Underexplored Opportunities for Natural Products in Drug Discovery.

PubMed

DeCorte, Bart L

2016-10-27

The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity.

Pharmacogenomic Biomarkers: an FDA Perspective on Utilization in Biological Product Labeling.

PubMed

Schuck, Robert N; Grillo, Joseph A

2016-05-01

Precision medicine promises to improve both the efficacy and safety of therapeutic products by better informing why some patients respond well to a drug, and some experience adverse reactions, while others do not. Pharmacogenomics is a key component of precision medicine and can be utilized to select optimal doses for patients, more precisely identify individuals who will respond to a treatment and avoid serious drug-related toxicities. Since pharmacogenomic biomarker information can help inform drug dosing, efficacy, and safety, pharmacogenomic data are critically reviewed by FDA staff to ensure effective use of pharmacogenomic strategies in drug development and appropriate incorporation into product labels. Pharmacogenomic information may be provided in drug or biological product labeling to inform health care providers about the impact of genotype on response to a drug through description of relevant genomic markers, functional effects of genomic variants, dosing recommendations based on genotype, and other applicable genomic information. The format and content of labeling for biologic drugs will generally follow that of small molecule drugs; however, there are notable differences in pharmacogenomic information that might be considered useful for biologic drugs in comparison to small molecule drugs. Furthermore, the rapid entry of biologic drugs for treatment of rare genetic diseases and molecularly defined subsets of common diseases will likely lead to increased use of pharmacogenomic information in biologic drug labels in the near future. In this review, we outline the general principles of therapeutic product labeling and discuss the utilization of pharmacogenomic information in biologic drug labels.

Propolis: A Complex Natural Product with a Plethora of Biological Activities That Can Be Explored for Drug Development

PubMed Central

Silva-Carvalho, Ricardo; Baltazar, Fátima; Almeida-Aguiar, Cristina

2015-01-01

The health industry has always used natural products as a rich, promising, and alternative source of drugs that are used in the health system. Propolis, a natural resinous product known for centuries, is a complex product obtained by honey bees from substances collected from parts of different plants, buds, and exudates in different geographic areas. Propolis has been attracting scientific attention since it has many biological and pharmacological properties, which are related to its chemical composition. Several in vitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolated compounds, as well as to evaluate and validate its potential. Yet, there is a lack of information concerning clinical effectiveness. The goal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerning the chemical composition and the biological properties of this natural compound from different geographic origins. PMID:26106433

Versatile and on-demand biologics co-production in yeast.

PubMed

Cao, Jicong; Perez-Pinera, Pablo; Lowenhaupt, Ky; Wu, Ming-Ru; Purcell, Oliver; de la Fuente-Nunez, Cesar; Lu, Timothy K

2018-01-08

Current limitations to on-demand drug manufacturing can be addressed by technologies that streamline manufacturing processes. Combining the production of two or more drugs into a single batch could not only be useful for research, clinical studies, and urgent therapies but also effective when combination therapies are needed or where resources are scarce. Here we propose strategies to concurrently produce multiple biologics from yeast in single batches by multiplexing strain development, cell culture, separation, and purification. We demonstrate proof-of-concept for three biologics co-production strategies: (i) inducible expression of multiple biologics and control over the ratio between biologic drugs produced together; (ii) consolidated bioprocessing; and (iii) co-expression and co-purification of a mixture of two monoclonal antibodies. We then use these basic strategies to produce drug mixtures as well as to separate drugs. These strategies offer a diverse array of options for on-demand, flexible, low-cost, and decentralized biomanufacturing applications without the need for specialized equipment.

21 CFR 310.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Biologics; products subject to license control... to license control. (a) If a drug has an approved license under section 351 of the Public Health.... (b) To obtain marketing approval for radioactive biological products for human use, as defined in...

21 CFR 310.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Biologics; products subject to license control... to license control. (a) If a drug has an approved license under section 351 of the Public Health.... (b) To obtain marketing approval for radioactive biological products for human use, as defined in...

21 CFR 310.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Biologics; products subject to license control... to license control. (a) If a drug has an approved license under section 351 of the Public Health.... (b) To obtain marketing approval for radioactive biological products for human use, as defined in...

21 CFR 310.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Biologics; products subject to license control... to license control. (a) If a drug has an approved license under section 351 of the Public Health.... (b) To obtain marketing approval for radioactive biological products for human use, as defined in...

21 CFR 310.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Biologics; products subject to license control... to license control. (a) If a drug has an approved license under section 351 of the Public Health.... (b) To obtain marketing approval for radioactive biological products for human use, as defined in...

21 CFR 601.50 - Confidentiality of data and information in an investigational new drug notice for a biological...

Code of Federal Regulations, 2010 CFR

2010-04-01

... investigational new drug notice for a biological product. 601.50 Section 601.50 Food and Drugs FOOD AND DRUG... Information § 601.50 Confidentiality of data and information in an investigational new drug notice for a biological product. (a) The existence of an IND notice for a biological product will not be disclosed by the...

Evaluation of the Safety of Drugs and Biological Products Used During Lactation: Workshop Summary

PubMed Central

Wang, J; Johnson, T; Sahin, L; Tassinari, MS; Anderson, PO; Baker, TE; Bucci-Rechtweg, C; Burckart, GJ; Chambers, CD; Hale, TW; Johnson-Lyles, D; Nelson, RM; Nguyen, C; Pica-Branco, D; Ren, Z; Sachs, H; Sauberan, J; Zajicek, A; Ito, S; Yao, LP

2017-01-01

This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies. This workshop is part of continuing efforts to raise the awareness of the public for women who choose to breastfeed their infants. PMID:28510297

Synthetic biology for pharmaceutical drug discovery

PubMed Central

Trosset, Jean-Yves; Carbonell, Pablo

2015-01-01

Synthetic biology (SB) is an emerging discipline, which is slowly reorienting the field of drug discovery. For thousands of years, living organisms such as plants were the major source of human medicines. The difficulty in resynthesizing natural products, however, often turned pharmaceutical industries away from this rich source for human medicine. More recently, progress on transformation through genetic manipulation of biosynthetic units in microorganisms has opened the possibility of in-depth exploration of the large chemical space of natural products derivatives. Success of SB in drug synthesis culminated with the bioproduction of artemisinin by microorganisms, a tour de force in protein and metabolic engineering. Today, synthetic cells are not only used as biofactories but also used as cell-based screening platforms for both target-based and phenotypic-based approaches. Engineered genetic circuits in synthetic cells are also used to decipher disease mechanisms or drug mechanism of actions and to study cell–cell communication within bacteria consortia. This review presents latest developments of SB in the field of drug discovery, including some challenging issues such as drug resistance and drug toxicity. PMID:26673570

21 CFR 510.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Biologics; products subject to license control. 510.4 Section 510.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS General Provisions § 510.4...

21 CFR 600.14 - Reporting of biological product deviations by licensed manufacturers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... this section? (1) You, the manufacturer who holds the biological product license and who had control... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Reporting of biological product deviations by... HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS BIOLOGICAL PRODUCTS: GENERAL Establishment Standards...

21 CFR 600.14 - Reporting of biological product deviations by licensed manufacturers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Reporting of biological product deviations by... § 600.14 Reporting of biological product deviations by licensed manufacturers. (a) Who must report under...) For biological products regulated by the Center for Biologics Evaluation and Research (CBER), send the...

Biological and nonbiological complex drugs for multiple sclerosis in Latin America: regulations and risk management.

PubMed

Carrá, Adriana; Macías Islas, Miguel Angel; Tarulla, Adriana; Bichuetti, Denis Bernardi; Finkelsztejn, Alessandro; Fragoso, Yara Dadalti; Árcega-Revilla, Raul; Cárcamo Rodríguez, Claudia; Durán, Juan Carlos; Bonitto, Juan García; León, Rosalba; Oehninger Gatti, Carlos; Orozco, Geraldine; Vizcarra Escobar, Darwin

2015-06-01

Biological drugs and nonbiological complex drugs with expired patents are followed by biosimilars and follow-on drugs that are supposedly similar and comparable with the reference product in terms of quality, safety and efficacy. Unlike simple molecules that can be copied and reproduced, biosimilars and follow-on complex drugs are heterogeneous and need specific regulations from health and pharmacovigilance agencies. A panel of 14 Latin American experts on multiple sclerosis from nine different countries met to discuss the recommendations regarding biosimilars and follow-on complex drugs for treating multiple sclerosis. Specific measures relating to manufacturing, therapeutic equivalence assessment and pharmacovigilance reports need to be implemented before commercialization. Physical, chemical, biological and immunogenic characterizations of the new product need to be available before clinical trials start. The new product must maintain the same immunogenicity as the original. Automatic substitution of biological and complex drugs poses unacceptable risks to the patient.

21 CFR 510.4 - Biologics; products subject to license control.

Code of Federal Regulations, 2010 CFR

2010-04-01

... SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS General Provisions § 510.4 Biologics; products subject to license control. An animal drug produced and distributed in full conformance with the animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et seq. ) and...

78 FR 60884 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-02

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Immunoregulation, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics...

76 FR 44016 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-22

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Allergenic Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research...

Rediscovering natural products as a source of new drugs.

PubMed

Koehn, Frank E; Carter, Guy T

2005-04-01

Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small-molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost-effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage.

77 FR 3780 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-25

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, FDA. The...

[Interchangeability of biological drugs: considerations about the approval of biogeneric formulations in Chile].

PubMed

Saavedra S, Iván; Quiñones S, Luis

2006-12-01

Once drug patents expire, the health authorities can approve the registry of similar products. They must request to the manufacturer, the bibliographic background of the original product and the analytical results that certify drug quality. An inspection of the premises of the manufacturer is also required. The main goal of this approval is to decrease cost, considering that the original product is usually more expensive. This is a current situation due to the imminent expiration of the patents of many biopharmaceutical products. Therefore, in Chile, the Public Health (ISP) and the Ministry of Health should consider that for this kind of products, until now, there are no interchangeable generic drugs, and that the similar drugs that are offered have a different chemical composition, since they have been manufactured through different processes. In the case of biological drugs (e.g. erythropoietir, somatotropin, heparin) the quality and homogeneity depend from the manufacture process. Its complete composition can not be absolutely elucidated; therefore small impurities or conformational variants can elicit an altered immune response or unexpected adverse reactions. This indicates that the approval of a biogeneric drug requires in addition to pharmacokinetic studies, preclinical and clinical analytical studies such as physicochemical assays, biological and immunological test. This issues have been established by WHO and have been incorporated for the main drug registry entities all over the world (FDA, EMEA, ANVISA) to approve biogeneric products.

42 CFR 409.13 - Drugs and biologicals.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 2 2012-10-01 2012-10-01 false Drugs and biologicals. 409.13 Section 409.13 Public... § 409.13 Drugs and biologicals. (a) Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as inpatient hospital or inpatient CAH services only if— (1) They represent...

42 CFR 409.13 - Drugs and biologicals.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Drugs and biologicals. 409.13 Section 409.13 Public... § 409.13 Drugs and biologicals. (a) Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as inpatient hospital or inpatient CAH services only if— (1) They represent...

42 CFR 409.13 - Drugs and biologicals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Drugs and biologicals. 409.13 Section 409.13 Public... § 409.13 Drugs and biologicals. (a) Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as inpatient hospital or inpatient CAH services only if— (1) They represent...

42 CFR 409.13 - Drugs and biologicals.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 2 2013-10-01 2013-10-01 false Drugs and biologicals. 409.13 Section 409.13 Public... § 409.13 Drugs and biologicals. (a) Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as inpatient hospital or inpatient CAH services only if— (1) They represent...

42 CFR 409.13 - Drugs and biologicals.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 2 2014-10-01 2014-10-01 false Drugs and biologicals. 409.13 Section 409.13 Public... § 409.13 Drugs and biologicals. (a) Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as inpatient hospital or inpatient CAH services only if— (1) They represent...

Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans. Final rule.

PubMed

2010-09-29

The Food and Drug Administration (FDA) is amending its regulations governing safety reporting requirements for human drug and biological products subject to an investigational new drug application (IND). The final rule codifies the agency's expectations for timely review, evaluation, and submission of relevant and useful safety information and implements internationally harmonized definitions and reporting standards. The revisions will improve the utility of IND safety reports, reduce the number of reports that do not contribute in a meaningful way to the developing safety profile of the drug, expedite FDA's review of critical safety information, better protect human subjects enrolled in clinical trials, subject bioavailability and bioequivalence studies to safety reporting requirements, promote a consistent approach to safety reporting internationally, and enable the agency to better protect and promote public health.

78 FR 20663 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-05

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function..., Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, FDA. FDA intends to...

76 FR 13646 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-14

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Polysaccharides, Division of Bacterial, Parasitic, and Allergenic Products, Office of Vaccines Research and Review...

76 FR 55397 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-07

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Laboratory of Method Development, Division of Viral Products, Office of Vaccines Research and Review, Center...

75 FR 47605 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-06

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Laboratory of Vector Borne Virus Diseases, Division of Viral Products, Office of Vaccines Research and Review...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

Use of Natural Products as Chemical Library for Drug Discovery and Network Pharmacology

PubMed Central

Gu, Jiangyong; Gui, Yuanshen; Chen, Lirong; Yuan, Gu; Lu, Hui-Zhe; Xu, Xiaojie

2013-01-01

Background Natural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products. Methodology We collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model. Conclusions Analysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins. PMID:23638153

Evaluating the administration costs of biologic drugs: development of a cost algorithm.

PubMed

Tetteh, Ebenezer K; Morris, Stephen

2014-12-01

Biologic drugs, as with all other medical technologies, are subject to a number of regulatory, marketing, reimbursement (financing) and other demand-restricting hurdles applied by healthcare payers. One example is the routine use of cost-effectiveness analyses or health technology assessments to determine which medical technologies offer value-for-money. The manner in which these assessments are conducted suggests that, holding all else equal, the economic value of biologic drugs may be determined by how much is spent on administering these drugs or trade-offs between drug acquisition and administration costs. Yet, on the supply-side, it seems very little attention is given to how manufacturing and formulation choices affect healthcare delivery costs. This paper evaluates variations in the administration costs of biologic drugs, taking care to ensure consistent inclusion of all relevant cost resources. From this, it develops a regression-based algorithm with which manufacturers could possibly predict, during process development, how their manufacturing and formulation choices may impact on the healthcare delivery costs of their products.

42 CFR 409.25 - Drugs, biologicals, supplies, appliances, and equipment.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Drugs, biologicals, supplies, appliances, and... Drugs, biologicals, supplies, appliances, and equipment. (a) Drugs and biologicals. Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as posthospital SNF care...

42 CFR 409.25 - Drugs, biologicals, supplies, appliances, and equipment.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Drugs, biologicals, supplies, appliances, and... Drugs, biologicals, supplies, appliances, and equipment. (a) Drugs and biologicals. Except as specified in paragraph (b) of this section, Medicare pays for drugs and biologicals as posthospital SNF care...

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 ...

78 FR 32667 - Draft Guidance for Industry on Rheumatoid Arthritis: Developing Drug Products for Treatment...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-31

...] Draft Guidance for Industry on Rheumatoid Arthritis: Developing Drug Products for Treatment... support the approval of drug products for the treatment of patients with rheumatoid arthritis (RA). It... Drugs, Devices, and Biological Products for the Treatment of Rheumatoid Arthritis (RA),'' published in...

75 FR 59729 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-28

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... vaccines for a post-exposure prophylaxis indication using the animal rule. On November 17, 2010, the...

77 FR 42319 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-18

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Vaccines and Related Biological Products Advisory Committee. General Function of the Committee: To provide... consideration of the appropriateness of cell lines derived from human tumors for vaccine manufacture. FDA...

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

PubMed Central

Crane, Erika A.

2016-01-01

Abstract Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products. PMID:26833854

77 FR 30887 - Amendments to Sterility Test Requirements for Biological Products; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-24

... Biological Products; Correction AGENCY: Food and Drug Administration, HHS. ACTION: Final rule, correction... Evaluation and Research (HFM-17), Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 600, 610, and...

76 FR 3639 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-20

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Vaccines and Related Biological Products Advisory Committee. General Function of the Committee: To provide... the influenza virus vaccine for the 2011-2012 influenza season. The committee will also hear an update...

78 FR 5465 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-25

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Vaccines and Related Biological Products Advisory Committee. General Function of the Committee: To provide... virus vaccine for the 2013- 2014 influenza season. FDA intends to make background material available to...

75 FR 2876 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-19

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Vaccines and Related Biological Products Advisory Committee. General Function of the Committee: To provide... virus vaccine for the 2010 - 2011 influenza season. FDA intends to make background material available to...

Design control considerations for biologic-device combination products.

