.; Soumerai, Stephen B.; Zhang, Fang; Toh, Sengwee; Andrade, Susan E.; Wagner, Joann L.; Shoaibi, Azadeh; Gurwitz, Jerry H.

2013-01-01

Purpose To conduct a synthesis of the literature on methods to evaluate the impacts of FDA regulatory actions, and identify best practices for future evaluations. Methods We searched MEDLINE for manuscripts published between January 1948 and August 2011 that included terms related to FDA, regulatory actions, and empirical evaluation; the review additionally included FDA-identified literature. We used a modified Delphi method to identify preferred methodologies. We included studies with explicit methods to address threats to validity, and identified designs and analytic methods with strong internal validity that have been applied to other policy evaluations. Results We included 18 studies out of 243 abstracts and papers screened. Overall, analytic rigor in prior evaluations of FDA regulatory actions varied considerably; less than a quarter of studies (22%) included control groups. Only 56% assessed changes in the use of substitute products/services, and 11% examined patient health outcomes. Among studies meeting minimal criteria of rigor, 50% found no impact or weak/modest impacts of FDA actions and 33% detected unintended consequences. Among those studies finding significant intended effects of FDA actions, all cited the importance of intensive communication efforts. There are preferred methods with strong internal validity that have yet to be applied to evaluations of FDA regulatory actions. Conclusions Rigorous evaluations of the impact of FDA regulatory actions have been limited and infrequent. Several methods with strong internal validity are available to improve trustworthiness of future evaluations of FDA policies. PMID:23847020

Abundance and stratification of soil macroarthropods in a Caatinga Forest in Northeast Brazil.

PubMed

Araújo, V F P; Bandeira, A G; Vasconcellos, A

2010-10-01

In arid and semiarid environments, seasonality usually exerts a strong influence on the composition and dynamics of the soil community. The soil macroarthropods were studied in a Caatinga forest located in the Reserva Particular do Patrimônio Natural (RPPN) Fazenda Almas, São José dos Cordeiros, Paraíba, Brazil. Samples were collected during the dry and rainy seasons following the method proposed by the Tropical Soil Biology and Fertility Program (TSBF), with minor modifications. At each station, 15 soil blocks (20 × 20 × 30 cm: 12 L) were extracted and divided into three layers: A (0-10 cm), B (10-20 cm), and C (20-30 cm). In the rainy and dry seasons 1,306 ± 543(se) and 458 ± 212 ind.m-2 macroarthropods were found, respectively, with 35 and 18 respective taxa recorded. The abundance of individuals and taxa were significantly higher in the rainy season. Isoptera (57.8%) was the most abundant taxon, followed by Hymenoptera: Formicidae (17.2%), Coleoptera larvae (7.3%), and Araneae (3.5%). In the rainy season, abundance in layer A (576 ± 138 ind.m-2) was significantly higher than that of layer C (117 ± 64 ind.m-2), but was not different from layer B (613 ± 480 ind.m-2). There was also no difference between the layer B and C abundances. In the dry season, abundance in layer B (232 ± 120 ind.m-2) was not significantly different compared to layer A (182 ± 129 ind.m-2), but was significantly higher than abundance in layer C (44 ± 35 ind.m-2). During the rainy season, layer A (34 taxa) was significantly richer in taxa than layers B (19 taxa) and C (11 taxa). On the other hand, during the dry season the richness of layers A (12 taxa) and B (12 taxa) was equal, but significantly higher than that of layer C (6 taxa). Richness of taxa and abundance were positively correlated with soil organic matter and negatively correlated with soil temperature. The community of soil macroarthropods in the area of Caatinga studied has taxonomic and functional structures that are relatively complex and is therefore likely to exert an influence on ecosystem productivity due to its physical effects on soil profile and necromass fragmentation, as occurs in other arid and semiarid ecosystems throughout the world.

Prévalence et caractéristiques des effets indésirables des antihypertenseurs chez les patients suivis en ambulatoire au Centre Hospitalier Universitaire Yalgado Ouédraogo

PubMed Central

Millogo, Georges Rosario Christian; Zongo, Ragomzingba Frank Edgard; Benao, Anita; Youl, Estelle Noëla Hoho; Bassoleth, Blaise Alexandre Bazona; Ouédraogo, Moussa; Zabsonré, Patrice; Guissou, Innocent Pierre

2018-01-01

La prise en charge médicamenteuse de l'hypertension artérielle (HTA) entraine des effets indésirables qui peuvent être gênants et ainsi influencer l'observance du patient. Nous avons étudié ces effets indésirables dans le service de cardiologie du Centre hospitalier universitaire Yalgado Ouédraogo afin de déterminer leurs fréquences et leurs caractéristiques. Il s'agissait d'une étude transversale de juillet à septembre 2015 chez les patients suivis en ambulatoire pour HTA. Les données ont été obtenues à partir de l'interrogatoire, des carnets de suivi des patients et des fiches de consultations. Au total 278 patients ont été inclus. La population d'étude incluait 69,1% de femmes. L'âge moyen était de 52,2 ans avec des extrêmes de 23 et 86 ans. Quatre vingt et sept virgule huit pourcent (87,8%) vivaient en milieu urbain. Le tabagisme, la dyslipidémie et les antécédents familiaux d'HTA représentaient respectivement 9%, 35,6% et 57,2%. Au plan thérapeutique, 43,2% étaient sous monothérapie, 35,6% sous bithérapie à l'initiation du traitement. Les inhibiteurs calciques (59,7%) étaient la classe thérapeutique la plus utilisée. La prévalence globale des effets indésirables était de 60,1%. Les inhibiteurs calciques étaient impliqués dans 53,6% suivis des diurétiques (48,6%) dans la survenue de l'effet indésirable. La prévalence spécifique par molécule était 28,1% pour l'amlodipine et 24,5% pour l'hydrochlorothiazide. La diurèse excessive (13,7%), la toux (12,9%) et les vertiges (11,5%) étaient les effets indésirables les plus fréquemment évoqués par les patients. Le système nerveux central et périphérique et le système ostéo-musculaire étaient les systèmes les plus atteints. Les effets indésirables sont un déterminant majeur de l'adhésion aux traitements antihypertenseur, car leur impact sur la vie quotidienne des patients peut s'avérer significatif. PMID:29875965

A comparison of new drugs approved by the FDA, the EMA, and Swissmedic: an assessment of the international harmonization of drugs.

PubMed

Zeukeng, Minette-Joëlle; Seoane-Vazquez, Enrique; Bonnabry, Pascal

2018-06-01

This study compared the characteristics of new human drugs approved by the Food and Drug Administration (FDA), the European Medicine Agency (EMA), and Swissmedic (SMC) in the period 2007 to 2016. The list of new drugs and therapeutic biologics approved by the FDA, the EMA, and SMC in the period 2007 to 2016 was collected from websites of those agencies. The study included regulatory information, approval date, and indication for each drug. Descriptive statistical t tests and x 2 -tests were performed for the analysis. From 2007 to 2016, 134 new drugs were approved by all three regulatory agencies. Overall, 66.4% of the drugs were first approved by the FDA, 30.6% by the EMA, and 3.0% by SMC. The difference in approval dates between SMC and the EMA, SMC and the FDA, and the FDA and the EMA were statistically significant. The indications approved by the FDA, the EMA, and SMC for the same drugs were similar in content for 23.1% drugs and different in 76.9% of the drugs. Significant differences in indications existed between the FDA and SMC and the FDA and the EMA, but not between the EMA and SMC. There were differences in the characteristics of new drugs approved by the EMA, the FDA, and SMC in the period 2007-2016. Overall, two thirds of the new drugs were first approved by the FDA. Differences in indications were found in three out of four new drugs approved by the three regulatory agencies. Despite international drug regulation harmonization efforts, significant differences in the characteristics of new drugs approved by different agencies persist.

Association of the FDA Amendment Act with trial registration, publication, and outcome reporting.

PubMed

Phillips, Adam T; Desai, Nihar R; Krumholz, Harlan M; Zou, Constance X; Miller, Jennifer E; Ross, Joseph S

2017-07-18

Selective clinical trial publication and outcome reporting has the potential to bias the medical literature. The 2007 Food and Drug Administration (FDA) Amendment Act (FDAAA) mandated clinical trial registration and outcome reporting on ClinicalTrials.gov, a publicly accessible trial registry. Using publicly available data from ClinicalTrials.gov, FDA documents, and PubMed, we determined registration, publication, and reporting of findings for all efficacy trials supporting FDA approval of new drugs for cardiovascular disease and diabetes between 2005 and 2014, before and after the FDAAA. For published trials, we compared the published interpretation of the findings (positive, equivocal, or negative) with the FDA reviewer's interpretation. Between 2005 and 2014, the FDA approved 30 drugs for 32 indications of cardiovascular disease (n = 17) and diabetes (n = 15) on the basis of 183 trials (median per indication 5.7 (IQR, 3-8)). Compared with pre FDAAA, post-FDAAA studies were more likely to be registered (78 of 78 (100%) vs 73 of 105 (70%); p < 0.001), to be published (76 of 78 (97%) vs 93 of 105 (89%); p = 0.03), and to present findings concordant with the FDA reviewer's interpretation (74 of 76 (97%) vs 78 of 93 (84%); p = 0.004). Pre FDAAA, the FDA reviewer interpreted 80 (76%) trials as positive and 91 (98%) were published as positive. Post FDAAA, the FDA reviewer interpreted 71 (91%) trials as positive and 71 (93%) were published as positive. FDAAA was associated with increased registration, publication, and FDA-concordant outcome reporting for trials supporting FDA approval of new drugs for cardiovascular disease and diabetes.

Spin in RCTs of anxiety medication with a positive primary outcome: a comparison of concerns expressed by the US FDA and in the published literature.

PubMed

Beijers, Lian; Jeronimus, Bertus F; Turner, Erick H; de Jonge, Peter; Roest, Annelieke M

2017-03-29

This study aimed to determine the presence of spin in papers on positive randomised clinical trials (RCTs) of antidepressant medication for anxiety disorders by comparing concerns expressed in the Food and Drug Administration (FDA) reviews with those expressed in the published paper. For every positive anxiety medication trial with a matching publication (n=41), two independent reviewers identified the concerns raised in the US FDA reviews and those in the published literature. Spin was identified when concerns or limitations were expressed by the FDA (about the efficacy of the study drug) but not in the corresponding published paper. Concerns mentioned in the papers but not by the FDA were scored as 'non-FDA' concerns. Only six out of 35 (17%) of the FDA concerns pertaining to drug efficacy were reported in the papers. Two papers mentioned a concern that fit the FDA categories, but was not mentioned in the corresponding FDA review. Eighty-seven non-FDA concerns were counted, which often reflected general concerns or concerns related to the study design. Results indicate the presence of substantial spin in the clinical trial literature on drugs for anxiety disorders. In papers describing RCTs on anxiety medication, the concerns raised by the authors differed from those raised by the FDA. Published papers mentioned a large number of generic concerns about RCTs, such as a lack of long-term research and limited generalisability, while they mentioned few concerns about drug efficacy. These results warrant the promotion of independent statistical review, reporting of patient-level data, more study of spin, and an increased expectation that authors report FDA concerns. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

A Safety Study on Intrathecal Delivery of Autologous Mesenchymal Stromal Cells in Rabbits Directly Supporting Phase I Human Trials

PubMed Central

Chen, Bingkun K.; Staff, Nathan P.; Knight, Andrew M.; Nesbitt, Jarred J.; Butler, Greg W.; Padley, Douglas J.; Parisi, Joseph E.; Dietz, Allan B.; Windebank, Anthony J.

2014-01-01

Background There are no effective treatments that slow the progression of neurodegenerative diseases. A major challenge of treatment in neurodegenerative diseases is appropriate delivery of pharmaceuticals into the cerebrospinal fluid (CSF) of affected individuals. Mesenchymal stromal cells (MSCs – either naïve or modified) are a promising therapy in neurodegenerative diseases and may be delivered directly into the CSF where they can reside for months. In this preclinical study, we evaluated the safety of intrathecal autologous MSCs in a rabbit model. Methods Autologous adipose-derived MSCs (or a-CSF) were delivered intrathecally, either with single or repeated injections into the foramen magnum of healthy rabbits, and monitored for 4 and 12 weeks, respectively. Results Rabbits tolerated injections well and no definitive MSC-related side effects were observed apart from three rabbits that had delayed death secondary to traumatic foramen magnum puncture. Functional assessments and body weights were equivalent between groups. Gross pathology and histology did not reveal any abnormalities or tumor growth. Complete blood count (CBC) data were normal and there were no differences in CSF IL-6 levels in all groups tested. Discussion Our data suggest that intrathecal delivery of autologous MSCs is safe in a rabbit model. Data from this study has supported two successful Investigational New Drug (IND) applications to the FDA, resulting in the initiation of two clinical trials using autologous MSCs in amyotrophic lateral sclerosis and multiple system atrophy. PMID:25413276

Enhancing the incorporation of the patient's voice in drug development and evaluation.

PubMed

Chalasani, Meghana; Vaidya, Pujita; Mullin, Theresa

2018-01-01

People living with a condition are uniquely positioned to inform the understanding of the therapeutic context for drug development and evaluation. In 2012, the U.S. Food and Drug Administration (FDA) established the Patient-Focused Drug Development (PFDD) initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. PFDD meetings are unique among FDA public meetings, with a format designed to engage patients and elicit their perspectives on two topic areas: (1) the most significant symptoms of their condition and the impact of the condition on daily life; and, (2) their current approaches to treatment. FDA has conducted 24 disease-specific PFDD meetings to date. The lessons learned from PFDD meetings range from experiences common across rare diseases to more disease specific experiences that matter most to patients. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Patient-focused drug development is an ongoing effort and FDA looks forward to the next steps in advancing the science and the utilization of patient input throughout drug development and evaluation. The U.S. Food and Drug Administration (FDA) has multiple mechanisms for its regulators and staff to interact with patients -- but none quite like its novel Patient-Focused Drug Development (PFDD) initiative. FDA established the PFDD initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. Since the initiative's inception in 2012, FDA has held 24 PFDD meetings, covering a range of disease areas and hearing directly from thousands of patients and caregivers. FDA's PFDD meetings have also provided key stakeholders, including patient advocates, researchers, drug developers, healthcare providers, and other government officials, an opportunity to hear the patient's voice. The lessons learned include but are not limited to specific experiences that matter most to patients, patient perspectives on meaningful treatment benefits and how patients want to be engaged in the drug development process. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Further enhancing the incorporation of the patient's voice in drug development and evaluation continues to be a priority for FDA.

78 FR 40267 - Chicago, Central & Pacific Railroad Company-Amended Trackage Rights Exemption-Grand Trunk Western...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

...) at or near milepost 36.1, at Griffith, Ind., and GTW's Railport Yard at or near milepost 6.9 in... Griffith and milepost 43.3 in Spring Lake, Ind. \\1\\ See Chi., Cent. & Pac. R.R.--Trackage Rights Exemption-- Grand Trunk W. R.R., FD 35278 (STB served Aug. 17, 2009). EJ&E subsequently was merged into Wisconsin...

The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression.

PubMed

Maes, Michael; Yirmyia, Raz; Noraberg, Jens; Brene, Stefan; Hibbeln, Joe; Perini, Giulia; Kubera, Marta; Bob, Petr; Lerer, Bernard; Maj, Mario

2009-03-01

Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.

Effects of a La Niña event on hydrological patterns and copepod community structure in a shallow tropical estuary (Taperaçu, Northern Brazil)

NASA Astrophysics Data System (ADS)

Andrade, Marcela P.; Magalhães, André; Pereira, Luci C. C.; Flores-Montes, Manuel J.; Pardal, Emarielle C.; Andrade, Thamara P.; Costa, Rauquírio M.