PubMed

Anderson, Dave; Liu, Roger; Anand Subramony, J; Cammack, Jon

2017-03-01

Combination products are therapeutic and diagnostic medical products that combine drugs, devices, and/or biological products with one another. Historically, biologics development involved identifying efficacious doses administered to patients intravenously or perhaps by a syringe. Until fairly recently, there has been limited focus on developing an accompanying medical device, such as a prefilled syringe or auto-injector, to enable easy and more efficient delivery. For the last several years, and looking forward, where there may be little to distinguish biologics medicines with relatively similar efficacy profiles, the biotechnology market is beginning to differentiate products by patient-focused, biologic-device based combination products. As innovative as biologic-device combination products are, they can pose considerable development, regulatory, and commercialization challenges due to unique physicochemical properties and special clinical considerations (e.g., dosing volumes, frequency, co-medications, etc.) of the biologic medicine. A biologic-device combination product is a marriage between two partners with "cultural differences," so to speak. There are clear differences in the development, review, and commercialization processes of the biologic and the device. When these two cultures come together in a combination product, developers and reviewers must find ways to address the design controls and risk management processes of both the biologic and device, and knit them into a single entity with supporting product approval documentation. Moreover, digital medicine and connected health trends are pushing the boundaries of combination product development and regulations even further. Despite an admirable cooperation between industry and FDA in recent years, unique product configurations and design features have resulted in review challenges. These challenges have prompted agency reviewers to modernize consultation processes, while at the same time, promoting

76 FR 52668 - Vaccines and Related Biological Products Advisory Committee; Amendment of Notice

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-23

...] Vaccines and Related Biological Products Advisory Committee; Amendment of Notice AGENCY: Food and Drug... notice of meeting of the Vaccines and Related Biological Products Advisory Committee. This meeting was... INFORMATION: In the Federal Register of July 22, 2011, FDA announced that a meeting of the Vaccines and...

Potential of Continuous Manufacturing for Liposomal Drug Products.

PubMed

Worsham, Robert D; Thomas, Vaughan; Farid, Suzanne S

2018-05-21

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g. improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application. This article is protected by copyright. All rights reserved.

PCMO L01-Setting Specifications for Biological Investigational Medicinal Products.

PubMed

Krause, Stephan O

2015-01-01

This paper provides overall guidance and best practices for the setting of specifications for clinical biological drug substances and drug products within the framework of ICH guidelines on pharmaceutical development [Q8(R2) and Q11], quality risk management (Q9), and quality systems (Q10). A review is provided of the current regulatory expectations for the specification setting process as part of a control strategy during product development, pointing to existing challenges for the investigational new drug/investigational medicinal product dossier (IND/IMPD) sponsor. A case study illustrates how the investigational medicinal product specification revision process can be managed within a flexible quality system, and how specifications can be set and justified for early and late development stages. This paper provides an overview for the setting of product specifications for investigational medicinal products used in clinical trials. A case study illustrates how product specifications of investigational medicinal products can be justified and managed within a modern product quality system. © PDA, Inc. 2015.

Drug-device combination products: regulatory landscape and market growth.

PubMed

Bayarri, L

2015-08-01

Combination products are therapeutic and diagnostic products that combine drugs, devices and/or biological products, leading to safer and more effective treatments thanks to careful and precise drug targeting, local administration and individualized therapy. These technologies can especially benefit patients suffering from serious diseases and conditions such as cancer, heart disease, multiple sclerosis and diabetes, among others. On the other hand, drug-device combination products have also introduced a new dynamic in medical product development, regulatory approval and corporate interaction. Due to the increasing integration of drugs and devices observed in the latest generation of combination products, regulatory agencies have developed specific competences and regulations over the last decade. Manufacturers are required to fully understand the specific requirements in each country in order to ensure timely and accurate market access of new combination products, and the development of combination products involves a very specific pattern of interactions between manufacturers and regulatory agencies. The increased sophistication of the products brought to market over the last couple of decades has accentuated the need to develop drugs and devices collaboratively using resources from both industries, fostering the need of business partnering and technology licensing. This review will provide a global overview of the market trends, as well as (in the last section) an analysis of the drug-device combination products approved by the FDA during the latest 5 years. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Systems biology impact on antiepileptic drug discovery.

PubMed

Margineanu, Doru Georg

2012-02-01

Systems biology (SB), a recent trend in bioscience research to consider the complex interactions in biological systems from a holistic perspective, sees the disease as a disturbed network of interactions, rather than alteration of single molecular component(s). SB-relying network pharmacology replaces the prevailing focus on specific drug-receptor interaction and the corollary of rational drug design of "magic bullets", by the search for multi-target drugs that would act on biological networks as "magic shotguns". Epilepsy being a multi-factorial, polygenic and dynamic pathology, SB approach appears particularly fit and promising for antiepileptic drug (AED) discovery. In fact, long before the advent of SB, AED discovery already involved some SB-like elements. A reported SB project aimed to find out new drug targets in epilepsy relies on a relational database that integrates clinical information, recordings from deep electrodes and 3D-brain imagery with histology and molecular biology data on modified expression of specific genes in the brain regions displaying spontaneous epileptic activity. Since hitting a single target does not treat complex diseases, a proper pharmacological promiscuity might impart on an AED the merit of being multi-potent. However, multi-target drug discovery entails the complicated task of optimizing multiple activities of compounds, while having to balance drug-like properties and to control unwanted effects. Specific design tools for this new approach in drug discovery barely emerge, but computational methods making reliable in silico predictions of poly-pharmacology did appear, and their progress might be quite rapid. The current move away from reductionism into network pharmacology allows expecting that a proper integration of the intrinsic complexity of epileptic pathology in AED discovery might result in literally anti-epileptic drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Enriching the biological space of natural products and charting drug metabolites, through real time biotransformation monitoring: The NMR tube bioreactor.

PubMed

Chatzikonstantinou, Alexandra V; Chatziathanasiadou, Maria V; Ravera, Enrico; Fragai, Marco; Parigi, Giacomo; Gerothanassis, Ioannis P; Luchinat, Claudio; Stamatis, Haralambos; Tzakos, Andreas G

2018-01-01

Natural products offer a wide range of biological activities, but they are not easily integrated in the drug discovery pipeline, because of their inherent scaffold intricacy and the associated complexity in their synthetic chemistry. Enzymes may be used to perform regioselective and stereoselective incorporation of functional groups in the natural product core, avoiding harsh reaction conditions, several protection/deprotection and purification steps. Herein, we developed a three step protocol carried out inside an NMR-tube. 1st-step: STD-NMR was used to predict the: i) capacity of natural products as enzyme substrates and ii) possible regioselectivity of the biotransformations. 2nd-step: The real-time formation of multiple-biotransformation products in the NMR-tube bioreactor was monitored in-situ. 3rd-step: STD-NMR was applied in the mixture of the biotransformed products to screen ligands for protein targets. Herein, we developed a simple and time-effective process, the "NMR-tube bioreactor", that is able to: (i) predict which component of a mixture of natural products can be enzymatically transformed, (ii) monitor in situ the transformation efficacy and regioselectivity in crude extracts and multiple substrate biotransformations without fractionation and (iii) simultaneously screen for interactions of the biotransformation products with pharmaceutical protein targets. We have developed a green, time-, and cost-effective process that provide a simple route from natural products to lead compounds for drug discovery. This process can speed up the most crucial steps in the early drug discovery process, and reduce the chemical manipulations usually involved in the pipeline, improving the environmental compatibility. Copyright © 2017 Elsevier B.V. All rights reserved.

Advanced systems biology methods in drug discovery and translational biomedicine.

PubMed

Zou, Jun; Zheng, Ming-Wu; Li, Gen; Su, Zhi-Guang

2013-01-01

Systems biology is in an exponential development stage in recent years and has been widely utilized in biomedicine to better understand the molecular basis of human disease and the mechanism of drug action. Here, we discuss the fundamental concept of systems biology and its two computational methods that have been commonly used, that is, network analysis and dynamical modeling. The applications of systems biology in elucidating human disease are highlighted, consisting of human disease networks, treatment response prediction, investigation of disease mechanisms, and disease-associated gene prediction. In addition, important advances in drug discovery, to which systems biology makes significant contributions, are discussed, including drug-target networks, prediction of drug-target interactions, investigation of drug adverse effects, drug repositioning, and drug combination prediction. The systems biology methods and applications covered in this review provide a framework for addressing disease mechanism and approaching drug discovery, which will facilitate the translation of research findings into clinical benefits such as novel biomarkers and promising therapies.

Stabilities and Biological Activities of Vanadium Drugs: What is the Nature of the Active Species?

PubMed

Levina, Aviva; Lay, Peter A

2017-07-18

Diverse biological activities of vanadium(V) drugs mainly arise from their abilities to inhibit phosphatase enzymes and to alter cell signaling. Initial interest focused on anti-diabetic activities but has shifted to anti-cancer and anti-parasitic drugs. V-based anti-diabetics are pro-drugs that release active components (e.g., H 2 VO 4 - ) in biological media. By contrast, V anti-cancer drugs are generally assumed to enter cells intact; however, speciation studies indicate that nearly all drugs are likely to react in cell culture media during in vitro assays and the same would apply in vivo. The biological activities are due to V V and/or V IV reaction products with cell culture media, or the release of ligands (e.g., aromatic diimines, 8-hydroxyquinolines or thiosemicarbazones) that bind to essential metal ions in the media. Careful consideration of the stability and speciation of V complexes in cell culture media and in biological fluids is essential to design targeted V-based anti-cancer therapies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Marine natural products: a new wave of drugs?

PubMed Central

Montaser, Rana; Luesch, Hendrik

2011-01-01

The largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover novel ‘validated’ structures with novel modes of action that cover biologically relevant chemical space. Several challenges, including the supply problem and target identification, need to be met for successful drug development of these often complex molecules; however, approaches are available to overcome the hurdles. Advances in technologies such as sampling strategies, nanoscale NMR for structure determination, total chemical synthesis, fermentation and biotechnology are all crucial to the success of marine natural products as drug leads. We illustrate the high degree of innovation in the field of marine natural products, which in our view will lead to a new wave of drugs that flow into the market and pharmacies in the future. PMID:21882941

Discovery of novel drug targets and their functions using phenotypic screening of natural products.

PubMed

Chang, Junghwa; Kwon, Ho Jeong

2016-03-01

Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

Practical considerations in clinical strategy to support the development of injectable drug-device combination products for biologics.

PubMed

Li, Zhaoyang; Easton, Rachael

2018-01-01

The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely. There is currently no single developmental paradigm, but a risk-based hierarchical approach has been well accepted. The rigor required of a bridging package depends on the level of risk associated with the changes. Clinical pharmacokinetic/pharmacodynamic comparability or outcome studies are only required when important changes occur at a late stage. Moreover, an injectable DDC needs to be user-centric, and usability assessment in real-world clinical settings may be required to support the approval of a DDC. In this review, we discuss the common issues during the manufacturing process and presentation development of an injectable DDC and practical considerations in establishing a clinical strategy to address these issues, including key elements of clinical studies. We also analyze the current practice in the industry and review relevant and status of regulatory guidance in the DDC field.

Natural products with health benefits from marine biological resources

USDA-ARS?s Scientific Manuscript database

The ocean is the cradle of lives, which provides a diverse array of intriguing natural products that has captured scientists’ attention in the past few decades due to their significant and extremely potent biological activities. In addition to being rich sources for pharmaceutical drugs, marine nat...

42 CFR 419.64 - Transitional pass-through payments: Drugs and biologicals.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., 2000. (2) Cancer therapy drugs and biologicals. A drug or biological that is used in cancer therapy... 42 Public Health 3 2014-10-01 2014-10-01 false Transitional pass-through payments: Drugs and...-through payments: Drugs and biologicals. (a) Eligibility for pass-through payment. CMS makes a...

42 CFR 419.64 - Transitional pass-through payments: Drugs and biologicals.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., 2000. (2) Cancer therapy drugs and biologicals. A drug or biological that is used in cancer therapy... 42 Public Health 3 2012-10-01 2012-10-01 false Transitional pass-through payments: Drugs and...-through payments: Drugs and biologicals. (a) Eligibility for pass-through payment. CMS makes a...

42 CFR 419.64 - Transitional pass-through payments: Drugs and biologicals.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., 2000. (2) Cancer therapy drugs and biologicals. A drug or biological that is used in cancer therapy... 42 Public Health 3 2013-10-01 2013-10-01 false Transitional pass-through payments: Drugs and...-through payments: Drugs and biologicals. (a) Eligibility for pass-through payment. CMS makes a...

Bone effects of biologic drugs in rheumatoid arthritis.

PubMed

Corrado, Addolorata; Neve, Anna; Maruotti, Nicola; Cantatore, Francesco Paolo

2013-01-01

Biologic agents used in the treatment of rheumatoid arthritis (RA) are able to reduce both disease activity and radiographic progression of joint disease. These drugs are directed against several proinflammatory cytokines (TNF α , IL-6, and IL-1) which are involved both in the pathogenesis of chronic inflammation and progression of joint structural damage and in systemic and local bone loss typically observed in RA. However, the role of biologic drugs in preventing bone loss in clinical practice has not yet clearly assessed. Many clinical studies showed a trend to a positive effect of biologic agents in preventing systemic bone loss observed in RA. Although the suppression of inflammation is the main goal in the treatment of RA and the anti-inflammatory effects of biologic drugs exert a positive effect on bone metabolism, the exact relationship between the prevention of bone loss and control of inflammation has not been clearly established, and if the available biologic drugs against TNF α , IL-1, and IL-6 can exert their effect on systemic and local bone loss also through a direct mechanism on bone cell metabolism is still to be clearly defined.

"Pruning of biomolecules and natural products (PBNP)": an innovative paradigm in drug discovery.

PubMed

Bathula, Surendar Reddy; Akondi, Srirama Murthy; Mainkar, Prathama S; Chandrasekhar, Srivari

2015-06-21

The source or inspiration of many marketed drugs can be traced back to natural product research. However, the chemical structure of natural products covers a wide spectrum from very simple to complex. With more complex structures it is often desirable to simplify the molecule whilst retaining the desired biological activity. This approach seeks to identify the structural unit or pharmacophore responsible for the desired activity. Such pharmacophores have been the start point for a wide range of lead generation and optimisation programmes using techniques such as Biology Oriented Synthesis, Diversity Oriented Synthesis, Diverted Total Synthesis, and Fragment Based Drug Discovery. This review discusses the literature precedence of simplification strategies in four areas of natural product research: proteins, polysaccharides, nucleic acids, and compounds isolated from natural product extracts, and their impact on identifying therapeutic products.

Practical considerations in clinical strategy to support the development of injectable drug-device combination products for biologics

PubMed Central

Easton, Rachael

2018-01-01

ABSTRACT The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely. There is currently no single developmental paradigm, but a risk-based hierarchical approach has been well accepted. The rigor required of a bridging package depends on the level of risk associated with the changes. Clinical pharmacokinetic/pharmacodynamic comparability or outcome studies are only required when important changes occur at a late stage. Moreover, an injectable DDC needs to be user-centric, and usability assessment in real-world clinical settings may be required to support the approval of a DDC. In this review, we discuss the common issues during the manufacturing process and presentation development of an injectable DDC and practical considerations in establishing a clinical strategy to address these issues, including key elements of clinical studies. We also analyze the current practice in the industry and review relevant and status of regulatory guidance in the DDC field. PMID:29035675

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

PubMed

Kiyosawa, Naoki; Manabe, Sunao

2016-01-01

Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP).

PubMed

Paskiet, Diane; Jenke, Dennis; Ball, Douglas; Houston, Christopher; Norwood, Daniel L; Markovic, Ingrid

2013-01-01

The Product Quality Research Institute (PQRI) is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality and development. The collaborative activities of PQRI participants have, in the case of orally inhaled and nasal drug products (OINDPs), resulted in comprehensive and widely-accepted recommendations for leachables assessments to help ensure patient safety with respect to this class of packaged drug products. These recommendations, which include scientifically justified safety thresholds for leachables, represent a significant milestone towards establishing standardized approaches for safety qualification of leachables in OINDP. To build on the success of the OINDP effort, PQRI's Parenteral and Ophthalmic Drug Products (PODP) Leachables and Extractables Working Group was formed to extrapolate the OINDP threshold concepts and best practice recommendations to other dosage forms with high concern for interaction with packaging/delivery systems. This article considers the general aspects of leachables and their safety assessment, introduces the PODP Work Plan and initial study Protocol, discusses the laboratory studies being conducted by the PODP Chemistry Team, outlines the strategy being developed by the PODP Toxicology Team for the safety qualification of PODP leachables, and considers the issues associated with application of the safety thresholds, particularly with respect to large-volume parenterals. Lastly, the unique leachables issues associated with biologics are described. The Product Quality Research Institute (PQRI) is a non-profit consortium involving industry organizations, academia, and regulatory agencies that together provide recommendations in support of regulatory guidance to advance drug product quality. The collaborative activities of the PQRI Orally Inhaled and Nasal Drug Products Leachables and Extractables Working Group resulted in a

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

PubMed

Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

2017-06-01

Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

RNA interference: from biology to drugs and therapeutics.

PubMed

Appasani, Krishnarao

2004-07-01

RNA interference (RNAi) is a newly discovered and popular technology platform among researchers not only in the fields of RNA biology and molecular cell biology. It has created excitement in clinical sciences such as oncology, neurology, endocrinology, infectious diseases and drug discovery. There is an urgent need to educate and connect academic and industry researchers for the purpose of knowledge transfer. Thus, GeneExpression Systems of Waltham organized its Second International Conference in Waltham City (May 2-4, 2004, MA, USA) on the theme of 'RNA interference: From Biology to Drugs & Therapeutics.' About 200 participants and 32 speakers attended this two and half-day event which was arranged in six scientific and three technology sessions and ended with a panel discussion. This report covers a few representative talks from academia, biotech and the drug industry.