2016-12-01

The influences of the 2011 La Niña event on the hydrological patterns and copepod community structure were investigated in a shallow tropical estuary, the Taperaçu, in northern Brazil. Specifically, this study aimed to explore the response of the most dominant copepod species and ecological indices (diversity, evenness and richness) to temporal changes in rainfall regime and water parameters in a tropical meso-macro tidal setting. Zooplankton samples were collected from three sampling sites using a conical plankton net (120 μm mesh), with both water and zooplankton samples analyzed by standard methods. In 2011, the physical, chemical and biological parameters of the water were exacerbated by increased rainfall levels resulting from the La Niña event. This resulted in a reduction in the salinity and an increase in dissolved nutrient concentrations and phytoplankton biomass in the study area. These conditions had a direct effect on the monthly dynamics of copepods as a whole, and in particular of five species, O. oswaldocruzi (169,090 ± 254,609 ind. m- 3; p < 0.0001), P. acutus (301,133 ± 518,065 ind. m- 3; p < 0.05), P. marshi (329,391 ± 563,009 ind. m- 3; p > 0.05), O. hebes (40,888 ± 64,893 ind. m- 3; p < 0.05) and A. tonsa (10,680 ± 13,877 ind. m- 3; p > 0.05), all of which were represented by higher densities in February. An extremely high recruitment rate of copepod nauplii was also observed during this month (3,088,309 ± 5,206,645 ind. m- 3; p < 0.05), with this peak in density thus overlapping that of the adult forms. The anomalous period of rainfall was also reflected in reduced species richness and diversity, which not only affected the structure of the copepod community, but may also have provoked shifts in trophic dynamics at higher levels, such as zooplanktivorous fishes.

Emergence of an exotic strain of serotype O foot-and-mouth disease virus O/ME-SA/Ind-2001d in South-East Asia in 2015.

PubMed

Qiu, Y; Abila, R; Rodtian, P; King, D P; Knowles, N J; Ngo, L T; Le, V T; Khounsy, S; Bounma, P; Lwin, S; Verin, B C; Widders, P

2018-02-01

The O/Middle East-South Asia (ME-SA)/Ind-2001 lineage of foot-and-mouth disease virus (FMDV) is endemic in the Indian subcontinent and has been reported in the Middle East and North Africa, but it had not been detected in South-East Asia (SEA) before 2015. This study reports the recent incursions of this viral lineage into SEA, which caused outbreaks in Vientiane Capital of Lao People's Democratic Republic (PDR) in April 2015, in Dak Nong, Dak Lak and Ninh Thuan Provinces of Vietnam from May to October 2015, and in Rakhine State of Myanmar in October 2015. Disease investigations were conducted during the outbreaks and followed up after laboratory results confirmed the involvement of FMDV O/ME-SA/Ind-2001 sublineage d (O/ME-SA/Ind-2001d). Affected host species included cattle, buffalo and pig, and all the outbreaks resolved within 2 months. Animals with clinical signs were separated, and affected premises were disinfected. However, strict movement restrictions were not enforced, and emergency vaccinations were only implemented in Vientiane Capital of Lao PDR and Dak Nong and Ninh Thuan Provinces of Vietnam. Clinical samples were collected from each outbreak and examined by nucleotide sequencing of the FMDV viral protein 1 coding region. Sequence analysis revealed that the O/ME-SA/Ind-2001d isolates from Lao PDR and Vietnam were closely related to each other and similar to viruses previously circulating in India in 2013. Viruses collected from Myanmar were divergent from viruses of the same sublineage recovered from Lao PDR and Vietnam but were closely related to viruses present in Bangladesh in 2015. These findings imply that at least two independent introductions of O/ME-SA/Ind-2001d into SEA have occurred. Our study highlights the transboundary nature of foot-and-mouth disease (FMD) and reinforces the importance of improved FMD surveillance and promotion of safer cross-border trade in SEA to control the risk of introduction and spread of exotic FMDV strains. © 2017 Blackwell Verlag GmbH.

A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history.

PubMed

Sosenko, Jay M; Skyler, Jay S; DiMeglio, Linda A; Beam, Craig A; Krischer, Jeffrey P; Greenbaum, Carla J; Boulware, David; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Mahon, Jeffrey; Palmer, Jerry P

2015-02-01

We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. An approach based on prediction and natural history appears to have utility for diagnosing T1D. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Population density of Sotalia guianensis (Cetacea: Delphinidae) in the Cananéia region, Southeastern Brazil.

PubMed

Havukainen, Liisa; Monteiro, Emygdio Leite de Araujo Fiho; Filla, Gislaine de Fatima

2011-09-01

Population density in cetaceans can be estimated through photo-identification, mark-recapture, land-based observations and visual estimative. We the aim to contribute with conservation strategies, we used line transects (distance method) to estimate the population density of the river dolphin, S. guianensis, in the estuarine region of Cananéia, Southeastern Brazil. The study, developed from May 2003 until April 2004, during dry and rainy seasons and different times of the day, included a sampling area divided into three sectors according to their proximity to the open sea: Sector I (the closest to the open sea); Sector II (with a large flow of fresh water and a salient declivity); and Sector III (with a large flow of fresh water and non salient declivity). Onboard random sampling was carried out in all three sectors, and dolphins seen from the bow to 90 degrees on both port and starboard sides, were registered along with their position and distance from the boat. The total density found was 12.41 ind/km2 (CV = 25.53%) with an average of 2.2 individuals per group for both periods of the day, morning and afternoon. Densities also varied between dry and rainy seasons, being lower in the first with 5.77 ind/km2 (CV = 27.87%) than in the second 20.28 ind/km2 (CV = 31.95%), respectively. Regarding the three sectors, a non-causal heterogeneous distribution was found: Sector I was the most populated (D = 33.10 ind/km2, CV = 13.34%), followed by Sector II (D = 7.8 ind/km2, CV = 21.07%) and Sector III (D = 3.04 ind/km2, CV = 34.04%). The aforementioned area, due to its proximity to the open sea, has the highest salinity level and therefore has the greatest chance of holding most of the marine fish schools which can be cornered by dolphins on high declivity areas during fishing activities. This suggests that food availability may be the most important factor on the river dolphin's distribution in the estuary. Similar studies will contribute to a better understanding of these populations and are essential for future conservation strategies.

75 FR 29561 - Memorandum of Understanding Between the Food and Drug Administration and Drugs.Com

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-26

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0004] [FDA 225-09-0012] Memorandum of Understanding Between the Food and Drug Administration and Drugs.Com... Administration (FDA) is providing notice of a memorandum of understanding (MOU) between FDA and Drugs.Com. The...

21 CFR 314.127 - Refusal to approve an abbreviated new drug application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA... application. (a) FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of... FDA with respect to the active ingredient, route of administration, dosage form, or strength that is...

21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false The Food and Drug Administration's (FDA's... and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. (a) If data or other information available to FDA, including data...

21 CFR 314.105 - Approval of an application and an abbreviated application.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA...) FDA will approve an application and issue the applicant an approval letter on the basis of draft... labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed...

21 CFR 314.105 - Approval of an application and an abbreviated application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA...) FDA will approve an application and issue the applicant an approval letter on the basis of draft... labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed...

21 CFR 806.30 - FDA access to records.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false The Food and Drug Administration's (FDA's... (CONTINUED) FOOD ADDITIVES Premarket Notifications § 170.105 The Food and Drug Administration's (FDA's... data or other information available to FDA, including data not submitted by the manufacturer or...

21 CFR 314.127 - Refusal to approve an abbreviated new drug application.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA... application. (a) FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of... FDA with respect to the active ingredient, route of administration, dosage form, or strength that is...

21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true The Food and Drug Administration's (FDA's... and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. (a) If data or other information available to FDA, including data...

21 CFR 516.34 - FDA recognition of exclusive marketing rights.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

21 CFR 314.160 - Approval of an application or abbreviated application for which approval was previously refused...

Code of Federal Regulations, 2010 CFR

2010-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated... of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the...

21 CFR 314.160 - Approval of an application or abbreviated application for which approval was previously refused...

Code of Federal Regulations, 2012 CFR

2012-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated... of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 314.160 - Approval of an application or abbreviated application for which approval was previously refused...

Code of Federal Regulations, 2011 CFR

2011-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated... of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the...

21 CFR 806.30 - FDA access to records.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

21 CFR 314.160 - Approval of an application or abbreviated application for which approval was previously refused...

Code of Federal Regulations, 2014 CFR

2014-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated... of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the...

21 CFR 314.127 - Refusal to approve an abbreviated new drug application.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA... application. (a) FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of... FDA with respect to the active ingredient, route of administration, dosage form, or strength that is...

21 CFR 314.105 - Approval of an application and an abbreviated application.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA...) FDA will approve an application and issue the applicant an approval letter on the basis of draft... labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed...

21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false The Food and Drug Administration's (FDA's... and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. (a) If data or other information available to FDA, including data...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 314.162 - Removal of a drug product from the list.

Code of Federal Regulations, 2014 CFR

2014-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.162 Removal of a drug product from the list. (a) FDA will remove a... that the withdrawal from the market has ceased or is not for safety or effectiveness reasons. (b) FDA...

77 FR 55845 - Science Board to the Food and Drug Administration: Request for Nominations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-11

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001... Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is requesting nominations to serve on the Science Board to FDA (Science Board). FDA seeks to include the views of women and men...

21 CFR 314.162 - Removal of a drug product from the list.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.162 Removal of a drug product from the list. (a) FDA will remove a... that the withdrawal from the market has ceased or is not for safety or effectiveness reasons. (b) FDA...

21 CFR 314.127 - Refusal to approve an abbreviated new drug application.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA... application. (a) FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of... FDA with respect to the active ingredient, route of administration, dosage form, or strength that is...

21 CFR 806.30 - FDA access to records.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

21 CFR 314.105 - Approval of an application and an abbreviated application.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA...) FDA will approve an application and issue the applicant an approval letter on the basis of draft... labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed...

21 CFR 516.34 - FDA recognition of exclusive marketing rights.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 6 2011-04-01 2011-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

76 FR 62073 - Guidance for Industry on Implementation of the Fee Provisions of the FDA Food Safety...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0721] Guidance for Industry on Implementation of the Fee Provisions of the FDA Food Safety Modernization Act... Administration (FDA) is announcing the availability of a guidance for industry entitled ``Implementation of the...

21 CFR 314.105 - Approval of an application and an abbreviated application.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA...) FDA will approve an application and issue the applicant an approval letter on the basis of draft... labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed...

21 CFR 516.34 - FDA recognition of exclusive marketing rights.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 314.160 - Approval of an application or abbreviated application for which approval was previously refused...

Code of Federal Regulations, 2013 CFR

2013-04-01

... HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated... of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 1271.27 - Will FDA assign me a registration number?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Will FDA assign me a registration number? 1271.27..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b...

21 CFR 516.34 - FDA recognition of exclusive marketing rights.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

21 CFR 314.162 - Removal of a drug product from the list.

Code of Federal Regulations, 2012 CFR

2012-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.162 Removal of a drug product from the list. (a) FDA will remove a... that the withdrawal from the market has ceased or is not for safety or effectiveness reasons. (b) FDA...

21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false The Food and Drug Administration's (FDA's... and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. (a) If data or other information available to FDA, including data...

21 CFR 516.34 - FDA recognition of exclusive marketing rights.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false FDA recognition of exclusive marketing rights. 516... SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive marketing rights. (a) FDA will send the sponsor (or the permanent-resident U.S. agent, if applicable) timely...

21 CFR 314.127 - Refusal to approve an abbreviated new drug application.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA... application. (a) FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of... FDA with respect to the active ingredient, route of administration, dosage form, or strength that is...

21 CFR 314.162 - Removal of a drug product from the list.

Code of Federal Regulations, 2013 CFR

2013-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.162 Removal of a drug product from the list. (a) FDA will remove a... that the withdrawal from the market has ceased or is not for safety or effectiveness reasons. (b) FDA...

21 CFR 314.162 - Removal of a drug product from the list.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and Abbreviated Applications § 314.162 Removal of a drug product from the list. (a) FDA will remove a... that the withdrawal from the market has ceased or is not for safety or effectiveness reasons. (b) FDA...

21 CFR 806.30 - FDA access to records.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

21 CFR 806.30 - FDA access to records.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all reasonable...

78 FR 5463 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-25

... currently assessing any additional data requirements. In this regard, FDA published an Advance Notice of... report. Here, e-form FDA 3744a and reporting via the Electronic Submission Gateway are provided by FDA... January 17, 2012 (77 FR 2302), FDA published a 60-day notice requesting public comment on the proposed...

Drugs and Alcohol in Civil Aviation Accident Pilot Fatalities from 2004-2008

DTIC Science & Technology

2011-09-01

Quinine 16 0.9 19 1.1 37 2.3 42 3.1 FDA 򒾅 Salicylatesβ 96 5.2 114 6.8 41 2.6 11 0.8 FDA 򒾅 Simethicone 0 0.0 0 0.0 0 0.0 1 0.1 FDA 1996... Simethicone 0 0.0 0 0.0 0 0.0 1 0.1 FDA 1996 Triprolidine 0 0.0 0 0.0 2 0.1 2 0.1 FDA 򒾅 β – Screening Cutoff Increased in 2002 μ - Public Law

Removal of Review and Reclassification Procedures for Biological Products Licensed Prior to July 1, 1972. Final rule.

PubMed

2016-02-12

The Food and Drug Administration (FDA, the Agency, or we) is removing two regulations that prescribe procedures for FDA's review and classification of biological products licensed before July 1, 1972. FDA is taking this action because the two regulations are obsolete and no longer necessary in light of other statutory and regulatory authorities established since 1972, which allow FDA to evaluate and monitor the safety and effectiveness of all biological products. In addition, other statutory and regulatory authorities authorize FDA to revoke a license for biological products because they are not safe and effective, or are misbranded. FDA is taking this action as part of its retrospective review of its regulations to promote improvement and innovation.

Clouds vertical properties over the Northern Hemisphere monsoon regions from CloudSat-CALIPSO measurements

NASA Astrophysics Data System (ADS)

Das, Subrata Kumar; Golhait, R. B.; Uma, K. N.

2017-01-01

The CloudSat spaceborne radar and Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) space-borne lidar measurements, provide opportunities to understand the intriguing behavior of the vertical structure of monsoon clouds. The combined CloudSat-CALIPSO data products have been used for the summer season (June-August) of 2006-2010 to present the statistics of cloud macrophysical (such as cloud occurrence frequency, distribution of cloud top and base heights, geometrical thickness and cloud types base on occurrence height), and microphysical (such as ice water content, ice water path, and ice effective radius) properties of the Northern Hemisphere (NH) monsoon region. The monsoon regions considered in this work are the North American (NAM), North African (NAF), Indian (IND), East Asian (EAS), and Western North Pacific (WNP). The total cloud fraction over the IND (mostly multiple-layered cloud) appeared to be more frequent as compared to the other monsoon regions. Three distinctive modes of cloud top height distribution are observed over all the monsoon regions. The high-level cloud fraction is comparatively high over the WNP and IND. The ice water content and ice water path over the IND are maximum compared to the other monsoon regions. We found that the ice water content has little variations over the NAM, NAF, IND, and WNP as compared to their macrophysical properties and thus give an impression that the regional differences in dynamics and thermodynamics properties primarily cause changes in the cloud frequency or coverage and only secondary in the cloud ice properties. The background atmospheric dynamics using wind and relative humidity from the ERA-Interim reanalysis data have also been investigated which helps in understanding the variability of the cloud properties over the different monsoon regions.

Recommendations from the Investigational New Drug/Investigational Device Exemption Task Force of the clInical and Translational Science Award Consortium: developing and implementing a sponsor-investigators training program.

PubMed

Holbein, M E Blair; Berglund, Jelena Petrovic; O'Reilly, Erin K; Hartman, Karen; Speicher, Lisa A; Adamo, Joan E; O'Riordan, Gerri; Brown, Jennifer Swanton; Schuff, Kathryn G

2014-06-01

The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration-regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.