42 CFR 410.29 - Limitations on drugs and biologicals.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Limitations on drugs and biologicals. 410.29 Section 410.29 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... § 410.29 Limitations on drugs and biologicals. Medicare part B does not pay for the following: (a...

42 CFR 410.29 - Limitations on drugs and biologicals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Limitations on drugs and biologicals. 410.29 Section 410.29 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... § 410.29 Limitations on drugs and biologicals. Medicare part B does not pay for the following: (a...

Using X-Ray Crystallography to Simplify and Accelerate Biologics Drug Development.

PubMed

Brader, Mark L; Baker, Edward N; Dunn, Michael F; Laue, Thomas M; Carpenter, John F

2017-02-01

Every major biopharmaceutical company incorporates a protein crystallography unit that is central to its structure-based drug discovery efforts. Yet these capabilities are rarely leveraged toward the formal higher order structural characterization that is so challenging but integral to large-scale biologics manufacturing. Although the biotech industry laments the shortcomings of its favored biophysical techniques, x-ray crystallography is not even considered for drug development. Why not? We suggest that this is due, at least in part, to outdated thinking (for a recent industry-wide survey, see Gabrielson JP, Weiss IV WF. Technical decision-making with higher order structure data: starting a new dialogue. J Pharm Sci. 2015;104(4):1240-1245). We examine some myths surrounding protein crystallography and highlight the inherent properties of protein crystals (molecular identity, biochemical purity, conformational uniformity, and macromolecular crowding) as having practicable commonalities with today's patient-focused liquid drug products. In the new millennium, protein crystallography has become essentially a routine analytical test. Its application may aid the identification of better candidate molecules that are more amenable to high-concentration processing, formulation, and analysis thereby helping to make biologics drug development quicker, simpler, and cheaper. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Characterizing Cancer Drug Response and Biological Correlates: A Geometric Network Approach.

PubMed

Pouryahya, Maryam; Oh, Jung Hun; Mathews, James C; Deasy, Joseph O; Tannenbaum, Allen R

2018-04-23

In the present work, we apply a geometric network approach to study common biological features of anticancer drug response. We use for this purpose the panel of 60 human cell lines (NCI-60) provided by the National Cancer Institute. Our study suggests that mathematical tools for network-based analysis can provide novel insights into drug response and cancer biology. We adopted a discrete notion of Ricci curvature to measure, via a link between Ricci curvature and network robustness established by the theory of optimal mass transport, the robustness of biological networks constructed with a pre-treatment gene expression dataset and coupled the results with the GI50 response of the cell lines to the drugs. Based on the resulting drug response ranking, we assessed the impact of genes that are likely associated with individual drug response. For genes identified as important, we performed a gene ontology enrichment analysis using a curated bioinformatics database which resulted in biological processes associated with drug response across cell lines and tissue types which are plausible from the point of view of the biological literature. These results demonstrate the potential of using the mathematical network analysis in assessing drug response and in identifying relevant genomic biomarkers and biological processes for precision medicine.

Filamentous fungal biofilm for production of human drug metabolites.

PubMed

Amadio, Jessica; Casey, Eoin; Murphy, Cormac D

2013-07-01

In drug development, access to drug metabolites is essential for assessment of toxicity and pharmacokinetic studies. Metabolites are usually acquired via chemical synthesis, although biological production is potentially more efficient with fewer waste management issues. A significant problem with the biological approach is the effective half-life of the biocatalyst, which can be resolved by immobilisation. The fungus Cunninghamella elegans is well established as a model of mammalian metabolism, although it has not yet been used to produce metabolites on a large scale. Here, we describe immobilisation of C. elegans as a biofilm, which can transform drugs to important human metabolites. The biofilm was cultivated on hydrophilic microtiter plates and in shake flasks containing a steel spring in contact with the glass. Fluorescence and confocal scanning laser microscopy revealed that the biofilm was composed of a dense network of hyphae, and biochemical analysis demonstrated that the matrix was predominantly polysaccharide. The medium composition was crucial for both biofilm formation and biotransformation of flurbiprofen. In shake flasks, the biofilm transformed 86% of the flurbiprofen added to hydroxylated metabolites within 24 h, which was slightly more than planktonic cultures (76%). The biofilm had a longer effective lifetime than the planktonic cells, which underwent lysis after 2×72 h cycles, and diluting the Sabouraud dextrose broth enabled the thickness of the biofilm to be controlled while retaining transformation efficiency. Thus, C. elegans biofilm has the potential to be applied as a robust biocatalyst for the production of human drug metabolites required for drug development.

Lipid-lipid and lipid-drug interactions in biological membranes

NASA Astrophysics Data System (ADS)

Martynowycz, Michael W.

Interactions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms responsible for hydrophobic drug permeation remain elusive. Many small molecule drugs are hydrophobic. These drugs inhibit proteins in the cellular interior. The rise of antibiotic resistance in bacteria is thought to be caused by mutations in protein structure, changing drug kinetics to favor growth. However, small molecule drugs have been shown to have different mechanisms depending in the structure of the lipid membrane of the target cell. Biological membranes are investigated using Langmuir monolayers at the air-liquid interface. These offer the highest level of control in the mimetic system and allow them to be investigated using complementary techniques. Langmuir isotherms and insertion assays are used to determine the area occupied by each lipid in the membrane and the change in area caused by the introduction of a drug molecule, respectively. Specular X-ray reflectivity is used to determine the electron density of the monolayer, and grazing incidence X-ray diffraction is used to determine the in-plane order of the monolayer. These methods determine the affinity of the drug and the mechanism of action. Studies are presented on hydrophobic drugs with mammalian membrane mimics using warfarin along with modified analogues, called superwarfarins. Data shows that toxicity of these modified drugs are modulated by the membrane cholesterol content in cells; explaining several previously unexplained effects of the drugs. Membrane mimics of bacteria are investigated along with their interactions with a hydrophobic antibiotic, novobiocin. Data suggests that permeation of the drug is mediated by modifications to the membrane lipids, and completely ceases translocation under certain circumstances. Circumventing deficiencies in small, hydrophobic drugs is approached by using biologically mimetic oligomers. Peptoids, mimetic of host

Regulatory concerns in the development of biologic-biomaterial combinations. United States Food and Drug Administration.

PubMed

Chapekar, M S

1996-01-01

Several biologic-biomaterial combinations are currently under development in an attempt to modulate tissue or organ function in patients. The FDA regulations on combination products and the intercenter agreements among the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Center for Drugs Evaluation and Research (CDER) provide further guidance on center jurisdiction of combination products and other products where there are jurisdictional concerns. The biological component of biologic-biomaterial combinations raises a number of issues that relate to the safety and bioactivity of the final product. For example, transmission of adventitious agents to patients via somatic cells, tissue, or cell-derived products is a major safety concern as are in vivo inflammatory responses elicited by the biomaterial component. CBER has drafted a number of "Points to Consider" documents to provide further guidance in the development of biological products. The intent of this article is to provide the highlights of the FDA regulations for combination products and the intercenter agreement between CBER and CDRH delineating the responsibilities of each center for medical device activities. In addition, the article focuses on the CBER's concerns related to the development of somatic cell-biomaterial combinations for therapeutic use.

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2011-09-01

Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories.   Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation 'push' and may reduce the bioavailability of the system. A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

The impact of natural products upon modern drug discovery.

PubMed

Ganesan, A

2008-06-01

In the period 1970-2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five. The second is a 'parallel universe' that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of logP and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules. We believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more likely than purely synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.

Assessing congenital malformation risk from medications used in pregnancy: The contribution of NBDPS in pregnancy labeling of prescription drug products.

PubMed

Tassinari, Melissa S; Sahin, Leyla; Yao, Lynne P

2015-08-01

Obtaining human pregnancy data to inform product labeling is important for drug and biological products. Collection and analyses of safety data on their use during pregnancy is usually performed after approval. The Centers for Disease Control National Birth Defects Prevention Study has provided important data on the relationship between drug use in pregnancy and birth defects. The Pregnancy and Lactation Labeling Rule will set new and improved standards for the inclusion of information about the use of prescription drugs and biological products during pregnancy; the National Birth Defects Prevention Study, along with other data sources, will be critical for providing safety data to inform product labeling. © 2015 Wiley Periodicals, Inc.

Application of chemical biology in target identification and drug discovery.

PubMed

Zhu, Yue; Xiao, Ting; Lei, Saifei; Zhou, Fulai; Wang, Ming-Wei

2015-09-01

Drug discovery and development is vital to the well-being of mankind and sustainability of the pharmaceutical industry. Using chemical biology approaches to discover drug leads has become a widely accepted path partially because of the completion of the Human Genome Project. Chemical biology mainly solves biological problems through searching previously unknown targets for pharmacologically active small molecules or finding ligands for well-defined drug targets. It is a powerful tool to study how these small molecules interact with their respective targets, as well as their roles in signal transduction, molecular recognition and cell functions. There have been an increasing number of new therapeutic targets being identified and subsequently validated as a result of advances in functional genomics, which in turn led to the discovery of numerous active small molecules via a variety of high-throughput screening initiatives. In this review, we highlight some applications of chemical biology in the context of drug discovery.

FDA 101: Regulating Biological Products

MedlinePlus

... Home For Consumers Consumer Updates FDA 101: Regulating Biological Products Share Tweet Linkedin Pin it More sharing ... about this diverse and highly important field. What biological products does FDA regulate? The Center for Biologics ...

Drug Development Process

MedlinePlus

... Home Food Drugs Medical Devices Radiation-Emitting Products Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products For Patients Home For Patients Learn About Drug and Device Approvals The Drug Development Process The Drug Development Process Share Tweet Linkedin Pin ...

Natural product synthesis at the interface of chemistry and biology

PubMed Central

2014-01-01

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. PMID:25043880

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...

9 CFR 114.6 - Mixing biological products.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Mixing biological products. 114.6... BIOLOGICAL PRODUCTS § 114.6 Mixing biological products. Each biological product, when in liquid form, shall be mixed thoroughly in a single container. During bottling operations, the product shall be...

9 CFR 114.6 - Mixing biological products.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Mixing biological products. 114.6... BIOLOGICAL PRODUCTS § 114.6 Mixing biological products. Each biological product, when in liquid form, shall be mixed thoroughly in a single container. During bottling operations, the product shall be...

9 CFR 114.6 - Mixing biological products.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Mixing biological products. 114.6... BIOLOGICAL PRODUCTS § 114.6 Mixing biological products. Each biological product, when in liquid form, shall be mixed thoroughly in a single container. During bottling operations, the product shall be...

9 CFR 114.6 - Mixing biological products.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Mixing biological products. 114.6... BIOLOGICAL PRODUCTS § 114.6 Mixing biological products. Each biological product, when in liquid form, shall be mixed thoroughly in a single container. During bottling operations, the product shall be...

9 CFR 114.6 - Mixing biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mixing biological products. 114.6... BIOLOGICAL PRODUCTS § 114.6 Mixing biological products. Each biological product, when in liquid form, shall be mixed thoroughly in a single container. During bottling operations, the product shall be...

Genomics, systems biology and drug development for infectious diseases.

PubMed

Sakata, Tomoyo; Winzeler, Elizabeth A

2007-12-01

Although a variety of drugs are available for many infectious diseases that predominantly affect the developing world reasons remain for continuing to search for new chemotherapeutics. First, the development of microbial resistance has made some of the most effective and inexpensive drug regimes unreliable and dangerous to use on severely ill patients. Second, many existing antimicrobial drugs show toxicity or are too expensive for countries where the per capita income is in the order of hundreds of dollars per year. In recognition of this, new publicly and privately financed drug discovery efforts have been established to identify and develop new therapies for diseases such as tuberculosis, malaria and AIDS. This in turn, has intensified the need for tools to facilitate drug identification for those microbes whose molecular biology is poorly understood, or which are difficult to grow in the laboratory. While much has been written about how functional genomics can be used to find novel protein targets for chemotherapeutics this review will concentrate on how genome-wide, systems biology approaches may be used following whole organism, cell-based screening to understand the mechanism of drug action or to identify biological targets of small molecules. Here we focus on protozoan parasites, however, many of the approaches can be applied to pathogenic bacteria or parasitic helminths, insects or disease-causing fungi.

Novel opportunities for computational biology and sociology in drug discovery☆

PubMed Central

Yao, Lixia; Evans, James A.; Rzhetsky, Andrey

2013-01-01

Current drug discovery is impossible without sophisticated modeling and computation. In this review we outline previous advances in computational biology and, by tracing the steps involved in pharmaceutical development, explore a range of novel, high-value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy–industry links for scientific and human benefit. Attention to these opportunities could promise punctuated advance and will complement the well-established computational work on which drug discovery currently relies. PMID:20349528

Novel opportunities for computational biology and sociology in drug discovery

PubMed Central

Yao, Lixia

2009-01-01

Drug discovery today is impossible without sophisticated modeling and computation. In this review we touch on previous advances in computational biology and by tracing the steps involved in pharmaceutical development, we explore a range of novel, high value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy-industry ties for scientific and human benefit. Attention to these opportunities could promise punctuated advance, and will complement the well-established computational work on which drug discovery currently relies. PMID:19674801

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

9 CFR 114.4 - Identification of biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Identification of biological products... REQUIREMENTS FOR BIOLOGICAL PRODUCTS § 114.4 Identification of biological products. Suitable tags or labels of... biological products, all component parts to be combined to form a biological product, all biological products...

Delegations of authority and organization; Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Drug Evaluation and Research--FDA. Final rule.

PubMed

1991-11-21

The Food and Drug Administration (FDA) is amending the regulations for delegations of authority relating to premarket approval of products that are or contain a biologic, a device, or a drug. The amendment grants directors, deputy directors, and certain other supervisory personnel in the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Center for Drug Evaluation and Research (CDER) reciprocal premarket approval authority to approve such products.

Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs.

PubMed

Liu, Mei; Wu, Yonghui; Chen, Yukun; Sun, Jingchun; Zhao, Zhongming; Chen, Xue-wen; Matheny, Michael Edwin; Xu, Hua

2012-06-01

Adverse drug reaction (ADR) is one of the major causes of failure in drug development. Severe ADRs that go undetected until the post-marketing phase of a drug often lead to patient morbidity. Accurate prediction of potential ADRs is required in the entire life cycle of a drug, including early stages of drug design, different phases of clinical trials, and post-marketing surveillance. Many studies have utilized either chemical structures or molecular pathways of the drugs to predict ADRs. Here, the authors propose a machine-learning-based approach for ADR prediction by integrating the phenotypic characteristics of a drug, including indications and other known ADRs, with the drug's chemical structures and biological properties, including protein targets and pathway information. A large-scale study was conducted to predict 1385 known ADRs of 832 approved drugs, and five machine-learning algorithms for this task were compared. This evaluation, based on a fivefold cross-validation, showed that the support vector machine algorithm outperformed the others. Of the three types of information, phenotypic data were the most informative for ADR prediction. When biological and phenotypic features were added to the baseline chemical information, the ADR prediction model achieved significant improvements in area under the curve (from 0.9054 to 0.9524), precision (from 43.37% to 66.17%), and recall (from 49.25% to 63.06%). Most importantly, the proposed model successfully predicted the ADRs associated with withdrawal of rofecoxib and cerivastatin. The results suggest that phenotypic information on drugs is valuable for ADR prediction. Moreover, they demonstrate that different models that combine chemical, biological, or phenotypic information can be built from approved drugs, and they have the potential to detect clinically important ADRs in both preclinical and post-marketing phases.

Alcohol and Drug Prevention Curriculum Resource Guide Grades 10-12: Science--Biology.

ERIC Educational Resources Information Center

North Carolina State Dept. of Public Instruction, Raleigh. Alcohol and Drug Defense Program.

This curriculum resource guide on alcohol and drug prevention provides suggested activities for teachers of grades 10 through 12. Three integrated learning activities for science/biology and healthful living are presented. The science/biology goal is understanding the biology of humans. Healthful living goals include analyzing drug and alcohol use…

Linking neuroethology to the chemical biology of natural products: interactions between cone snails and their fish prey, a case study.

PubMed

Olivera, Baldomero M; Raghuraman, Shrinivasan; Schmidt, Eric W; Safavi-Hemami, Helena

2017-09-01

From a biological perspective, a natural product can be defined as a compound evolved by an organism for chemical interactions with another organism including prey, predator, competitor, pathogen, symbiont or host. Natural products hold tremendous potential as drug leads and have been extensively studied by chemists and biochemists in the pharmaceutical industry. However, the biological purpose for which a natural product evolved is rarely addressed. By focusing on a well-studied group of natural products-venom components from predatory marine cone snails-this review provides a rationale for why a better understanding of the evolution, biology and biochemistry of natural products will facilitate both neuroscience and the potential for drug leads. The larger goal is to establish a new sub-discipline in the broader field of neuroethology that we refer to as "Chemical Neuroethology", linking the substantial work carried out by chemists on natural products with accelerating advances in neuroethology.

Natural product synthesis at the interface of chemistry and biology.

PubMed

Hong, Jiyong

2014-08-11

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Network-based drug discovery by integrating systems biology and computational technologies

PubMed Central

Leung, Elaine L.; Cao, Zhi-Wei; Jiang, Zhi-Hong; Zhou, Hua

2013-01-01

Network-based intervention has been a trend of curing systemic diseases, but it relies on regimen optimization and valid multi-target actions of the drugs. The complex multi-component nature of medicinal herbs may serve as valuable resources for network-based multi-target drug discovery due to its potential treatment effects by synergy. Recently, robustness of multiple systems biology platforms shows powerful to uncover molecular mechanisms and connections between the drugs and their targeting dynamic network. However, optimization methods of drug combination are insufficient, owning to lacking of tighter integration across multiple ‘-omics’ databases. The newly developed algorithm- or network-based computational models can tightly integrate ‘-omics’ databases and optimize combinational regimens of drug development, which encourage using medicinal herbs to develop into new wave of network-based multi-target drugs. However, challenges on further integration across the databases of medicinal herbs with multiple system biology platforms for multi-target drug optimization remain to the uncertain reliability of individual data sets, width and depth and degree of standardization of herbal medicine. Standardization of the methodology and terminology of multiple system biology and herbal database would facilitate the integration. Enhance public accessible databases and the number of research using system biology platform on herbal medicine would be helpful. Further integration across various ‘-omics’ platforms and computational tools would accelerate development of network-based drug discovery and network medicine. PMID:22877768

Prescription Drugs, Over-the-Counter Drugs, Supplements and Herbal Products

MedlinePlus

... at risk? Zika virus and pregnancy Folic acid Medicine safety and pregnancy Birth defects prevention Learn how ... the-counter drugs, supplements and herbal products Prescription drugs, over-the-counter drugs, supplements and herbal products ...

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

PubMed

Hussaarts, Leonie; Mühlebach, Stefan; Shah, Vinod P; McNeil, Scott; Borchard, Gerrit; Flühmann, Beat; Weinstein, Vera; Neervannan, Sesha; Griffiths, Elwyn; Jiang, Wenlei; Wolff-Holz, Elena; Crommelin, Daan J A; de Vlieger, Jon S B

2017-11-01

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids.

PubMed

Hamilton, Gregory S

2015-09-01

Antibody-drug conjugates (ADCs) are a new class of therapeutic agents that combine the targeting ability of monoclonal antibodies (mAbs) with small molecule drugs. The combination of a mAb targeting a cancer-specific antigen with a cytotoxin has tremendous promise as a new type of targeted cancer therapy. Two ADCs have been approved and many more are in clinical development, suggesting that this new class of drugs is coming to the forefront. Because of their unique nature as biologic-small drug hybrids, ADCs are challenging to develop, from both the scientific and regulatory perspectives. This review discusses both these aspects in current practice, and surveys the current state of the art of ADC drug development. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Market uptake of biologic and small-molecule--targeted oncology drugs in Europe.

PubMed

Obradovic, Marko; Mrhar, Ales; Kos, Mitja

2009-12-01

The aim of this study was to investigate the market uptake of biologic and small-molecule-targeted oncology drugs in Europe. Targeted oncology drugs that were used in one of the selected European countries before the end of 2007 were eligible for inclusion in the analysis. The following European countries were included: Austria, Croatia, France, Germany, Hungary, Italy, Slovenia, and the United Kingdom. Monetary market uptake of targeted oncology drugs was assessed by using sales data (in euros) obtained from 2 large data- bases for the period 1997-2007. Market uptake was assessed in terms of expenditures for specific drugs in euros per capita and in market shares. The monetary market uptake of targeted oncology drugs had an exponential growth from 1997 to 2007 in all comparison countries and reached 40% of the total oncology drug market in 2007. Although the various European countries allocate substantially different amounts of resources per capita for oncology drugs, the share of expenditures attributed to targeted oncology drugs did not differ substantially among the countries. Biologic molecules were used in clinical practice before the small-molecule-targeted oncology drugs. Targeted oncology drugs that were introduced first to clinical practice in most of the comparison countries (ie, rituximab, trastuzumab, imatinib mesylate) maintained the leading positions on the market throughout the period of the analysis. In 2007, approximately 25% of all expenditures for oncology drugs were attributed to biologic oncology drugs, and approximately 15% were spent on small-molecule-targeted oncology drugs. Expenditures on targeted oncology drugs have been increasing exponentially in Europe throughout the past decade and have reached a 40% share of the oncology drug market. As of 2007, the market share of biologic oncology drugs was higher than the market share of small-molecule-targeted oncology drugs. Copyright 2009 Excerpta Medica Inc. All rights reserved.

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... § 211.134 Drug product inspection. (a) Packaged and labeled products shall be examined during finishing...

9 CFR 106.1 - Biological products; exemption.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS EXEMPTION FOR BIOLOGICAL PRODUCTS USED IN DEPARTMENT PROGRAMS OR UNDER DEPARTMENT CONTROL OR SUPERVISION § 106.1 Biological products... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Biological products; exemption. 106.1...

9 CFR 106.1 - Biological products; exemption.

Code of Federal Regulations, 2014 CFR

2014-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS EXEMPTION FOR BIOLOGICAL PRODUCTS USED IN DEPARTMENT PROGRAMS OR UNDER DEPARTMENT CONTROL OR SUPERVISION § 106.1 Biological products... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Biological products; exemption. 106.1...

9 CFR 106.1 - Biological products; exemption.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS EXEMPTION FOR BIOLOGICAL PRODUCTS USED IN DEPARTMENT PROGRAMS OR UNDER DEPARTMENT CONTROL OR SUPERVISION § 106.1 Biological products... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Biological products; exemption. 106.1...

9 CFR 106.1 - Biological products; exemption.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS EXEMPTION FOR BIOLOGICAL PRODUCTS USED IN DEPARTMENT PROGRAMS OR UNDER DEPARTMENT CONTROL OR SUPERVISION § 106.1 Biological products... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Biological products; exemption. 106.1...

9 CFR 106.1 - Biological products; exemption.

Code of Federal Regulations, 2011 CFR

2011-01-01

... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS EXEMPTION FOR BIOLOGICAL PRODUCTS USED IN DEPARTMENT PROGRAMS OR UNDER DEPARTMENT CONTROL OR SUPERVISION § 106.1 Biological products... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Biological products; exemption. 106.1...

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2017-04-29

Sturge-Weber Syndrome (SWS) is among the neurocutaneous diseases, which has several clinical manifestations of ocular (glaucoma), cutaneous (port-wine stain), neurological (seizures) and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for the SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against this syndrome. Development of such platforms of bioassay can bring along the implementation of high throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of biological targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholine esterase, alkaline phosphatase, gamma-aminobutyricacidergic, Hypoxia-Inducible Factor (HIF) -1α and 2α are suggested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness.

PubMed

Boyce, Richard D; Horn, John R; Hassanzadeh, Oktie; Waard, Anita de; Schneider, Jodi; Luciano, Joanne S; Rastegar-Mojarad, Majid; Liakata, Maria

2013-01-26

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug's efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File - Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness

PubMed Central

2013-01-01

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug’s efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File – Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug

Natural product and natural product derived drugs in clinical trials.

PubMed

Butler, Mark S; Robertson, Avril A B; Cooper, Matthew A

2014-11-01

There are a significant number of natural product (NP) drugs in development. We review the 100 NP and NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component being evaluated in clinical trials or in registration at the end of 2013. 38 of these compounds and 33 ADCs are being investigated as potential oncology treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurology. There was a spread of the NP and NP-derived compounds through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compounds were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compounds for which clinical trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analysed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compounds in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clinical trials. The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2018-02-01

Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested. © 2017 John Wiley & Sons A/S.

Drug Discovery Prospect from Untapped Species: Indications from Approved Natural Product Drugs

PubMed Central

Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Zhang, Cun Long; Tan, Chun Yan; Chen, Yu Zong; Jiang, Yu Yang

2012-01-01

Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery. PMID:22808057

Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

PubMed Central

Bhattacharya, Sudin; Shoda, Lisl K.M.; Zhang, Qiang; Woods, Courtney G.; Howell, Brett A.; Siler, Scott Q.; Woodhead, Jeffrey L.; Yang, Yuching; McMullen, Patrick; Watkins, Paul B.; Andersen, Melvin E.

2012-01-01

We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of “toxicity pathways” is described in the context of the 2007 US National Academies of Science report, “Toxicity testing in the 21st Century: A Vision and A Strategy.” Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity) – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular “virtual tissue” model of the liver lobule that combines molecular circuits in individual hepatocytes with cell–cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the aryl hydrocarbon receptor toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsym™) to understand drug-induced liver injury (DILI), the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological

Synthetic biology: Emerging bioengineering in Indonesia

NASA Astrophysics Data System (ADS)

Suhandono, Sony

2017-05-01

The development of synthetic biology will shape the new era of science and technology. It is an emerging bioengineering technique involving genetic engineering which can alter the phenotype and behavior of the cell or the new product. Synthetic biology may produce biomaterials, drugs, vaccines, biosensors, and even a recombinant secondary metabolite used in herbal and complementary medicine, such as artemisinin, a malaria drug which is usually extracted from the plant Artemisia annua. The power of synthetic biology has encouraged scientists in Indonesia, and is still in early development. This paper also covers some research from an Indonesian research institute in synthetic biology such as observing the production of bio surfactants and the enhanced production of artemisinin using a transient expression system. Synthetic biology development in Indonesia may also be related to the iGEM competition, a large synthetic biology research competition which was attended by several universities in Indonesia. The application of synthetic biology for drug discovery will be discussed.

Biology of Addiction: Drugs and Alcohol Can Hijack Your Brain

MedlinePlus

... Special Issues Subscribe October 2015 Print this issue Biology of Addiction Drugs and Alcohol Can Hijack Your ... scientists are working to learn more about the biology of addiction. They’ve shown that addiction is ...

Solid-Phase Biological Assays for Drug Discovery

NASA Astrophysics Data System (ADS)

Forsberg, Erica M.; Sicard, Clémence; Brennan, John D.

2014-06-01

In the past 30 years, there has been a significant growth in the use of solid-phase assays in the area of drug discovery, with a range of new assays being used for both soluble and membrane-bound targets. In this review, we provide some basic background to typical drug targets and immobilization protocols used in solid-phase biological assays (SPBAs) for drug discovery, with emphasis on particularly labile biomolecular targets such as kinases and membrane-bound receptors, and highlight some of the more recent approaches for producing protein microarrays, bioaffinity columns, and other devices that are central to small molecule screening by SPBA. We then discuss key applications of such assays to identify drug leads, with an emphasis on the screening of mixtures. We conclude by highlighting specific advantages and potential disadvantages of SPBAs, particularly as they relate to particular assay formats.

Raman Barcode for Counterfeit Drug Product Detection.

PubMed

Lawson, Latevi S; Rodriguez, Jason D

2016-05-03

Potential infiltration of counterfeit drug products-containing the wrong or no active pharmaceutical ingredient (API)-into the bona fide drug supply poses a significant threat to consumers worldwide. Raman spectroscopy offers a rapid, nondestructive avenue to screen a high throughput of samples. Traditional qualitative Raman identification is typically done with spectral correlation methods that compare the spectrum of a reference sample to an unknown. This is often effective for pure materials but is quite challenging when dealing with drug products that contain different formulations of active and inactive ingredients. Typically, reliable identification of drug products using common spectral correlation algorithms can only be made if the specific product under study is present in the library of reference spectra, thereby limiting the scope of products that can be screened. In this paper, we introduce the concept of the Raman barcode for identification of drug products by comparing the known peaks in the API reference spectrum to the peaks present in the finished drug product under study. This method requires the transformation of the Raman spectra of both API and finished drug products into a barcode representation by assigning zero intensity to every spectral frequency except the frequencies that correspond to Raman peaks. By comparing the percentage of nonzero overlap between the expected API barcode and finished drug product barcode, the identity of API present can be confirmed. In this study, 18 approved finished drug products and nine simulated counterfeits were successfully identified with 100% accuracy utilizing this method.

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.

First-principles modeling of biological systems and structure-based drug-design.

PubMed

Sgrignani, Jacopo; Magistrato, Alessandra

2013-03-01

Molecular modeling techniques play a relevant role in drug design providing detailed information at atomistic level on the structural, dynamical, mechanistic and electronic properties of biological systems involved in diseases' onset, integrating and supporting commonly used experimental approaches. These information are often not accessible to the experimental techniques taken singularly, but are of crucial importance for drug design. Due to the enormous increase of the computer power in the last decades, quantum mechanical (QM) or first-principles-based methods have become often used to address biological issues of pharmaceutical relevance, providing relevant information for drug design. Due to their complexity and their size, biological systems are often investigated by means of a mixed quantum-classical (QM/MM) approach, which treats at an accurate QM level a limited chemically relevant portion of the system and at the molecular mechanics (MM) level the remaining of the biomolecule and its environment. This method provides a good compromise between computational cost and accuracy, allowing to characterize the properties of the biological system and the (free) energy landscape of the process in study with the accuracy of a QM description. In this review, after a brief introduction of QM and QM/MM methods, we will discuss few representative examples, taken from our work, of the application of these methods in the study of metallo-enzymes of pharmaceutical interest, of metal-containing anticancer drugs targeting the DNA as well as of neurodegenerative diseases. The information obtained from these studies may provide the basis for a rationale structure-based drug design of new and more efficient inhibitors or drugs.

Population biological principles of drug-resistance evolution in infectious diseases.

PubMed

zur Wiesch, Pia Abel; Kouyos, Roger; Engelstädter, Jan; Regoes, Roland R; Bonhoeffer, Sebastian

2011-03-01

The emergence of resistant pathogens in response to selection pressure by drugs and their possible disappearance when drug use is discontinued are evolutionary processes common to many pathogens. Population biological models have been used to study the dynamics of resistance in viruses, bacteria, and eukaryotic microparasites both at the level of the individual treated host and of the treated host population. Despite the existence of generic features that underlie such evolutionary dynamics, different conclusions have been reached about the key factors affecting the rate of resistance evolution and how to best use drugs to minimise the risk of generating high levels of resistance. Improved understanding of generic versus specific population biological aspects will help to translate results between different studies, and allow development of a more rational basis for sustainable drug use than exists at present. Copyright © 2011 Elsevier Ltd. All rights reserved.

Examination of the regulatory frameworks applicable to biologic drugs (including stem cells and their progeny) in Europe, the U.S., and Australia: part I--a method of manual documentary analysis.

PubMed

Ilic, Nina; Savic, Snezana; Siegel, Evan; Atkinson, Kerry; Tasic, Ljiljana

2012-12-01

Recent development of a wide range of regulatory standards applicable to production and use of tissues, cells, and other biologics (or biologicals), as advanced therapies, indicates considerable interest in the regulation of these products. The objective of this study was to analyze and compare high-tier documents within the Australian, European, and U.S. biologic drug regulatory environments using qualitative methodology. Cohort 1 of the selected 18 high-tier regulatory documents from the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and the Therapeutic Goods Administration (TGA) regulatory frameworks were subject to a manual documentary analysis. These documents were consistent with the legal requirements for manufacturing and use of biologic drugs in humans and fall into six different categories. Manual analysis included a terminology search. The occurrence, frequency, and interchangeable use of different terms and phrases were recorded in the manual documentary analysis. Despite obvious differences, manual documentary analysis revealed certain consistency in use of terminology across analyzed frameworks. Phrase search frequencies have shown less uniformity than the search of terms. Overall, the EMA framework's documents referred to "medicinal products" and "marketing authorization(s)," the FDA documents discussed "drug(s)" or "biologic(s)," and the TGA documents referred to "biological(s)." Although high-tier documents often use different terminology they share concepts and themes. Documents originating from the same source have more conjunction in their terminology although they belong to different frameworks (i.e., Good Clinical Practice requirements based on the Declaration of Helsinki, 1964). Automated (software-based) documentary analysis should be obtained for the conceptual and relational analysis.

Patient-Reported Outcomes Labeling for Products Approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014).

PubMed

Gnanasakthy, Ari; DeMuro, Carla; Clark, Marci; Haydysch, Emily; Ma, Esprit; Bonthapally, Vijayveer

2016-06-01

To review the use of patient-reported outcome (PRO) data in medical product labeling granted by the US Food and Drug Administration (FDA) for new molecular entities and biologic license applications by the FDA Office of Hematology and Oncology Products (OHOP) between January 2010 and December 2014, to elucidate challenges faced by OHOP for approving PRO labeling, and to understand challenges faced by drug manufacturers to include PRO end points in oncology clinical trials. FDA Drug Approval Reports by Month were reviewed to obtain the number of new molecular entities and biologic license applications approved from 2010 to 2014. Drugs approved by the FDA OHOP during this period were selected for further review, focusing on brand and generic name; approval date; applicant; indication; PRO labeling describing treatment benefit, measures, end point status, and significant results; FDA reviewer feedback on PRO end points; and study design of registration trials. First in class, priority review, fast track, orphan drug, or accelerated approval status was retrieved for selected oncology drugs from 2011 to 2014. Descriptive analyses were performed by using Microsoft Excel 2010. Of 160 drugs approved by the FDA (2010-2014), 40 were approved by OHOP. Three (7.5%) of the 40 received PRO-related labeling (abiraterone acetate, ruxolitinib phosphate, and crizotinib). Compared with nononcology drugs (2011-2014), oncology drugs were more likely to be orphan and first in class. The majority of oncology drug reviews by FDA were fast track, priority, or accelerated. Although symptoms and functional decrements are common among patients with cancer, PRO labeling is rare in the United States, likely because of logistical hurdles and oncology study design. Recent developments within the FDA OHOP to capture PROs in oncology studies for the purpose of product labeling are encouraging. © 2016 by American Society of Clinical Oncology.