Smallest detectable change and test-retest reliability of a self-reported outcome measure: Results of the Center for Epidemiologic Studies Depression Scale, General Self-Efficacy Scale, and 12-item General Health Questionnaire.

PubMed

Ohno, Shotaro; Takahashi, Kana; Inoue, Aimi; Takada, Koki; Ishihara, Yoshiaki; Tanigawa, Masaru; Hirao, Kazuki

2017-12-01

This study aims to examine the smallest detectable change (SDC) and test-retest reliability of the Center for Epidemiologic Studies Depression Scale (CES-D), General Self-Efficacy Scale (GSES), and 12-item General Health Questionnaire (GHQ-12). We tested 154 young adults at baseline and 2 weeks later. We calculated the intra-class correlation coefficients (ICCs) for test-retest reliability with a two-way random effects model for agreement. We then calculated the standard error of measurement (SEM) for agreement using the ICC formula. The SEM for agreement was used to calculate SDC values at the individual level (SDC ind ) and group level (SDC group ). The study participants included 137 young adults. The ICCs for all self-reported outcome measurement scales exceeded 0.70. The SEM of CES-D was 3.64, leading to an SDC ind of 10.10 points and SDC group of 0.86 points. The SEM of GSES was 1.56, leading to an SDC ind of 4.33 points and SDC group of 0.37 points. The SEM of GHQ-12 with bimodal scoring was 1.47, leading to an SDC ind of 4.06 points and SDC group of 0.35 points. The SEM of GHQ-12 with Likert scoring was 2.44, leading to an SDC ind of 6.76 points and SDC group of 0.58 points. To confirm that the change was not a result of measurement error, a score of self-reported outcome measurement scales would need to change by an amount greater than these SDC values. This has important implications for clinicians and epidemiologists when assessing outcomes. © 2017 John Wiley & Sons, Ltd.

Joint CO2 and CH4 accountability for global warming

PubMed Central

Smith, Kirk R.; Desai, Manish A.; Rogers, Jamesine V.; Houghton, Richard A.

2013-01-01

We propose a transparent climate debt index incorporating both methane (CH4) and carbon dioxide (CO2) emissions. We develop national historic emissions databases for both greenhouse gases to 2005, justifying 1950 as the starting point for global perspectives. We include CO2 emissions from fossil sources [CO2(f)], as well as, in a separate analysis, land use change and forestry. We calculate the CO2(f) and CH4 remaining in the atmosphere in 2005 from 205 countries using the Intergovernmental Panel on Climate Change’s Fourth Assessment Report impulse response functions. We use these calculations to estimate the fraction of remaining global emissions due to each country, which is applied to total radiative forcing in 2005 to determine the combined climate debt from both greenhouse gases in units of milliwatts per square meter per country or microwatts per square meter per person, a metric we term international natural debt (IND). Australia becomes the most indebted large country per capita because of high CH4 emissions, overtaking the United States, which is highest for CO2(f). The differences between the INDs of developing and developed countries decline but remain large. We use IND to assess the relative reduction in IND from choosing between CO2(f) and CH4`control measures and to contrast the imposed versus experienced health impacts from climate change. Based on 2005 emissions, the same hypothetical impact on world 2050 IND could be achieved by decreasing CH4 emissions by 46% as stopping CO2 emissions entirely, but with substantial differences among countries, implying differential optimal strategies. Adding CH4 shifts the basic narrative about differential international accountability for climate change. PMID:23847202

Joint CO2 and CH4 accountability for global warming.

PubMed

Smith, Kirk R; Desai, Manish A; Rogers, Jamesine V; Houghton, Richard A

2013-07-30

We propose a transparent climate debt index incorporating both methane (CH4) and carbon dioxide (CO2) emissions. We develop national historic emissions databases for both greenhouse gases to 2005, justifying 1950 as the starting point for global perspectives. We include CO2 emissions from fossil sources [CO2(f)], as well as, in a separate analysis, land use change and forestry. We calculate the CO2(f) and CH4 remaining in the atmosphere in 2005 from 205 countries using the Intergovernmental Panel on Climate Change's Fourth Assessment Report impulse response functions. We use these calculations to estimate the fraction of remaining global emissions due to each country, which is applied to total radiative forcing in 2005 to determine the combined climate debt from both greenhouse gases in units of milliwatts per square meter per country or microwatts per square meter per person, a metric we term international natural debt (IND). Australia becomes the most indebted large country per capita because of high CH4 emissions, overtaking the United States, which is highest for CO2(f). The differences between the INDs of developing and developed countries decline but remain large. We use IND to assess the relative reduction in IND from choosing between CO2(f) and CH4`control measures and to contrast the imposed versus experienced health impacts from climate change. Based on 2005 emissions, the same hypothetical impact on world 2050 IND could be achieved by decreasing CH4 emissions by 46% as stopping CO2 emissions entirely, but with substantial differences among countries, implying differential optimal strategies. Adding CH4 shifts the basic narrative about differential international accountability for climate change.

Substantial air quality and climate co-benefits achievable now with sectoral mitigation strategies in China.

PubMed

Peng, Wei; Yang, Junnan; Wagner, Fabian; Mauzerall, Denise L

2017-11-15

China is the world's top carbon emitter and suffers from severe air pollution. We examine near-term air quality and CO 2 co-benefits of various current sector-based policies in China. Using a 2015 base case, we evaluate the potential benefits of four sectoral mitigation strategies. All scenarios include a 20% increase in conventional air pollution controls as well as the following sector-specific fuel switching or technology upgrade strategies. Power sector (POW): 80% replacement of small coal power plants with larger more efficient ones; Industry sector (IND): 10% improvement in energy efficiency; Transport sector (TRA): replacement of high emitters with average vehicle fleet emissions; and Residential sector (RES): replacement of 20% of coal-based stoves with stoves using liquefied petroleum gas (LPG). Conducting an integrated assessment using the regional air pollution model WRF-Chem, we find that the IND scenario reduces national air-pollution-related deaths the most of the four scenarios examined (27,000, 24,000, 13,000 and 23,000 deaths reduced annually in IND, POW, TRA and RES, respectively). In addition, the IND scenario reduces CO 2 emissions more than 8times as much as any other scenario (440, 53, 0 and 52Mt CO 2 reduced in IND, POW, TRA and RES, respectively). We also examine the benefits of an industrial efficiency improvement of just 5%. We find the resulting air quality and health benefits are still among the largest of the sectoral scenarios, while the carbon mitigation benefits remain more than 3 times larger than any other scenario. Our analysis hence highlights the importance of even modest industrial energy efficiency improvements and air pollution control technology upgrades for air quality, health and climate benefits in China. Copyright © 2017 Elsevier B.V. All rights reserved.

OpenFDA: an innovative platform providing access to a wealth of FDA’s publicly available data

PubMed Central

Kass-Hout, Taha A; Mohebbi, Matthew; Nelsen, Hans; Baker, Adam; Levine, Jonathan; Johanson, Elaine; Bright, Roselie A

2016-01-01

Objective The objective of openFDA is to facilitate access and use of big important Food and Drug Administration public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Materials and Methods Using cutting-edge technologies deployed on FDA’s new public cloud computing infrastructure, openFDA provides open data for easier, faster (over 300 requests per second per process), and better access to FDA datasets; open source code and documentation shared on GitHub for open community contributions of examples, apps and ideas; and infrastructure that can be adopted for other public health big data challenges. Results Since its launch on June 2, 2014, openFDA has developed four APIs for drug and device adverse events, recall information for all FDA-regulated products, and drug labeling. There have been more than 20 million API calls (more than half from outside the United States), 6000 registered users, 20,000 connected Internet Protocol addresses, and dozens of new software (mobile or web) apps developed. A case study demonstrates a use of openFDA data to understand an apparent association of a drug with an adverse event. Conclusion With easier and faster access to these datasets, consumers worldwide can learn more about FDA-regulated products. PMID:26644398

78 FR 65334 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-31

... information, including certain labeling information, to FDA for approval to market a product in interstate... and in a form that FDA can process, review, and archive. This requirement is in addition to the....12(b) in table 1 of this document. In July 1997, FDA revised Form FDA 356h ``Application to Market a...