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

2016-07-21

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

42 CFR 419.64 - Transitional pass-through payments: Drugs and biologicals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... biologicals. 419.64 Section 419.64 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF... biologicals. (a) Eligibility for pass-through payment. CMS makes a transitional pass-through payment for the following drugs and biologicals that are furnished as part of an outpatient hospital service: (1) Orphan...

42 CFR 419.64 - Transitional pass-through payments: Drugs and biologicals.

Code of Federal Regulations, 2011 CFR

2011-10-01

... biologicals. 419.64 Section 419.64 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF... biologicals. (a) Eligibility for pass-through payment. CMS makes a transitional pass-through payment for the following drugs and biologicals that are furnished as part of an outpatient hospital service: (1) Orphan...

Development Considerations for Nanocrystal Drug Products.

PubMed

Chen, Mei-Ling; John, Mathew; Lee, Sau L; Tyner, Katherine M

2017-05-01

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

Generic Drugs: Questions and Answers

MedlinePlus

... Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Drugs Home Drugs Resources for You Information for Consumers (Drugs) Questions & Answers Generic Drugs: Questions & Answers Share Tweet Linkedin Pin it More ...

9 CFR 113.50 - Ingredients of biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Ingredients of biological products... REQUIREMENTS Ingredient Requirements § 113.50 Ingredients of biological products. All ingredients used in a licensed biological product shall meet accepted standards of purity and quality; shall be sufficiently...

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

PubMed

Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U

2011-08-01

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike. Copyright © 2011 Wiley-Liss, Inc.

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

PubMed

Foley, Daniel J; Craven, Philip G E; Collins, Patrick M; Doveston, Richard G; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank; Marsden, Stephen P; Nelson, Adam

2017-10-26

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp 3 -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification.

PubMed

Tarkang, Protus Arrey; Appiah-Opong, Regina; Ofori, Michael F; Ayong, Lawrence S; Nyarko, Alexander K

2016-01-01

There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly-pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi-target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development.

Solid Phase Microextraction and Related Techniques for Drugs in Biological Samples

PubMed Central

Moein, Mohammad Mahdi; Said, Rana; Bassyouni, Fatma

2014-01-01

In drug discovery and development, the quantification of drugs in biological samples is an important task for the determination of the physiological performance of the investigated drugs. After sampling, the next step in the analytical process is sample preparation. Because of the low concentration levels of drug in plasma and the variety of the metabolites, the selected extraction technique should be virtually exhaustive. Recent developments of sample handling techniques are directed, from one side, toward automatization and online coupling of sample preparation units. The primary objective of this review is to present the recent developments in microextraction sample preparation methods for analysis of drugs in biological fluids. Microextraction techniques allow for less consumption of solvent, reagents, and packing materials, and small sample volumes can be used. In this review the use of solid phase microextraction (SPME), microextraction in packed sorbent (MEPS), and stir-bar sorbtive extraction (SBSE) in drug analysis will be discussed. In addition, the use of new sorbents such as monoliths and molecularly imprinted polymers will be presented. PMID:24688797

Natural production of biological optical systems

NASA Astrophysics Data System (ADS)

Choi, Seung Ho; Kim, Young L.

2015-03-01

Synthesis and production in nature often provide ideas to design and fabricate advanced biomimetic photonic materials and structures, leading to excellent physical properties and enhanced performance. In addition, the recognition and utilization of natural or biological substances have been typical routes to develop biocompatible and biodegradable materials for medical applications. In this respect, biological lasers utilizing such biomaterials and biostructures have been received considerable attention, given a variety of implications and potentials for bioimaging, biosensing, implantation, and therapy. However, without relying on industrial facilities, eco-friendly massive production of such optical components or systems has not yet been investigated. We show examples of bioproduction of biological lasers using agriculture and fisheries. We anticipate that such approaches will open new possibilities for scalable eco-friendly `green' production of biological photonics components and systems.

9 CFR 103.1 - Preparation of experimental biological products.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Preparation of experimental biological... PRODUCTION, DISTRIBUTION, AND EVALUATION OF BIOLOGICAL PRODUCTS PRIOR TO LICENSING § 103.1 Preparation of experimental biological products. Except as otherwise provided in this section, experimental biological...

9 CFR 103.1 - Preparation of experimental biological products.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Preparation of experimental biological... PRODUCTION, DISTRIBUTION, AND EVALUATION OF BIOLOGICAL PRODUCTS PRIOR TO LICENSING § 103.1 Preparation of experimental biological products. Except as otherwise provided in this section, experimental biological...

9 CFR 103.1 - Preparation of experimental biological products.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Preparation of experimental biological... PRODUCTION, DISTRIBUTION, AND EVALUATION OF BIOLOGICAL PRODUCTS PRIOR TO LICENSING § 103.1 Preparation of experimental biological products. Except as otherwise provided in this section, experimental biological...

Identification of transformation products of antiviral drugs formed during biological wastewater treatment and their occurrence in the urban water cycle.

PubMed

Funke, Jan; Prasse, Carsten; Ternes, Thomas A

2016-07-01

The fate of five antiviral drugs (abacavir, emtricitabine, ganciclovir, lamivudine and zidovudine) was investigated in biological wastewater treatment. Investigations of degradation kinetics were accompanied by the elucidation of formed transformation products (TPs) using activated sludge lab experiments and subsequent LC-HRMS analysis. Degradation rate constants ranged between 0.46 L d(-1) gSS(-1) (zidovudine) and 55.8 L d(-1) gSS(-1) (abacavir). Despite these differences of the degradation kinetics, the same main biotransformation reaction was observed for all five compounds: oxidation of the terminal hydroxyl-moiety to the corresponding carboxylic acid (formation of carboxy-TPs). In addition, the oxidation of thioether moieties to sulfoxides was observed for emtricitabine and lamivudine. Antiviral drugs were detected in influents of municipal wastewater treatment plants (WWTPs) with concentrations up to 980 ng L(-1) (emtricitabine), while in WWTP effluents mainly the TPs were found with concentration levels up to 1320 ng L(-1) (carboxy-abacavir). Except of zidovudine none of the original antiviral drugs were detected in German rivers and streams, whereas the concentrations of the TPs ranged from 16 ng L(-1) for carboxy-lamivudine up to 750 ng L(-1) for carboxy-acyclovir. These concentrations indicate an appreciable portion from WWTP effluents present in rivers and streams, as well as the high environmental persistence of the carboxy-TPs. As a result three of the carboxylic TPs were detected in finished drinking water. Copyright © 2016 Elsevier Ltd. All rights reserved.

The impact of the Orphan Drug Act on drug discovery.

PubMed

Haffner, Marlene E; Maher, Paul D

2006-11-01

For nearly a quarter of a century the FDA Office of Orphan Products Development has administered the US Orphan Drug Act, which assists in bringing a wide variety of drug and biological (drug) products to treat rare diseases to market. Enthusiasm for rare disease product development has been sustained, seen throughout a wide spectrum of product types and disease conditions, and has resulted in clinically meaningful medical advances. Development of programmes for rare disease treatment worldwide, coupled with the development of drugs for diseases affecting developing countries, attests to the strength of this legislation. The marketing of almost 300 products in the US for rare diseases also testifies to the depth and intensity of scientific endeavour in this area.

Working with the U.S. Food and Drug Administration to obtain approval of products under the Animal Rule.

PubMed

Park, Glen D; Mitchel, Jules T

2016-06-01

While the development of medical products and approval by the U.S. Food and Drug Administration (FDA) is well known, the development of countermeasures against exposure to toxic levels of radiation, chemicals, and infectious agents requires special consideration, and there has been, to date, little experience in working with the FDA to obtain approval of these products. The FDA has published a regulation entitled "Approval of Biological Products when Human Efficacy Studies are not Ethical or Feasible." This regulation, known simply as the "Animal Rule," was designed to permit approval or licensing of drugs and biologics when efficacy studies in humans are not ethical or feasible. To date, 12 products have been approved under the Animal Rule. It is highly recommended that sponsors of products that are to be developed under the Animal Rule meet with the FDA and other government entities early in the development process to ensure that the efficacy and safety studies that are planned will meet the FDA's requirements for approval of the product. © 2016 New York Academy of Sciences.

Aging Biology and Novel Targets for Drug Discovery

PubMed Central

McLachlan, Andrew J.; Quinn, Ronald J.; Simpson, Stephen J.; de Cabo, Rafael

2012-01-01

Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become “blockbusters.” To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process. PMID:21693687

Applied metabolomics in drug discovery.

PubMed

Cuperlovic-Culf, M; Culf, A S

2016-08-01

The metabolic profile is a direct signature of phenotype and biochemical activity following any perturbation. Metabolites are small molecules present in a biological system including natural products as well as drugs and their metabolism by-products depending on the biological system studied. Metabolomics can provide activity information about possible novel drugs and drug scaffolds, indicate interesting targets for drug development and suggest binding partners of compounds. Furthermore, metabolomics can be used for the discovery of novel natural products and in drug development. Metabolomics can enhance the discovery and testing of new drugs and provide insight into the on- and off-target effects of drugs. This review focuses primarily on the application of metabolomics in the discovery of active drugs from natural products and the analysis of chemical libraries and the computational analysis of metabolic networks. Metabolomics methodology, both experimental and analytical is fast developing. At the same time, databases of compounds are ever growing with the inclusion of more molecular and spectral information. An increasing number of systems are being represented by very detailed metabolic network models. Combining these experimental and computational tools with high throughput drug testing and drug discovery techniques can provide new promising compounds and leads.

9 CFR 102.5 - U.S. Veterinary Biological Product License.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false U.S. Veterinary Biological Product... BIOLOGICAL PRODUCTS § 102.5 U.S. Veterinary Biological Product License. (a) Authorization to produce each biological product shall be specified on a U.S. Veterinary Biological Product License, issued by the...

9 CFR 102.5 - U.S. Veterinary Biological Product License.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false U.S. Veterinary Biological Product... BIOLOGICAL PRODUCTS § 102.5 U.S. Veterinary Biological Product License. (a) Authorization to produce each biological product shall be specified on a U.S. Veterinary Biological Product License, issued by the...

Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening and knowledge of transporters: where drug discovery went wrong and how to fix it.

PubMed

Kell, Douglas B

2013-12-01

Despite the sequencing of the human genome, the rate of innovative and successful drug discovery in the pharmaceutical industry has continued to decrease. Leaving aside regulatory matters, the fundamental and interlinked intellectual issues proposed to be largely responsible for this are: (a) the move from 'function-first' to 'target-first' methods of screening and drug discovery; (b) the belief that successful drugs should and do interact solely with single, individual targets, despite natural evolution's selection for biochemical networks that are robust to individual parameter changes; (c) an over-reliance on the rule-of-5 to constrain biophysical and chemical properties of drug libraries; (d) the general abandoning of natural products that do not obey the rule-of-5; (e) an incorrect belief that drugs diffuse passively into (and presumably out of) cells across the bilayers portions of membranes, according to their lipophilicity; (f) a widespread failure to recognize the overwhelmingly important role of proteinaceous transporters, as well as their expression profiles, in determining drug distribution in and between different tissues and individual patients; and (g) the general failure to use engineering principles to model biology in parallel with performing 'wet' experiments, such that 'what if?' experiments can be performed in silico to assess the likely success of any strategy. These facts/ideas are illustrated with a reasonably extensive literature review. Success in turning round drug discovery consequently requires: (a) decent systems biology models of human biochemical networks; (b) the use of these (iteratively with experiments) to model how drugs need to interact with multiple targets to have substantive effects on the phenotype; (c) the adoption of polypharmacology and/or cocktails of drugs as a desirable goal in itself; (d) the incorporation of drug transporters into systems biology models, en route to full and multiscale systems biology models that

Principles of nanoparticle design for overcoming biological barriers to drug delivery

PubMed Central

Blanco, Elvin; Shen, Haifa; Ferrari, Mauro

2016-01-01

Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery. PMID:26348965

Midyear Commentary on Trends in Drug Delivery and Clinical Translational Medicine: Growth in Biosimilar (Complex Injectable Drug Formulation) Products Within Evolving Collaborative Regulatory Interagency (FDA, FTC, and DOJ) Practices and Enforcement

PubMed Central

Ho, Rodney J.Y.

2017-01-01

Before the 2009 Biologics Price Competition and Innovation Act that enabled the U.S. Federal Drug Administration (FDA) to create the 351(k) Biologic License Application–an abbreviated biosimilar approval process, FDA approved follow-on biomolecule products such as beta-interferon, glucagon, hyaluronidase, and somatropin (human growth hormone) under varying and evolving rules. With the 351(k) Biologic License Application biosimilar approval process in place, currently, there are 4 (licensed in 2015–2016) biosimilars available, namely Neupogen (filgrastim; $1 B/y), Humira (adalumumab; $14.2 B/y), Enbrel (etanercept; $8.7 B/y), and Remicade (infliximab; $6.5 B/y). With well-established product market capitalization of these and other top income producers—such as Rituxan (rituximab; $6.8 B/y), Herceptin (trastuzumab; $6.5 B/y), and Avastin (bevacizumab; $5.8 B/y), and a price differential of 15%–30% compared to branded products, there is an intense interest in development of biosimilars by established pharmaceutical companies. Currently, there are 160 biosimilar candidates in clinical studies, many of which are sponsored by large pharmaceutical companies known for product innovation. This trend will likely continue. Additional information on a biomolecule platform is presented in the Journal of Pharmaceutical Sciences Drug Delivery Clinical Trials Database (jpharmscidatabase.org). There are 44,789, 18,456, and 12,897 clinical trials registered to evaluate (1) drug delivery technology, (2) biomolecule platform, and (3) drug metabolism and pharmacokinetic-pharmacodynamic interactions; representing 19%–60% increase over the last 3 years. PMID:27876365

Drug product selection: the Florida experience.

PubMed Central

Vuturo, G J; Krischer, J P; McCormick, W C

1980-01-01

Drug product selection, the act of selecting and dispensing a lower cost generically equivalent product to that prescribed, is made possible in 46 states through recently enacted legislation. Florida's legislation is unique in that it requires pharmacists to product select under certain circumstances. This study reports on the results of a review of the Florida experience approximately one year after enactment of its drug product selection legislation. Nearly 132,000 prescriptions were sampled from 60 pharmacies during a four-month study period. This represents one per cent of all new prescriptions in the state and a three per cent sample of community pharmacies. Study results indicate that drug product selection on the average saves the consumer $1.92 per prescription. Further, under the provisions of this law the majority of cost savings (average reductions in acquisition costs between prescribed and dispensed products) are being passed along as savings to the consumer. During the four-month study period this amounted to a total prescription cost savings of nearly $425,000. Drug product selection occurs in approximately two per cent of all new prescriptions which compares favorably with results reported from other states but also suggests that additional savings can be realized under such legislation. PMID:7377418

Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point.

PubMed

Rodrigues, Tiago

2017-11-15

Natural products (NPs) present a privileged source of inspiration for chemical probe and drug design. Despite the biological pre-validation of the underlying molecular architectures and their relevance in drug discovery, the poor accessibility to NPs, complexity of the synthetic routes and scarce knowledge of their macromolecular counterparts in phenotypic screens still hinder their broader exploration. Cheminformatics algorithms now provide a powerful means of circumventing the abovementioned challenges and unlocking the full potential of NPs in a drug discovery context. Herein, I discuss recent advances in the computer-assisted design of NP mimics and how artificial intelligence may accelerate future NP-inspired molecular medicine.

[Synthetic biology toward microbial secondary metabolites and pharmaceuticals].

PubMed

Wu, Lin-Zhuan; Hong, Bin

2013-02-01

Microbial secondary metabolites are one of the major sources of anti-bacterial, anti-fungal, antitumor, anti-virus and immunosuppressive agents for clinical use. Present challenges in microbial pharmaceutical development are the discovery of novel secondary metabolites with significant biological activities, improving the fermentation titers of industrial microbial strains, and production of natural product drugs by re-establishing their biosynthetic pathways in suitable microbial hosts. Synthetic biology, which is developed from systematic biology and metabolic engineering, provides a significant driving force for microbial pharmaceutical development. The review describes the major applications of synthetic biology in novel microbial secondary metabolite discovery, improved production of known secondary metabolites and the production of some natural drugs in genetically modified or reconstructed model microorganisms.

Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery.

PubMed

Altmann, Karl-Heinz

2017-10-25

The marine environment harbors a vast number of species that are the source of a wide array of structurally diverse bioactive secondary metabolites. At this point in time, roughly 27'000 marine natural products are known, of which eight are (were) at the origin of seven marketed drugs, mostly for the treatment of cancer. The majority of these drugs and also of drug candidates currently undergoing clinical evaluation (excluding antibody-drug conjugates) are unmodified natural products, but synthetic chemistry has played a central role in the discovery and/or development of all but one of the approved marine-derived drugs. More than 1000 new marine natural products have been isolated per year over the last decade, but the pool of new and unique structures is far from exhausted. To fully leverage the potential offered by the structural diversity of marine-produced secondary metabolites for drug discovery will require their broad assessment for different bioactivities and the productive interplay between new fermentation technologies, synthetic organic chemistry, and medicinal chemistry, in order to secure compound supply and enable lead optimization.