21 CFR 1270.21 - Determination of donor suitability for human tissue intended for transplantation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... virus, Type 1 (e.g., FDA licensed screening test for anti-HIV-1); (2) Human immunodeficiency virus, Type 2 (e.g., FDA licensed screening test for anti-HIV-2); (3) Hepatitis B (e.g., FDA licensed screening... been tested and found negative using FDA licensed screening tests for HIV-1, HIV-2, hepatitis B, and...

21 CFR 1270.21 - Determination of donor suitability for human tissue intended for transplantation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... virus, Type 1 (e.g., FDA licensed screening test for anti-HIV-1); (2) Human immunodeficiency virus, Type 2 (e.g., FDA licensed screening test for anti-HIV-2); (3) Hepatitis B (e.g., FDA licensed screening... been tested and found negative using FDA licensed screening tests for HIV-1, HIV-2, hepatitis B, and...

21 CFR 1270.21 - Determination of donor suitability for human tissue intended for transplantation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... virus, Type 1 (e.g., FDA licensed screening test for anti-HIV-1); (2) Human immunodeficiency virus, Type 2 (e.g., FDA licensed screening test for anti-HIV-2); (3) Hepatitis B (e.g., FDA licensed screening... been tested and found negative using FDA licensed screening tests for HIV-1, HIV-2, hepatitis B, and...

21 CFR 1270.21 - Determination of donor suitability for human tissue intended for transplantation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... virus, Type 1 (e.g., FDA licensed screening test for anti-HIV-1); (2) Human immunodeficiency virus, Type 2 (e.g., FDA licensed screening test for anti-HIV-2); (3) Hepatitis B (e.g., FDA licensed screening... been tested and found negative using FDA licensed screening tests for HIV-1, HIV-2, hepatitis B, and...

21 CFR 1.392 - Who receives a copy of the detention order?

Code of Federal Regulations, 2013 CFR

2013-04-01

... Fda Order A Detention? § 1.392 Who receives a copy of the detention order? (a) FDA must issue the... place where the article is detained, FDA must provide a copy of the detention order to the owner of the article of food if the owner's identity can be determined readily. (b) If FDA issues a detention order for...

21 CFR 1.392 - Who receives a copy of the detention order?

Code of Federal Regulations, 2012 CFR

2012-04-01

... Fda Order A Detention? § 1.392 Who receives a copy of the detention order? (a) FDA must issue the... place where the article is detained, FDA must provide a copy of the detention order to the owner of the article of food if the owner's identity can be determined readily. (b) If FDA issues a detention order for...

21 CFR 111.610 - What records must be made available to FDA?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 2 2011-04-01 2011-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

Code of Federal Regulations, 2014 CFR

2014-04-01

... initiative of FDA. 14.171 Section 14.171 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... monitoring of the matter and consultation with FDA on behalf of the committee. The member or consultant may...

21 CFR 314.72 - Change in ownership of an application.

Code of Federal Regulations, 2013 CFR

2013-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications § 314.72... required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.45 of FDA's public...

21 CFR 1.378 - What criteria does FDA use to order a detention?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false What criteria does FDA use to order a detention? 1... General Provisions § 1.378 What criteria does FDA use to order a detention? An officer or qualified employee of FDA may order the detention of any article of food that is found during an inspection...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.392 - Who receives a copy of the detention order?

Code of Federal Regulations, 2011 CFR

2011-04-01

... Fda Order A Detention? § 1.392 Who receives a copy of the detention order? (a) FDA must issue the... place where the article is detained, FDA must provide a copy of the detention order to the owner of the article of food if the owner's identity can be determined readily. (b) If FDA issues a detention order for...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 1.378 - What criteria does FDA use to order a detention?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false What criteria does FDA use to order a detention? 1... General Provisions § 1.378 What criteria does FDA use to order a detention? An officer or qualified employee of FDA may order the detention of any article of food that is found during an inspection...

21 CFR 111.610 - What records must be made available to FDA?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

21 CFR 1.378 - What criteria does FDA use to order a detention?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false What criteria does FDA use to order a detention? 1... General Provisions § 1.378 What criteria does FDA use to order a detention? An officer or qualified employee of FDA may order the detention of any article of food that is found during an inspection...

21 CFR 111.610 - What records must be made available to FDA?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 2 2014-04-01 2014-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

21 CFR 1.378 - What criteria does FDA use to order a detention?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What criteria does FDA use to order a detention? 1... General Provisions § 1.378 What criteria does FDA use to order a detention? An officer or qualified employee of FDA may order the detention of any article of food that is found during an inspection...

21 CFR 314.72 - Change in ownership of an application.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications § 314.72... required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.45 of FDA's public...

21 CFR 314.72 - Change in ownership of an application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications § 314.72... required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.45 of FDA's public...

21 CFR 803.3 - How does FDA define the terms used in this part?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false How does FDA define the terms used in this part... SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING General Provisions § 803.3 How does FDA..., for an estimated period of time. FDA, we, or us means the Food and Drug Administration. Five-day...

21 CFR 111.610 - What records must be made available to FDA?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 2 2012-04-01 2012-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

21 CFR 803.3 - How does FDA define the terms used in this part?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false How does FDA define the terms used in this part... SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING General Provisions § 803.3 How does FDA..., for an estimated period of time. FDA, we, or us means the Food and Drug Administration. Five-day...

21 CFR 1.378 - What criteria does FDA use to order a detention?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false What criteria does FDA use to order a detention? 1... General Provisions § 1.378 What criteria does FDA use to order a detention? An officer or qualified employee of FDA may order the detention of any article of food that is found during an inspection...

21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

Code of Federal Regulations, 2011 CFR

2011-04-01

... initiative of FDA. 14.171 Section 14.171 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... monitoring of the matter and consultation with FDA on behalf of the committee. The member or consultant may...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 314.72 - Change in ownership of an application.

Code of Federal Regulations, 2012 CFR

2012-04-01

... (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Applications § 314.72... required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.45 of FDA's public...

21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

Code of Federal Regulations, 2012 CFR

2012-04-01

... initiative of FDA. 14.171 Section 14.171 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... monitoring of the matter and consultation with FDA on behalf of the committee. The member or consultant may...

21 CFR 803.3 - How does FDA define the terms used in this part?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false How does FDA define the terms used in this part... SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING General Provisions § 803.3 How does FDA..., for an estimated period of time. FDA, we, or us means the Food and Drug Administration. Five-day...

21 CFR 803.3 - How does FDA define the terms used in this part?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false How does FDA define the terms used in this part... SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING General Provisions § 803.3 How does FDA..., for an estimated period of time. FDA, we, or us means the Food and Drug Administration. Five-day...

21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

Code of Federal Regulations, 2013 CFR

2013-04-01

... initiative of FDA. 14.171 Section 14.171 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... monitoring of the matter and consultation with FDA on behalf of the committee. The member or consultant may...

21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you with...

21 CFR 111.610 - What records must be made available to FDA?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 2 2013-04-01 2013-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA when...

21 CFR 1.392 - Who receives a copy of the detention order?

Code of Federal Regulations, 2010 CFR

2010-04-01

... Fda Order A Detention? § 1.392 Who receives a copy of the detention order? (a) FDA must issue the... place where the article is detained, FDA must provide a copy of the detention order to the owner of the article of food if the owner's identity can be determined readily. (b) If FDA issues a detention order for...

Medicare covers the majority of FDA-approved devices and Part B drugs, but restrictions and discrepancies remain.

PubMed

Chambers, James D; May, Katherine E; Neumann, Peter J

2013-06-01

The Food and Drug Administration (FDA) and Medicare use different standards to determine, first, whether a new drug or medical device can be marketed to the public and, second, if the federal health insurance program will pay for use of the drug or device. This discrepancy creates hurdles and uncertainty for drug and device manufacturers. We analyzed discrepancies between FDA approval and Medicare national coverage determinations for sixty-nine devices and Part B drugs approved during 1999-2011. We found that Medicare covered FDA-approved drugs or devices 80 percent of the time. However, Medicare often added conditions beyond FDA approval, particularly for devices and most often restricting coverage to patients with the most severe disease. In some instances, Medicare was less restrictive than the FDA. Our findings highlight the importance for drug and device makers of anticipating Medicare's needs when conducting clinical studies to support their products. Our findings also provide important insights for the FDA's and Medicare's pilot parallel review program.