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

PubMed Central

Park, Yoo-Sin; Kim, Shin-Hee; Kim, Sang-Hyun; Jun, Min-Young

2011-01-01

Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring. PMID:21660146

Plankton Production Biology

DTIC Science & Technology

2013-09-30

population dynamics (growth rate, production, mortality) of copepod nauplii in the field or captured water columns (mesocosms). Since biology...36-45, doi:10.1016/j.dsr.2012.03.001, 2012. PUBLICATIONS Banse, K., Naqvi, S.W.A., Narvekar, P.V., Postel, J.R., Jayakumar , D.A. Oxygen minimum

78 FR 38053 - Determination That OPANA ER (Oxymorphone Hydrochloride) Drug Products Covered by New Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-25

...] Determination That OPANA ER (Oxymorphone Hydrochloride) Drug Products Covered by New Drug Application 21-610... (oxymorphone hydrochloride (HCl)) Extended-Release Tablet products approved under new drug application (NDA) 21... refer to these drug products, and it will allow FDA to continue to approve ANDAs for oxymorphone HCl...

Presence and biological activity of antibiotics used in fuel ethanol and corn co-product production.

PubMed

Compart, D M Paulus; Carlson, A M; Crawford, G I; Fink, R C; Diez-Gonzalez, F; Dicostanzo, A; Shurson, G C

2013-05-01

Antibiotics are used in ethanol production to control bacteria from competing with yeast for nutrients during starch fermentation. However, there is no published scientific information on whether antibiotic residues are present in distillers grains (DG), co-products from ethanol production, or whether they retain their biological activity. Therefore, the objectives of this study were to quantify concentrations of various antibiotic residues in DG and determine whether residues were biologically active. Twenty distillers wet grains and 20 distillers dried grains samples were collected quarterly from 9 states and 43 ethanol plants in the United States. Samples were analyzed for DM, CP, NDF, crude fat, S, P, and pH to describe the nutritional characteristics of the samples evaluated. Samples were also analyzed for the presence of erythromycin, penicillin G, tetracycline, tylosin, and virginiamycin M1, using liquid chromatography and mass spectrometry. Additionally, virginiamycin residues were determined, using a U.S. Food and Drug Administration-approved bioassay method. Samples were extracted and further analyzed for biological activity by exposing the sample extracts to 10(4) to 10(7) CFU/mL concentrations of sentinel bacterial strains Escherichia coli ATCC 8739 and Listeria monocytogenes ATCC 19115. Extracts that inhibited bacterial growth were considered to have biological activity. Physiochemical characteristics varied among samples but were consistent with previous findings. Thirteen percent of all samples contained low (≤1.12 mg/kg) antibiotic concentrations. Only 1 sample extract inhibited growth of Escherichia coli at 10(4) CFU/mL, but this sample contained no detectable concentrations of antibiotic residues. No extracts inhibited Listeria monocytogenes growth. These data indicate that the likelihood of detectable concentrations of antibiotic residues in DG is low; and if detected, they are found in very low concentrations. The inhibition in only 1 DG

COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach

PubMed Central

Kapetanovic, I.M.

2008-01-01

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415

What does systems biology mean for drug development?

PubMed

Schrattenholz, André; Soskić, Vukić

2008-01-01

The complexity and flexibility of cellular architectures is increasingly recognized by impressive progress on the side of molecular analytics, i.e. proteomics, genomics and metabolomics. One of the messages from systems biology is that the number of molecular species in cellular networks is orders of magnitude bigger than anticipated by genomic analysis, in particular by fast posttranslational modifications of proteins. The requirements to manage external signals, integrate spatiotemporal signal transduction inside an organism and at the same time optimizing networks of biochemical and chemical reactions result in chemically extremely fine tuned molecular entities. Chemical side reactions of enzymatic activity, like e.g. random oxidative damage of proteins by free radicals during aging constantly introduce epigenetic alterations of protein targets. These events gradually and on an individual stochastic scale, keep modifying activities of these targets, and their affinities and selectivities towards biological and pharmacological ligands. One further message is that many of the key reactions in living systems are essentially based on interactions of low affinities and even low selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. So, in complex disorders like cancer or neurodegenerative diseases, which are rooted in relatively subtle and multimodal dysfunction of important physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which still dominate the pharmaceutical industry increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade and the treatment of "complex diseases" remains a most pressing medical need. Currently a change of paradigm can be observed with

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

PubMed

Li, Rongshi

2016-01-01

Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents. © 2015 Wiley Periodicals, Inc.

21 CFR 211.208 - Drug product salvaging.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drug product salvaging. 211.208 Section 211.208 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.204 - Returned drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Returned drug products. 211.204 Section 211.204 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.204 - Returned drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Returned drug products. 211.204 Section 211.204 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.208 - Drug product salvaging.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drug product salvaging. 211.208 Section 211.208 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.204 - Returned drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Returned drug products. 211.204 Section 211.204 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.204 - Returned drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Returned drug products. 211.204 Section 211.204 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.208 - Drug product salvaging.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drug product salvaging. 211.208 Section 211.208 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.208 - Drug product salvaging.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drug product salvaging. 211.208 Section 211.208 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

21 CFR 211.204 - Returned drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Returned drug products. 211.204 Section 211.204 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Returned and Salvaged Drug...

Synthesis and Demonstration of the Biological Relevance of sp3‐rich Scaffolds Distantly Related to Natural Product Frameworks

PubMed Central

Foley, Daniel J.; Craven, Philip G. E.; Collins, Patrick M.; Doveston, Richard G.; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank

2017-01-01

Abstract The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top‐down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3‐rich scaffolds. The scaffolds have local natural product‐like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high‐throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. PMID:28983993

The yeast stands alone: the future of protein biologic production.

PubMed

Love, Kerry R; Dalvie, Neil C; Love, J Christopher

2017-12-22

Yeasts are promising alternative hosts for the manufacturing of recombinant protein therapeutics because they simply and efficiently meet needs for both platform and small-market drugs. Fast accumulation of biomass and low-cost media reduce the cost-of-goods when using yeast, which in turn can enable agile, small-volume manufacturing facilities. Small, tractable yeast genomes are amenable to rapid process development, facilitating strain and product quality by design. Specifically, Pichia pastoris is becoming a widely accepted yeast for biopharmaceutical manufacturing in much of the world owing to a clean secreted product and the rapidly expanding understanding of its cell biology as a host organism. We advocate for a near term partnership spanning industry and academia to promote open source, timely development of yeast hosts. Copyright © 2017. Published by Elsevier Ltd.

Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

PubMed

Drawnel, Faye Marie; Zhang, Jitao David; Küng, Erich; Aoyama, Natsuyo; Benmansour, Fethallah; Araujo Del Rosario, Andrea; Jensen Zoffmann, Sannah; Delobel, Frédéric; Prummer, Michael; Weibel, Franziska; Carlson, Coby; Anson, Blake; Iacone, Roberto; Certa, Ulrich; Singer, Thomas; Ebeling, Martin; Prunotto, Marco

2017-05-18

Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tunable and reversible drug control of protein production via a self-excising degron.

PubMed

Chung, Hokyung K; Jacobs, Conor L; Huo, Yunwen; Yang, Jin; Krumm, Stefanie A; Plemper, Richard K; Tsien, Roger Y; Lin, Michael Z

2015-09-01

An effective method for direct chemical control over the production of specific proteins would be widely useful. We describe small molecule-assisted shutoff (SMASh), a technique in which proteins are fused to a degron that removes itself in the absence of drug, resulting in the production of an untagged protein. Clinically tested HCV protease inhibitors can then block degron removal, inducing rapid degradation of subsequently synthesized copies of the protein. SMASh allows reversible and dose-dependent shutoff of various proteins in multiple mammalian cell types and in yeast. We also used SMASh to confer drug responsiveness onto an RNA virus for which no licensed inhibitors exist. As SMASh does not require the permanent fusion of a large domain, it should be useful when control over protein production with minimal structural modification is desired. Furthermore, as SMASh involves only a single genetic modification and does not rely on modulating protein-protein interactions, it should be easy to generalize to multiple biological contexts.

Application of a phenotypic drug discovery strategy to identify biological and chemical starting points for inhibition of TSLP production in lung epithelial cells

PubMed Central

Orellana, Adelina; García-González, Vicente; López, Rosa; Pascual-Guiral, Sonia; Lozoya, Estrella; Díaz, Julia; Casals, Daniel; Barrena, Antolín; Paris, Stephane; Andrés, Miriam; Segarra, Victor; Vilella, Dolors; Malhotra, Rajneesh; Eastwood, Paul; Planagumà, Anna; Miralpeix, Montserrat

2018-01-01

Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation. To this end, a phenotypic screen was performed using poly I:C / IL-4 stimulated NHBE cells interrogated with a 44,974 compound library. As a result, 85 hits which downregulated TSLP protein and mRNA levels were identified and a representative subset of 7 hits was selected for further characterization. These molecules inhibited the activity of several members of the MAPK, PI3K and tyrosine kinase families and some of them have been reported as modulators of cellular phenotypic endpoints like cell-cell contacts, microtubule polymerization and caspase activation. Characterization of the biological profile of the hits suggested that mTOR could be a key activity involved in the regulation of TSLP production in NHBE cells. Among other targeted kinases, inhibition of p38 MAPK and JAK kinases showed different degrees of correlation with TSLP downregulation, while Syk kinase did not seem to be related. Overall, inhibition of TSLP production by the selected hits, rather than resulting from inhibition of single isolated targets, appeared to be due to a combination of activities with different levels of relevance. Finally, a hit expansion exercise yielded additional active compounds that could be amenable to further optimization, providing an opportunity to dissociate TSLP inhibition from other non-desired activities. This study illustrates the potential of phenotypic drug discovery to complement target based approaches by providing new chemistry and biology

9 CFR 113.3 - Sampling of biological products.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Sampling of biological products. 113.3 Section 113.3 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... Applicability § 113.3 Sampling of biological products. Each licensee and permittee shall furnish representative...

9 CFR 113.3 - Sampling of biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Sampling of biological products. 113.3 Section 113.3 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... Applicability § 113.3 Sampling of biological products. Each licensee and permittee shall furnish representative...

Examination of the regulatory frameworks applicable to biologic drugs (including stem cells and their progeny) in Europe, the U.S., and Australia: part II--a method of software documentary analysis.

PubMed

Ilic, Nina; Savic, Snezana; Siegel, Evan; Atkinson, Kerry; Tasic, Ljiljana

2012-12-01

A wide range of regulatory standards applicable to production and use of tissues, cells, and other biologics (or biologicals), as advanced therapies, indicates considerable interest in the regulation of these products. The objective of this study was to analyze and compare high-tier documents within the Australian, European, and U.S. biologic drug regulatory environments using qualitative methodology. Eighteen high-tier documents from the European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA), and Therapeutic Goods Administration (TGA) regulatory frameworks were subject to automated text analysis. Selected documents were consistent with the legal requirements for manufacturing and use of biologic drugs in humans and fall into six different categories. Concepts, themes, and their co-occurrence were identified and compared. The most frequent concepts in TGA, FDA, and EMA frameworks were "biological," "product," and "medicinal," respectively. This was consistent with the previous manual terminology search. Good Manufacturing Practice documents, across frameworks, identified "quality" and "appropriate" as main concepts, whereas in Good Clinical Practice (GCP) documents it was "clinical," followed by "trial," "subjects," "sponsor," and "data." GCP documents displayed considerably higher concordance between different regulatory frameworks, as demonstrated by a smaller number of concepts, similar size, and similar distance between them. Although high-tier documents often use different terminology, they share concepts and themes. This paper may be a modest contribution to the recognition of similarities and differences between analyzed regulatory documents. It may also fill the literature gap and provide some foundation for future comparative research of biologic drug regulations on a global level.

21 CFR 310.509 - Parenteral drug products in plastic containers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Parenteral drug products in plastic containers... Parenteral drug products in plastic containers. (a) Any parenteral drug product packaged in a plastic... parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or...

21 CFR 310.509 - Parenteral drug products in plastic containers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Parenteral drug products in plastic containers... Parenteral drug products in plastic containers. (a) Any parenteral drug product packaged in a plastic... parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or...

21 CFR 310.509 - Parenteral drug products in plastic containers.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Parenteral drug products in plastic containers... Parenteral drug products in plastic containers. (a) Any parenteral drug product packaged in a plastic... parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or...

21 CFR 310.509 - Parenteral drug products in plastic containers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Parenteral drug products in plastic containers... Parenteral drug products in plastic containers. (a) Any parenteral drug product packaged in a plastic... parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or...

21 CFR 310.509 - Parenteral drug products in plastic containers.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Parenteral drug products in plastic containers... Parenteral drug products in plastic containers. (a) Any parenteral drug product packaged in a plastic... parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or...

21 CFR 341.78 - Labeling of expectorant drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Labeling of expectorant drug products. 341.78 Section 341.78 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR...

21 CFR 341.78 - Labeling of expectorant drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Labeling of expectorant drug products. 341.78 Section 341.78 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR...

21 CFR 341.78 - Labeling of expectorant drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Labeling of expectorant drug products. 341.78 Section 341.78 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR...

21 CFR 341.78 - Labeling of expectorant drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Labeling of expectorant drug products. 341.78 Section 341.78 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR...

21 CFR 341.78 - Labeling of expectorant drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Labeling of expectorant drug products. 341.78 Section 341.78 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR...

The use of HPLC-Q-TOF-MS for comprehensive screening of drugs and psychoactive substances in hair samples and several "legal highs" products.

PubMed

Aszyk, Justyna; Kot-Wasik, Agata

Non-targeted screening of drugs present in herbal products, known as "legal high" drugs and in hair as a biological matrix commonly used in toxicological investigations was accomplished with the use of high pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). In total, 25 and 14 therapeutical drugs and psychoactive substances/metabolites were detected in investigated hair samples and herbal products, respectively. We demonstrate that the HPLC-Q-TOF methodology seems to be a powerful tool in the qualitative analysis applied in identification of these designer drugs, thus enabling a laboratory to stay-up-to-date with the drugs that are being sold as legal high products on black market.

21 CFR 211.134 - Drug product inspection.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drug product inspection. 211.134 Section 211.134 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Packaging and Labeling Control...

21 CFR 340.50 - Labeling of stimulant drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Labeling of stimulant drug products. 340.50 Section 340.50 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE STIMULANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Labeling § 340.50...

Analytical surveillance of emerging drugs of abuse and drug formulations

PubMed Central

Thomas, Brian F.; Pollard, Gerald T.; Grabenauer, Megan

2012-01-01

Uncontrolled recreational drugs are proliferating in number and variety. Effects of long-term use are unknown, and regulation is problematic, as efforts to control one chemical often lead to several other structural analogs. Advanced analytical instrumentation and methods are continuing to be developed to identify drugs, chemical constituents of products, and drug substances and metabolites in biological fluids. Several mass spectrometry based approaches appear promising, particularly those that involve high resolution chromatographic and mass spectrometric methods that allow unbiased data acquisition and sophisticated data interrogation. Several of these techniques are shown to facilitate both targeted and broad spectrum analysis, which is often of particular benefit when dealing with misleadingly labeled products or assessing a biological matrix for illicit drugs and metabolites. The development and application of novel analytical approaches such as these will help to assess the nature and degree of exposure and risk and, where necessary, inform forensics and facilitate implementation of specific regulation and control measures. PMID:23154240

Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

PubMed

Isgut, Monica; Rao, Mukkavilli; Yang, Chunhua; Subrahmanyam, Vangala; Rida, Padmashree C G; Aneja, Ritu

2018-03-01

Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs. © 2017 Wiley Periodicals, Inc.

Use and Spending for Biologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Among US Medicare Beneficiaries.

PubMed

Yazdany, Jinoos; Tonner, Chris; Schmajuk, Gabriela

2015-09-01

Biologic therapies have assumed an important role in treating rheumatoid arthritis (RA). We sought to investigate use, spending, and patient cost-sharing for Medicare beneficiaries using biologic drugs for RA, comparing patients exposed to minimal cost-sharing because of a Part D low-income subsidy (LIS) to those facing substantial out-of-pocket costs (OOP). We performed a retrospective, nationwide study using 2009 Medicare claims for a 5% random sample of beneficiaries with RA who had at least 1 RA drug dispensed. We analyzed biologic drug utilization and costs across the Part B (medical benefit) and Part D (pharmacy benefit) programs by LIS status using multinomial regression. We also projected OOP costs as the Affordable Care Act (ACA) mandates closure of the Part D coverage gap by 2020. Among 6,932 beneficiaries, 1,812 (26.1%) received a biologic drug. LIS beneficiaries were significantly more likely to obtain Part D home-administered biologics (relative risk ratio [RRR] 2.98, 95% confidence interval [95% CI] 2.50-3.56), while non-LIS beneficiaries were less likely to receive Part D biologic agents (RRR 0.58, 95% CI 0.48-0.69). OOP costs in Part D were lower, as expected, for LIS beneficiaries ($72 versus $3,751 per year for non-LIS). Non-LIS beneficiaries had lower costs for Part B facility-administered biologic agents (range $0-$2,584) than for Part D home-administered biologic agents. ACA reforms will narrow OOP differences between Part D and B for non-LIS beneficiaries. In contrast to LIS beneficiaries who receive mostly Part D home-administered biologic DMARDs, nonsubsidized beneficiaries have significant cost-based incentives to obtain facility-administered biologic DMARDs through Part B. The ACA will result in only slightly lower costs for Part D biologic drugs for these beneficiaries. © 2015, American College of Rheumatology.

21 CFR 211.208 - Drug product salvaging.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drug product salvaging. 211.208 Section 211.208 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the...

Examining the production costs of antiretroviral drugs.

PubMed

Pinheiro, Eloan; Vasan, Ashwin; Kim, Jim Yong; Lee, Evan; Guimier, Jean Marc; Perriens, Joseph

2006-08-22

To present direct manufacturing costs and price calculations of individual antiretroviral drugs, enabling those responsible for their procurement to have a better understanding of the cost structure of their production, and to indicate the prices at which these antiretroviral drugs could be offered in developing country markets. Direct manufacturing costs and factory prices for selected first and second-line antiretroviral drugs were calculated based on cost structure data from a state-owned company in Brazil. Prices for the active pharmaceutical ingredients (API) were taken from a recent survey by the World Health Organization (WHO). The calculated prices for antiretroviral drugs are compared with quoted prices offered by privately-owned, for-profit manufacturers. The API represents the largest component of direct manufacturing costs (55-99%), while other inputs, such as salaries, equipment costs, and scale of production, have a minimal impact. The calculated prices for most of the antiretroviral drugs studied fall within the lower quartile of the range of quoted prices in developing country markets. The exceptions are those drugs, primarily for second-line therapy, for which the API is either under patent, in short supply, or in limited use in developing countries (e.g. abacavir, lopinavir/ritonavir, nelfinavir, saquinavir). The availability of data on the cost of antiretroviral drug production and calculation of factory prices under a sustainable business model provide benchmarks that bulk purchasers of antiretroviral drugs could use to negotiate lower prices. While truly significant price decreases for antiretroviral drugs will depend largely on the future evolution of API prices, the present study demonstrates that for several antiretroviral drugs price reduction is currently possible. Whether or not these reductions materialize will depend on the magnitude of indirect cost and profit added by each supplier over the direct production costs. The ability to

Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs.

PubMed

Li, Jianyu; Weber, Eckhard; Guth-Gundel, Sabine; Schuleit, Michael; Kuttler, Andreas; Halleux, Christine; Accart, Nathalie; Doelemeyer, Arno; Basler, Anne; Tigani, Bruno; Wuersch, Kuno; Fornaro, Mara; Kneissel, Michaela; Stafford, Alexander; Freedman, Benjamin R; Mooney, David J

2018-05-01

Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL -1 ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimization of the Bacterial Cytochrome P450 BM3 System for the Production of Human Drug Metabolites

PubMed Central

Di Nardo, Giovanna; Gilardi, Gianfranco

2012-01-01

Drug metabolism in human liver is a process involving many different enzymes. Among them, a number of cytochromes P450 isoforms catalyze the oxidation of most of the drugs commercially available. Each P450 isoform acts on more than one drug, and one drug may be oxidized by more than one enzyme. As a result, multiple products may be obtained from the same drug, and as the metabolites can be biologically active and may cause adverse drug reactions (ADRs), the metabolic profile of a new drug has to be known before this can be commercialized. Therefore, the metabolites of a certain drug must be identified, synthesized and tested for toxicity. Their synthesis must be in sufficient quantities to be used for metabolic tests. This review focuses on the progresses done in the field of the optimization of a bacterial self-sufficient and efficient cytochrome P450, P450 BM3 from Bacillus megaterium, used for the production of metabolites of human enzymes. The progress made in the improvement of its catalytic performance towards drugs, the substitution of the costly NADPH cofactor and its immobilization and scale-up of the process for industrial application are reported. PMID:23443101

Combination products regulation at the FDA.

PubMed

Lauritsen, K J; Nguyen, T

2009-05-01

The US Food and Drug Administration (FDA) is responsible for protecting the public health by assuring the safety, efficacy, and security of drugs, biological products, and medical devices. As single-entity products, drugs are generally regulated by the Center for Drug Evaluation and Research (CDER), devices by the Center for Devices and Radiological Health (CDRH), and biologics by the Center for Biologics Evaluation and Research (CBER). In recent years, technological advances have led to a blurring of the historical lines of separation between the centers.

Biological Evidence for Paradoxical Improvement of Psychiatric Disorder Symptoms by Addictive Drugs.

PubMed

Müller, Christian P; Kornhuber, Johannes

2017-06-01

Addiction biology has focused on the mechanisms of the positive and negative reinforcing actions of addictive drugs but neglected potential benefits. Two new studies provide the first insights into a neurobiology of psychoactive drug instrumentalization. This may help us design better models for addiction neuroscience and opens a new dimension for the development of personalized pharmacotherapy of drug addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

Concept of biosimilar products in Jordan.

PubMed

Haddadin, Rania Dakhlallah

2011-09-01

After the expiration of patents on originator biological products, Jordanian local manufacturers and the agents of international pharmaceutical companies in Jordan started to submit registration dossiers for biosimilar products. The Jordan Food and Drug Administration (JFDA) is the national regulatory authority responsible for the registration of biosimilar products. Biosimilars are registered under the same regulations used for drugs until specific guidelines for registration of biological and biosimilar products are released. Those regulations are called Criteria of Registration of Drugs, Vaccines, Sera and Biological Products, the Renewal of its Registration and the Cancellation of Any of them which was published in the official gazette in 2004 under the Provisional Law Number 80 of the year 2001, Drug and Pharmacy Law and its amendments of the year 2003. Also, the JFDA follows the EMA guidelines on similar biological medicinal products for specific active biological substances for non-clinical and clinical studies requirements and the EMA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. A post marketing surveillance study is requested after a biosimilar product is authorized. The JFDA keeps pace with all advances in the regulatory issues related to biosimilars in order to be capable of authorizing biosimilar products with a safe, effective and good quality profile. Copyright © 2011. Published by Elsevier Ltd.

Repurposing High-Throughput Image Assays Enables Biological Activity Prediction for Drug Discovery.

PubMed

Simm, Jaak; Klambauer, Günter; Arany, Adam; Steijaert, Marvin; Wegner, Jörg Kurt; Gustin, Emmanuel; Chupakhin, Vladimir; Chong, Yolanda T; Vialard, Jorge; Buijnsters, Peter; Velter, Ingrid; Vapirev, Alexander; Singh, Shantanu; Carpenter, Anne E; Wuyts, Roel; Hochreiter, Sepp; Moreau, Yves; Ceulemans, Hugo

2018-05-17

In both academia and the pharmaceutical industry, large-scale assays for drug discovery are expensive and often impractical, particularly for the increasingly important physiologically relevant model systems that require primary cells, organoids, whole organisms, or expensive or rare reagents. We hypothesized that data from a single high-throughput imaging assay can be repurposed to predict the biological activity of compounds in other assays, even those targeting alternate pathways or biological processes. Indeed, quantitative information extracted from a three-channel microscopy-based screen for glucocorticoid receptor translocation was able to predict assay-specific biological activity in two ongoing drug discovery projects. In these projects, repurposing increased hit rates by 50- to 250-fold over that of the initial project assays while increasing the chemical structure diversity of the hits. Our results suggest that data from high-content screens are a rich source of information that can be used to predict and replace customized biological assays. Copyright © 2018 Elsevier Ltd. All rights reserved.

Liposomal Drug Product Development and Quality: Current US Experience and Perspective.

PubMed

Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M

2017-05-01

Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.

The model of drugs distribution dynamics in biological tissue

NASA Astrophysics Data System (ADS)

Ginevskij, D. A.; Izhevskij, P. V.; Sheino, I. N.

2017-09-01

The dose distribution by Neutron Capture Therapy follows the distribution of 10B in the tissue. The modern models of pharmacokinetics of drugs describe the processes occurring in conditioned "chambers" (blood-organ-tumor), but fail to describe the spatial distribution of the drug in the tumor and in normal tissue. The mathematical model of the spatial distribution dynamics of drugs in the tissue, depending on the concentration of the drug in the blood, was developed. The modeling method is the representation of the biological structure in the form of a randomly inhomogeneous medium in which the 10B distribution occurs. The parameters of the model, which cannot be determined rigorously in the experiment, are taken as the quantities subject to the laws of the unconnected random processes. The estimates of 10B distribution preparations in the tumor and healthy tissue, inside/outside the cells, are obtained.

9 CFR 103.1 - Preparation of experimental biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Preparation of experimental biological products. 103.1 Section 103.1 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... PRODUCTION, DISTRIBUTION, AND EVALUATION OF BIOLOGICAL PRODUCTS PRIOR TO LICENSING § 103.1 Preparation of...

The production and sales of anti-tuberculosis drugs in China.

PubMed

Huang, Yang-Mu; Zhao, Qi-Peng; Ren, Qiao-Meng; Peng, Dan-Lu; Guo, Yan

2016-10-04

Tuberculosis (TB) is a major infectious disease globally. Adequate and proper use of anti-TB drugs is essential for TB control. This study aims to study China's production capacity and sales situation of anti-TB drugs, and to further discuss the potential for China to contribute to global TB control. The production data of anti-TB drugs in China from 2011 to 2013 and the sales data from 2010 to 2014 were extracted from Ministry of Industry and Information Technology database of China and IMS Health database, respectively. The number of drugs was standardized to the molecular level of the key components before calculating. All data were described and analyzed by Microsoft Excel. First-line drugs were the majority in both sales (89.5 %) and production (92.3 %) of anti-TB drugs in China. The production of rifampicin held the majority share in active pharmaceutical ingredients (APIs) and finished products, whilst ethambutol and pyrazinamide were the top two sales in finished products. Fixed-dose combinations only held small percentages in total production and sales weight, though a slight increase was observed. The production and sales of streptomycin showed a tendency of decrease after 2012. The trends and proportion of different anti-TB drugs were similar in production and sales, however, the production weight was much larger than that of sales, especially for rifampicin and isoniazid. First-line drugs were the predominant medicine produced and used in China. While the low production and sales of the second-line TB drugs and FDCs rose concerns for the treatment of multiple drug resistant TB. The redundant production amount, as well as the prompt influence of national policy on drug production and sales, indicated the potential for China to better contribute to global TB control.

Protein Complex Production from the Drug Discovery Standpoint.

PubMed

Moarefi, Ismail

2016-01-01

Small molecule drug discovery critically depends on the availability of meaningful in vitro assays to guide medicinal chemistry programs that are aimed at optimizing drug potency and selectivity. As it becomes increasingly evident, most disease relevant drug targets do not act as a single protein. In the body, they are instead generally found in complex with protein cofactors that are highly relevant for their correct function and regulation. This review highlights selected examples of the increasing trend to use biologically relevant protein complexes for rational drug discovery to reduce costly late phase attritions due to lack of efficacy or toxicity.

Anti-infectious drug repurposing using an integrated chemical genomics and structural systems biology approach.

PubMed

Ng, Clara; Hauptman, Ruth; Zhang, Yinliang; Bourne, Philip E; Xie, Lei

2014-01-01

The emergence of multi-drug and extensive drug resistance of microbes to antibiotics poses a great threat to human health. Although drug repurposing is a promising solution for accelerating the drug development process, its application to anti-infectious drug discovery is limited by the scope of existing phenotype-, ligand-, or target-based methods. In this paper we introduce a new computational strategy to determine the genome-wide molecular targets of bioactive compounds in both human and bacterial genomes. Our method is based on the use of a novel algorithm, ligand Enrichment of Network Topological Similarity (ligENTS), to map the chemical universe to its global pharmacological space. ligENTS outperforms the state-of-the-art algorithms in identifying novel drug-target relationships. Furthermore, we integrate ligENTS with our structural systems biology platform to identify drug repurposing opportunities via target similarity profiling. Using this integrated strategy, we have identified novel P. falciparum targets of drug-like active compounds from the Malaria Box, and suggest that a number of approved drugs may be active against malaria. This study demonstrates the potential of an integrative chemical genomics and structural systems biology approach to drug repurposing.

Dissolution Failure of Solid Oral Drug Products in Field Alert Reports.

PubMed

Sun, Dajun; Hu, Meng; Browning, Mark; Friedman, Rick L; Jiang, Wenlei; Zhao, Liang; Wen, Hong

2017-05-01

From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products. Interestingly, the generic drug products fail dissolution tests at an earlier time point during a stability study than the brand name drug products. Whether the dissolution failure of these solid oral drug products has any in vivo implication will require further pharmacokinetic, pharmacodynamic, clinical, and drug safety evaluation. Food and Drug Administration is currently conducting risk-based assessment using in-house dissolution testing, physiologically based pharmacokinetic modeling and simulation, and post-market surveillance tools. At the meantime, this interim report will outline a general scheme of monitoring dissolution failures of solid oral dosage forms as a pharmaceutical quality indicator. Published by Elsevier Inc.

42 CFR 405.517 - Payment for drugs and biologicals that are not paid on a cost or prospective payment basis.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Payment for drugs and biologicals that are not paid... biologicals that are not paid on a cost or prospective payment basis. (a) Applicability—(1) Payment for drugs and biologicals before January 1, 2004. Payment for a drug or biological that is not paid on a cost or...

42 CFR 405.517 - Payment for drugs and biologicals that are not paid on a cost or prospective payment basis.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Payment for drugs and biologicals that are not paid... biologicals that are not paid on a cost or prospective payment basis. (a) Applicability—(1) Payment for drugs and biologicals before January 1, 2004. Payment for a drug or biological that is not paid on a cost or...

76 FR 13629 - Revised Draft Guidance for Industry on User Fee Waivers, Reductions, and Refunds for Drug and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-14

...] Revised Draft Guidance for Industry on User Fee Waivers, Reductions, and Refunds for Drug and Biological... entitled ``User Fee Waivers, Reductions, and Refunds for Drug and Biological Products.'' This revised draft... industry entitled ``User Fee Waivers, Reductions, and Refunds for Drug and Biological Products.'' This...

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development.

PubMed

Tomar, Dheeraj S; Kumar, Sandeep; Singh, Satish K; Goswami, Sumit; Li, Li

2016-01-01

Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored.

Antibacterial cleaning products and drug resistance.

PubMed

Aiello, Allison E; Marshall, Bonnie; Levy, Stuart B; Della-Latta, Phyllis; Lin, Susan X; Larson, Elaine

2005-10-01

We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug-resistant bacteria on hands of household members. Households (N = 224) were randomized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in homes. Antibacterial product use did not lead to a significant increase in antimicrobial drug resistance after 1 year (odds ratio 1.33, 95% confidence interval 0.74-2.41), nor did it have an effect on bacterial susceptibility to triclosan. However, more extensive and longer term use of triclosan might provide a suitable environment for emergence of resistant species. Further research on this issue is needed.

21 CFR 333.150 - Labeling of first aid antibiotic drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Labeling of first aid antibiotic drug products... First Aid Antibiotic Drug Products § 333.150 Labeling of first aid antibiotic drug products. (a... identifies the product as a “first aid antibiotic.” (b) Indications. The labeling of the product states...

Natural Products: Key Prototypes to Drug Discovery Against Neglected Diseases Caused by Trypanosomatids.

PubMed

Varela, Marina Themoteo; Fernandes, Joao Paulo S

2018-04-30

Neglected tropical diseases are a group of infections caused by microorganisms and viruses that affect mainly poor regions of the world. In addition, most available drugs are associated with long periods of treatment and high toxicity which limits the application and patient compliance. Investment in research and development is not seen as an attractive deal by the pharmaceutical industry since the final product must ideally be cheap, not returning the amount invested. Natural products have always played an important source for bioactive compounds and are advantageous over synthetic compounds when considering the unique structural variety and biological activities. On the other hand, isolation difficulties and low yields, environmental impact and high cost usually limit their application as drug per se. In this review, the use of natural products as prototypes for the semi-synthesis or total synthesis, as well as natural products as promising hits are covered, specifically regarding compounds with activities against trypanosomatids such as Trypanosoma spp. and Leishmania spp. Selected reports from literature with this approach were retrieved. As summary, it can be concluded that natural products are an underestimated source for designing novel agents against these parasites. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

21 CFR 601.20 - Biologics licenses; issuance and conditions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Biologics licenses; issuance and conditions. 601.20 Section 601.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... examination of the product and upon a determination that the product complies with the standards established...

21 CFR 601.20 - Biologics licenses; issuance and conditions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Biologics licenses; issuance and conditions. 601.20 Section 601.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... only upon examination of the product and upon a determination that the product complies with the...

Assessing the drug-likeness of lamellarins, a marine-derived natural product class with diverse oncological activities.