Interview with Janet Woodcock: progress on the FDA's critical path initiative.

PubMed

Woodcock, Janet

2009-12-01

Janet Woodcock is the Director of the US FDA's Center for Drug Evaluation and Research. Dr Woodcock has held various positions within the FDA's Office of the Commissioner from October 2003 until 1 April, 2008, as Deputy Commissioner and Chief Medical Officer, Deputy Commissioner for Operations and Chief Operating Officer and Director of the Critical Path Programs. She oversaw scientific and medical regulatory operations for the FDA. Dr Woodcock served as Director of the Center for Drug Evaluation and Research at the FDA from 1994 to 2005. She previously served in other positions at the FDA including Director of the Office of Therapeutics Research and Review and Acting Deputy Director of the Center for Biologics Evaluation and Research. Dr Woodcock received her MD from Northwestern Medical School (IL, USA), and completed further training and held teaching appointments at the Pennsylvania State University (PA, USA)and the University of California in San Francisco (CA, USA). She joined the FDA in 1986.

8th GCC: consolidated feedback to US FDA on the 2013 draft FDA guidance on bioanalytical method validation.

PubMed

Bower, Joseph; Fast, Douglas; Garofolo, Fabio; Gouty, Dominique; Hayes, Roger; Lowes, Steve; Nicholson, Robert; LeLacheur, Richard; Bravo, Jennifer; Shoup, Ronald; Dumont, Isabelle; Carbone, Mary; Zimmer, Jennifer; Ortuno, Jordi; Caturla, Maria Cruz; Datin, Jim; Lansing, Tim; Fatmi, Saadya; Struwe, Petra; Sheldon, Curtis; Islam, Rafiqul; Yu, Mathilde; Hulse, Jim; Kamerud, John; Lin, John; Doughty, John; Kurylak, Kai; Tang, Daniel; Buonarati, Mike; Blanchette, Alexandre; Levesque, Ann; Gagnon-Carignan, Sofi; Lin, Jenny; Ray, Gene; Liu, Yanseng; Khan, Masood; Xu, Allan; El-Sulayman, Gibran; DiMarco, Chantal; Bouhajib, Mohammed; Tacey, Dick; Jenkins, Rand; der Strate, Barry van; Briscoe, Chad; Karnik, Shane; Rhyne, Paul; Garofolo, Wei; Schultz, Gary; Roberts, Andrew; Redrup, Mike; DuBey, Ira; Conliffe, Phyllis; Pekol, Teri; Hantash, Jamil; Cojocaru, Laura; Allen, Mike; Reuschel, Scott; Watson, Andrea; Farrell, Colin; Groeber, Elizabeth; Malone, Michele; Nowatzke, William; Fang, Xinping

2014-01-01

The 8th GCC Closed Forum for Bioanalysis was held in Baltimore, MD, USA on 5 December 2013, immediately following the 2013 AAPS Workshop (Crystal City V): Quantitative Bioanalytical Methods Validation and Implementation--The 2013 Revised FDA Guidance. This GCC meeting was organized to discuss the contents of the draft revised FDA Guidance on bioanalytical method validation that was published in September 2013 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants, from seven countries, representing 46 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the draft FDA Guidance, and to build unified comments to be provided to the FDA.

40 CFR Appendix A to Part 76 - Phase I Affected Coal-Fired Utility Units With Group 1 or Cell Burner Boilers

Code of Federal Regulations, 2011 CFR

2011-07-01

... Units With Group 1 or Cell Burner Boilers A Appendix A to Part 76 Protection of Environment... 1 or Cell Burner Boilers Table 1—Phase I Tangentially Fired Units State Plant Unit Operator ALABAMA... TOWER 9 CEN ILLINOIS PUB SER. INDIANA CULLEY 2 STHERN IND GAS & EL. INDIANA CULLEY 3 STHERN IND GAS & EL...

Skill Transfer and Virtual Training for IND Response Decision-Making: Project Summary and Next Steps

DTIC Science & Technology

2016-04-12

are likely to be very productive partners—independent video - game developers and academic game degree programs—are not familiar with working with...experimental validation. • Independent Video - Game Developers. Small companies and individuals that pursue video - game design and development can be...complexity, such as an improvised nuclear device (IND) detonation. The effort has examined game - based training methods to determine their suitability

78 FR 40267 - Illinois Central Railroad Company-Amended Trackage Rights Exemption-Grand Trunk Western Railroad...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

... connection with the Elgin, Joliet & Eastern Railway Company (EJ&E) at or near milepost 36.1, at Griffith, Ind... (formerly EJ&E) at or near milepost 36.1 in Griffith and milepost 43.3 in Spring Lake, Ind. \\1\\ See Ill. Cent. R.R.--Trackage Rights Exemption--Grand Trunk W. R.R., FD 35268 (STB served Aug. 17, 2009). EJ&E...

The PASM Parallel Processing System: Hardware Design and Intelligent Operating System Concepts

DTIC Science & Technology

1986-07-01

IND-3 Jac Logic 0ISCAUTO-3 UK Jus Parallel IrAorf act Pori 90-7 el MS. IND-3 P110-3 Logic = .CUTO-3 AC-4 0 Sow PAIS WK.110-7 --------- CSS CC. THO...process communication are part of the ment, which must be part of the task body: jitsu VP-20043 uses 32-bit integers. Pro- language. The compiler actually

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pasquale, David A.; Hansen, Richard G.

This paper discusses command and control issues relating to the operation of Incident Command Posts (ICPs) and Emergency Operations Centers (EOCs) in the surrounding area jurisdictions following the detonation of an Improvised Nuclear Device (IND). Although many aspects of command and control will be similar to what is considered to be normal operations using the Incident Command System (ICS) and the National Incident Management System (NIMS), the IND response will require many new procedures and associations in order to design and implement a successful response. The scope of this white paper is to address the following questions: • Would themore » current command and control framework change in the face of an IND incident? • What would the management of operations look like as the event unfolded? • How do neighboring and/or affected jurisdictions coordinate with the state? • If the target area’s command and control infrastructure is destroyed or disabled, how could neighboring jurisdictions assist with command and control of the targeted jurisdiction? • How would public health and medical services fit into the command and control structure? • How can pre-planning and common policies improve coordination and response effectiveness? • Where can public health officials get federal guidance on radiation, contamination and other health and safety issues for IND response planning and operations?« less

A cancer screening intervention for underserved Latina women by lay educators.

PubMed

Larkey, Linda K; Herman, Patricia M; Roe, Denise J; Garcia, Francisco; Lopez, A M; Gonzalez, J; Perera, Prasadini N; Saboda, Kathylynn

2012-05-01

Inadequate screening adherence for breast, cervical, and colorectal cancer among Latinas places them at greater risk for poor survival rates, once diagnosed. The purpose of this study was to examine two delivery methods of lay health educators (promotoras de salud) to increase screening behavior and evaluate costs. This community-based group randomized trial assigned Latinas due for breast, cervical, or colorectal cancer screening (n=1006) to promotora-taught cancer screening/prevention classes delivered individually (IND) or in social support groups (SSG) over 8 weeks. Screening behaviors were assessed immediately after and 3 and 15 months after intervention. Intervention costs per study arm were compared. Screening and maintenance behaviors were not significantly different between SSG and IND for any one type of cancer screening, but with a study entry requirement that participants were either never screened or due for screening, postintervention screening rates (that is, completing a screening that was due) were notable (39.4% and 45.5%, respectively). The cost of achieving any one screening was much higher for IND participants. SSG vs. IND delivery did not significantly affect cancer screening behaviors, but both interventions produced robust achievement of screenings for previously nonadherent participants. Group-based promotora-led interventions supporting social involvement are recommended as a more cost-effective approach to achieving cancer screening among Latina women.

Genetic and antigenic analysis of foot-and-mouth disease virus serotype O responsible for outbreaks in India during 2013.

PubMed

Subramaniam, Saravanan; Mohapatra, Jajati K; Das, Biswajit; Sanyal, Aniket; Pattnaik, Bramhadev

2015-03-01

In recent times, majority of the foot-and-mouth disease (FMD) outbreaks in India are caused by serotype O Ind2001 lineage. The lineage has diverged into four sub-lineages (Ind2001a, b, c and d). We report here the genetic and antigenic analyses of nine Ind2001d isolates that caused outbreaks during April 2013-March 2014 in India. The length of the genomes of outbreak viruses varied between 8153 and 8181 nucleotides without any insertion or deletion in the coding region. Of the nine isolates analyzed antigenically against the currently used Indian vaccine strain INDR2/1975, eight showed good cross serological match (>0.3) indicating optimal antigenic coverage by the vaccine strain. An unprecedented deletion of 22 nucleotides between position 57 and 78 was observed in the 3' untranslated region of one of the isolates without compromising the virus viability, which imply that partial distortion in SL2 of 3'UTR may not have influence on virus viability at least under in-vitro conditions. Recently the Ind2001 lineage has been reported from several countries including Libya and spread of this lineage across a wide geographical area needs to be monitored carefully to avoid any future pandemic. Copyright © 2014 Elsevier B.V. All rights reserved.

Measurement error in the Liebowitz Social Anxiety Scale: results from a general adult population in Japan.

PubMed

Takada, Koki; Takahashi, Kana; Hirao, Kazuki

2018-01-17

Although the self-report version of Liebowitz Social Anxiety Scale (LSAS) is frequently used to measure social anxiety, data is lacking on the smallest detectable change (SDC), an important index of measurement error. We therefore aimed to determine the SDC of LSAS. Japanese adults aged 20-69 years were invited from a panel managed by a nationwide internet research agency. We then conducted a test-retest internet survey with a two-week interval to estimate the SDC at the individual (SDC ind ) and group (SDC group ) levels. The analysis included 1300 participants. The SDC ind and SDC group for the total fear subscale (scoring range: 0-72) were 23.52 points (32.7%) and 0.65 points (0.9%), respectively. The SDC ind and SDC group for the total avoidance subscale (scoring range: 0-72) were 32.43 points (45.0%) and 0.90 points (1.2%), respectively. The SDC ind and SDC group for the overall total score (scoring range: 0-144) were 45.90 points (31.9%) and 1.27 points (0.9%), respectively. Measurement error is large and indicate the potential for major problems when attempting to use the LSAS to detect changes at the individual level. These results should be considered when using the LSAS as measures of treatment change.

Polychaeta (Annelida) associated with Thalassia testudinum in the northeastern coastal waters of Venezuela.

PubMed

Liñero Arana, Ildefonso; Díaz Díaz, Oscar

2006-09-01

Seasonal variations of polychaetes in a Thalassia testudinum bed were studied from June 2000 to April 2001 in Chacopata, northeastern Venezuela. Eight replicate samples were taken monthly with a 15 cm diameter core and the sediment was passed through a 0.5 mm mesh sieve. A total of 1,013 specimens, belonging to 35 species, was collected. The monthly density ranged from 387 ind/m2 (September) to 1,735 ind/m2 in May (x = 989+/-449 ind/m2). Species richness was lowest in August and September (8) and highest (25) in April (x = 18.00+/-5.29). The shoot density of Thalassia showed an average of 284+/-77.60 shoots/m2, with extreme values in February (164) and May (422). Species diversity ranged from 1.25 in August and 3.33 bits/ind in December (x = 2.47+/-0.64). Significant positive correlations were detected among the number of Thalassia shoots, polychaete abundance and species richness, as well as among species richness, polychaete abundance and species diversity. Species number and average density were found within the intervals of mean values reported in similar studies. The higher number of species and organisms obtained in March-April and June-July can be attributed to the recruitment correlated with the regional up-welling.

Antigenic and genetic comparison of foot-and-mouth disease virus serotype O Indian vaccine strain, O/IND/R2/75 against currently circulating viruses

PubMed Central

Mahapatra, Mana; Yuvaraj, S.; Madhanmohan, M.; Subramaniam, S.; Pattnaik, B.; Paton, D.J.; Srinivasan, V.A.; Parida, Satya

2015-01-01

Foot-and-mouth disease (FMD) virus serotype O is the most common cause of FMD outbreaks in India and three of the six lineages that have been described are most frequently detected, namely Ind2001, PanAsia and PanAsia 2. We report the full capsid sequence of 21 serotype O viruses isolated from India between 2002 and 2012. All these viruses belong to the Middle East–South Asia (ME–SA) topotype. The serological cross-reactivity of a bovine post-vaccination serum pool raised against the current Indian vaccine strain, O/IND/R2/75,was tested by virus neutralisation test with the 23 Indian field isolates, revealing a good match between the vaccine and the field isolates. The cross reactivity of the O/IND/R2/75 vaccine with 19 field isolates from other countries (mainly from Asia and Africa) revealed a good match to 79% of the viruses indicating that the vaccine strain is broadly cross-reactive and could be used to control FMD in other countries. Comparison of the capsid sequences of the serologically non-matching isolates with the vaccine strain sequence identified substitutions in neutralising antigenic sites 1 and 2, which could explain the observed serological differences. PMID:25500306

Structure of Mesozooplankton Communities in the Coastal Waters of Morocco

NASA Astrophysics Data System (ADS)

Lidvanov, V. V.; Grabko, O. G.; Kukuev, E. I.; Korolkova, T. G.

2018-03-01

Mero- and holoplanktonic organisms from 23 large taxa have been detected in the coastal waters of Morocco. Seven Cladocera species and 164 Copepoda species were identified. Copepod fauna mostly consisted of oceanic epipelagic widely tropical species, but the constant species group (frequency of occurrence over 50%) included neritic and neritic-oceanic widely tropical species. The neritic community that formed a biotopic association with coastal upwelling waters and the distant-neritic community associated with Canary Current waters were the two major communities detected. The former community was characterized by a high abundance and biomass (5700 ind./m3 and 260 mg/m3) and predominance of neritic species. The trophic structure was dominated by thin filter feeders, mixed-food consumers, and small grabbers; the species structure was dominated by Paracalanus indicus, Acartia clausi, and Oncaea curta; the indices of species diversity (3.07 bit/ind.) and evenness (0.63) were relatively low. The latter community was characterized by low abundance and biomass (1150 ind./m3 and 90 mg/m3); variable biotopic, trophic, and species structure; and higher Shannon indices (3.99 bit/ind.) and Pielou (0.75). Seasonal variation of the abundance of organisms was not detected in the communities. Anomalous mesozooplankton states were observed in summer 1998 and winter 1998-1999.

21 CFR 1.279 - When must prior notice be submitted to FDA?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false When must prior notice be submitted to FDA? 1.279... Imported Food § 1.279 When must prior notice be submitted to FDA? (a) Except as provided in paragraph (c) of this section, you must submit the prior notice to FDA and the prior notice submission must be...

21 CFR 1.279 - When must prior notice be submitted to FDA?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false When must prior notice be submitted to FDA? 1.279... Imported Food § 1.279 When must prior notice be submitted to FDA? (a) Except as provided in paragraph (c) of this section, you must submit the prior notice to FDA and the prior notice submission must be...

21 CFR 1.279 - When must prior notice be submitted to FDA?

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false When must prior notice be submitted to FDA? 1.279... Imported Food § 1.279 When must prior notice be submitted to FDA? (a) Except as provided in paragraph (c) of this section, you must submit the prior notice to FDA and the prior notice submission must be...

21 CFR 1.279 - When must prior notice be submitted to FDA?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false When must prior notice be submitted to FDA? 1.279... Imported Food § 1.279 When must prior notice be submitted to FDA? (a) Except as provided in paragraph (c) of this section, you must submit the prior notice to FDA and the prior notice submission must be...