PubMed

Chittchang, Montakarn; Gleeson, M Paul; Ploypradith, Poonsakdi; Ruchirawat, Somsak

2010-06-01

Natural products currently represent an underutilized source of leads for the pharmaceutical industry, especially when one considers that almost 50% of all drugs were either derived from such sources or are very closely related. Lamellarins are a class of natural products with diverse biological activities and have entered into preclinical development for the treatment of multidrug-resistant tumors. Although these compounds demonstrated good cell penetration, as observed by their low microM activity in whole cell models, they have not been extensively profiled from a physicochemical point of view, and this is the goal of this study. For this study, we have determined the experimental logP values of a set of 25 lamellarins, given it is the single most important parameter in determining multiple ADMET parameters. We also discuss the relationship between this natural product class, natural product derivatives in development and on the market, oral marketed drugs, as well as drug molecules in development, using a range of physicochemical parameters in conjunction with principal components analysis (PCA). The impact of this systematic analysis on our ongoing medicinal chemistry strategy is also discussed. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

21 CFR 314.108 - New drug product exclusivity.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false New drug product exclusivity. 314.108 Section 314.108 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and...

21 CFR 314.108 - New drug product exclusivity.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false New drug product exclusivity. 314.108 Section 314.108 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and...

21 CFR 314.108 - New drug product exclusivity.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false New drug product exclusivity. 314.108 Section 314.108 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and...

21 CFR 314.108 - New drug product exclusivity.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false New drug product exclusivity. 314.108 Section 314.108 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications and...

[Building confidence in biological products].

PubMed

Rosdahl, Nils; Hardy, Anne

2006-01-01

During the last decades of the 19th century, discoveries in microbiology paved the way for health programmes as an integral part of social modernisation. Public opinion about the consequences for governmental involvement differed, but in Denmark the state's openness to modern medicine encouraged the establishment of Statens Serum Institut (SSI) in 1902, initially for the production of anti-diphtheritic serum. Under its director, Thorvald Madsen (1870-1957), the SSI soon acquired a reputation for the high quality of its products and its cutting edge research. After qualifying in medicine in 1893, Madsen worked both at the Pasteur Institute and with Paul Ehrlich in Frankfurt. During World War I, he served with the Red Cross, caring for German, Austrian and Russian prisoners of war. He had an extensive and expanding network of international contacts, and he was eminently qualified to assume the elected office of President of the League of Nations' Health Committee. The Committee served as the 'parliamentary body' of the League of Nations Health Organisation (LNHO), and Madsen's hand can be seen in much of the work undertaken by the LNHO. The drive to achieve uniform standards for biological products related directly to his own as well as the SSI's interests and expertise. Undoubtedly, standardization of biological products had an immense importance for their distribution, scientifically, commercially and therapeutically. Madsen was president of the LNHO's Commission on Biological Standardisation from 1924, and during the interwar years, the SSI was heavily involved in establishing standards for biological products such as tuberculin and tetanus antitoxin. Madsen's interests extended to application of prevention technologies, and he utilised the opportunities in Denmark to further their use, notably in the case of tuberculosis. The introduction of the BCG vaccine promised a solution to the TB problem, but the Lübeck disaster generated a widespread reaction against the

Synthesis and Biological Response of Size-Specific, Monodisperse Drug-Silica Nanoconjugates

PubMed Central

Tang, Li; Fan, Timothy M.; Borst, Luke B.; Cheng, Jianjun

2012-01-01

Drug-containing nanoparticles (NPs) with monodisperse, controlled particle sizes are highly desirable for drug delivery. Accumulating evidence suggests that NPs with sizes less than 50 nm demonstrate superior performance in vitro and in vivo. However, it is difficult to fabricate monodisperse, drug-containing NPs with discrete and incremental difference in sizes required for studying and characterizing existing relationships among particle size, biologic processing, and therapeutic functionality. Here, we report a scalable process of fabricating drug-silica conjugated nanoparticles, termed drug-silica nanoconjugates (drug-NCs), which possess monodisperse size distributions and desirable particle sizes as small as 20 nm. We found that 20-nm NCs are superior to their 50-nm and 200-nm NC analogues by 2–5 and 10–20 folds, respectively, with regard to tumor accumulation and penetration, and cellular internalization. These fundamental findings underscore the importance and necessity of further miniaturizing nanomedicine size for optimized drug delivery applications. PMID:22494403

Chemistry and Biology of the Caged Garcinia Xanthones

PubMed Central

Chantarasriwong, Oraphin; Batova, Ayse; Chavasiri, Warinthorn

2011-01-01

Natural products have been a great source of many small molecule drugs for various diseases. In spite of recent advances in biochemical engineering and fermentation technologies that allow us to explore microorganisms and the marine environment as alternative sources of drugs, more than 70% of the current small molecule therapeutics derive their structures from plants used in traditional medicine. Natural-product-based drug discovery relies heavily on advances made in the sciences of biology and chemistry. Whereas biology aims to investigate the mode of action of a natural product, chemistry aims to overcome challenges related to its supply, bioactivity, and target selectivity. This review summarizes the explorations of the caged Garcinia xanthones, a family of plant metabolites that possess a unique chemical structure, potent bioactivities, and a promising pharmacology for drug design and development. PMID:20648491

Cheminformatic comparison of approved drugs from natural product versus synthetic origins.

PubMed

Stratton, Christopher F; Newman, David J; Tan, Derek S

2015-11-01

Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus completely synthetic origins that were approved between 1981 and 2010. Drugs based on natural product structures display greater chemical diversity and occupy larger regions of chemical space than drugs from completely synthetic origins. Notably, synthetic drugs based on natural product pharmacophores also exhibit lower hydrophobicity and greater stereochemical content than drugs from completely synthetic origins. These results illustrate that structural features found in natural products can be successfully incorporated into synthetic drugs, thereby increasing the chemical diversity available for small-molecule drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges.

PubMed

Ha, Dinh; Yang, Ningning; Nadithe, Venkatareddy

2016-07-01

Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body׳s own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed.

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

PubMed Central

Tomar, Dheeraj S.; Kumar, Sandeep; Singh, Satish K.; Goswami, Sumit; Li, Li

2016-01-01

ABSTRACT Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored. PMID:26736022

Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

PubMed

Stegemann, Sven

2018-06-01

The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

21 CFR 338.50 - Labeling of nighttime sleep-aid drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Labeling of nighttime sleep-aid drug products. 338... SERVICES (CONTINUED) DRUGS FOR HUMAN USE NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Labeling § 338.50 Labeling of nighttime sleep-aid drug products. (a) Statement of identity. The labeling of...

21 CFR 338.50 - Labeling of nighttime sleep-aid drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Labeling of nighttime sleep-aid drug products. 338... SERVICES (CONTINUED) DRUGS FOR HUMAN USE NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Labeling § 338.50 Labeling of nighttime sleep-aid drug products. (a) Statement of identity. The labeling of...

21 CFR 338.50 - Labeling of nighttime sleep-aid drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Labeling of nighttime sleep-aid drug products. 338... SERVICES (CONTINUED) DRUGS FOR HUMAN USE NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Labeling § 338.50 Labeling of nighttime sleep-aid drug products. (a) Statement of identity. The labeling of...

21 CFR 338.50 - Labeling of nighttime sleep-aid drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Labeling of nighttime sleep-aid drug products. 338... SERVICES (CONTINUED) DRUGS FOR HUMAN USE NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Labeling § 338.50 Labeling of nighttime sleep-aid drug products. (a) Statement of identity. The labeling of...

Differential Drug Survival of Second-Line Biologic Therapies in Patients with Psoriasis: Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

PubMed

Iskandar, Ireny Y K; Warren, Richard B; Lunt, Mark; Mason, Kayleigh J; Evans, Ian; McElhone, Kathleen; Smith, Catherine H; Reynolds, Nick J; Ashcroft, Darren M; Griffiths, Christopher E M

2018-04-01

Little is known about the drug survival of second-line biologic therapies for psoriasis in routine clinical practice. We assessed drug survival of second-line biologic therapies and estimated the risk of recurrent discontinuation due to adverse events or ineffectiveness in patients with psoriasis who had failed a first biologic therapy and switched to a second in a large, multicenter pharmacovigilance registry (n = 1,239; adalimumab, n = 538; etanercept, n = 104; ustekinumab, n = 597). The overall drug survival rate in the first year after switching was 77% (95% confidence interval = 74-79%), falling to 58% (55-61%) in the third year. Female sex, multiple comorbidities, concomitant therapy with cyclosporine, and a high Psoriasis Area and Severity Index at switching to the second-line biologic therapy were predictors of overall discontinuation (multivariable Cox proportional hazard model). Compared to adalimumab, patients receiving etanercept were more likely to discontinue therapy (hazard ratio = 1.87, 95% confidence interval = 1.24-2.83), whereas patients receiving ustekinumab were more likely to persist (hazard ratio = 0.46; 95% confidence interval = 0.33-0.64). Discontinuation of the first biologic therapy because of adverse events was associated with an increased rate of second drug discontinuation because of adverse events (hazard ratio = 2.55; 95% confidence interval = 1.50-4.32). In conclusion, drug survival rates differed among biologic therapies and decreased over time; second-line discontinuation because of adverse events was more common among those who discontinued first-line treatment for this reason. The results of this study should support clinical decision making when choosing second-line biologic therapy for patients with psoriasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

American Heart Association Principles on the Accessibility and Affordability of Drugs and Biologics: A Presidential Advisory From the American Heart Association.

PubMed

Antman, Elliott M; Creager, Mark A; Houser, Steven R; Warner, John J; Konig, Madeleine

2017-12-12

Net US spending on pharmaceuticals reached $309.5 billion in 2015, an 8.5% increase from the year before, and is expected to reach between $370 and $400 billion by 2020. These current and projected levels have raised serious concerns by policy makers, providers, payers, and patient groups that they are unsustainable and threaten the affordability of and accessibility to much-needed therapies for patients. Two trends related to drugs/biologics and generic drugs/biosimilars underlie this overall increase in spending. First, the market entry prices of innovator pharmaceutical products, or brand drugs and biologics, are at levels that some assessments consider unaffordable to the healthcare system. Second, prices for some established generic drugs such as digoxin and captopril have seen sharp and rapid increases. As an evidence-based patient advocacy organization dedicated to improving the cardiovascular health of all Americans, the American Heart Association has a unique role in advocating for treatments, including medicines that are available, affordable, and accessible to patients. This advisory serves to lay out a set of principles that will guide association engagement in pursuit of this goal. © 2017 American Heart Association, Inc.

76 FR 59705 - Guidance for Industry on User Fee Waivers, Reductions, and Refunds for Drug and Biological...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-27

... Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New..., and Development (HFM-40), Center for Biologics Evaluation and Research, Food and Drug Administration..., Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51...

Synthetic biology advances for pharmaceutical production

PubMed Central

Breitling, Rainer; Takano, Eriko

2015-01-01

Synthetic biology enables a new generation of microbial engineering for the biotechnological production of pharmaceuticals and other high-value chemicals. This review presents an overview of recent advances in the field, describing new computational and experimental tools for the discovery, optimization and production of bioactive molecules, and outlining progress towards the application of these tools to pharmaceutical production systems. PMID:25744872

Natural Product-Derived Drugs for the Treatment of Inflammatory Bowel Diseases

PubMed Central

2014-01-01

Natural products have been used as drugs for millennia, and the therapeutic potential of natural products has been studied for more than a century. Since the mid-1880s, approximately 60% of drugs have originated from natural products. Recently, the importance of using natural products has increased, as has interest in discovering efficient new drugs. Natural drugs are desirable for the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. This review discusses the discovery and development of drugs derived from natural products for the treatment of inflammatory bowel diseases. PMID:25349576

9 CFR 112.9 - Biological products imported for research and evaluation.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Biological products imported for research and evaluation. 112.9 Section 112.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... PACKAGING AND LABELING § 112.9 Biological products imported for research and evaluation. A biological...

9 CFR 112.9 - Biological products imported for research and evaluation.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Biological products imported for research and evaluation. 112.9 Section 112.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... PACKAGING AND LABELING § 112.9 Biological products imported for research and evaluation. A biological...

9 CFR 112.9 - Biological products imported for research and evaluation.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Biological products imported for research and evaluation. 112.9 Section 112.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... PACKAGING AND LABELING § 112.9 Biological products imported for research and evaluation. A biological...

9 CFR 112.9 - Biological products imported for research and evaluation.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Biological products imported for research and evaluation. 112.9 Section 112.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... PACKAGING AND LABELING § 112.9 Biological products imported for research and evaluation. A biological...

9 CFR 112.9 - Biological products imported for research and evaluation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Biological products imported for research and evaluation. 112.9 Section 112.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... PACKAGING AND LABELING § 112.9 Biological products imported for research and evaluation. A biological...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

Synthetic Biology and Personalized Medicine

PubMed Central

Jain, K.K.

2013-01-01

Synthetic biology, application of synthetic chemistry to biology, is a broad term that covers the engineering of biological systems with structures and functions not found in nature to process information, manipulate chemicals, produce energy, maintain cell environment and enhance human health. Synthetic biology devices contribute not only to improve our understanding of disease mechanisms, but also provide novel diagnostic tools. Methods based on synthetic biology enable the design of novel strategies for the treatment of cancer, immune diseases metabolic disorders and infectious diseases as well as the production of cheap drugs. The potential of synthetic genome, using an expanded genetic code that is designed for specific drug synthesis as well as delivery and activation of the drug in vivo by a pathological signal, was already pointed out during a lecture delivered at Kuwait University in 2005. Of two approaches to synthetic biology, top-down and bottom-up, the latter is more relevant to the development of personalized medicines as it provides more flexibility in constructing a partially synthetic cell from basic building blocks for a desired task. PMID:22907209

Natural products as a foundation for drug discovery.

PubMed

Beutler, John A

2009-09-01

Natural products have provided chemical leads for the development of many drugs for diverse indications. While most U.S. pharmaceutical firms have reduced or eliminated their in-house natural product groups, there is a renewed interest in this source of new chemical entities. Many of the reasons for the past decline in popularity of natural products are being addressed by the development of new techniques for screening and production. The aim of this unit is to review current strategies and techniques that increase the value of natural products as a source for novel drug candidates.

Charting, navigating, and populating natural product chemical space for drug discovery.

PubMed

Lachance, Hugo; Wetzel, Stefan; Kumar, Kamal; Waldmann, Herbert

2012-07-12

Natural products are a heterogeneous group of compounds with diverse, yet particular molecular properties compared to synthetic compounds and drugs. All relevant analyses show that natural products indeed occupy parts of chemical space not explored by available screening collections while at the same time largely adhering to the rule-of-five. This renders them a valuable, unique, and necessary component of screening libraries used in drug discovery. With ChemGPS-NP on the Web and Scaffold Hunter two tools are available to the scientific community to guide exploration of biologically relevant NP chemical space in a focused and targeted fashion with a view to guide novel synthesis approaches. Several of the examples given illustrate the possibility of bridging the gap between computational methods and compound library synthesis and the possibility of integrating cheminformatics and chemical space analyses with synthetic chemistry and biochemistry to successfully explore chemical space for the identification of novel small molecule modulators of protein function.The examples also illustrate the synergistic potential of the chemical space concept and modern chemical synthesis for biomedical research and drug discovery. Chemical space analysis can map under explored biologically relevant parts of chemical space and identify the structure types occupying these parts. Modern synthetic methodology can then be applied to efficiently fill this “virtual space” with real compounds.From a cheminformatics perspective, there is a clear demand for open-source and easy to use tools that can be readily applied by educated nonspecialist chemists and biologists in their daily research. This will include further development of Scaffold Hunter, ChemGPS-NP, and related approaches on the Web. Such a “cheminformatics toolbox” would enable chemists and biologists to mine their own data in an intuitive and highly interactive process and without the need for specialized computer

Effects of radio frequency identification-related radiation on in vitro biologics.

PubMed

Uysal, Ismail; Hohberger, Clive; Rasmussen, R Scott; Ulrich, David A; Emond, Jean-Pierre; Gutierrez, Alfonso

2012-01-01

The recent developments on the use of e-pedigree to identify the chain of custody of drugs suggests the use of advanced track and trace technologies such as two-dimensional barcodes and radio frequency identification (RFID) tags. RFID technology is used mainly for valuable commodities such as pharmaceutical products while incorporating additional functionalities like monitoring environmental variables to ensure product safety and quality. In its guidance for the use of RFID technologies for drugs (Compliance Policy Guide Section 400.210), the Food and Drug Administration outlined multiple parameters that would apply to any study or application using RFID. However, drugs approved under a Biologics License Application or protein drugs covered by a New Drug Application were excluded mainly due to concerns about the effects of radio frequency radiation (thermal and/or non-thermal) on biologics. Even though the thermal effects of radio frequency on biologics are relatively well understood, there are few studies in the literature about the non-thermal effects of radio frequency with regards to the protein structure integrity. In this paper, we analyze the non-thermal effects of radio frequency radiation by exposing a wide variety of biologics including biopharmaceuticals with vaccines, hormones, and immunoglobulins, as well as cellular blood products such as red blood cells and whole blood-derived platelets as well as fresh frozen plasma. In order to represent the majority of the frequency spectrum used in RFID applications, five different frequencies (13.56 MHz, 433 MHz, 868 MHz, 915 MHz, and 2.4 GHz) are used to account for the most commonly used international frequency bands for RFID. With the help of specialized radio frequency signal-generating hardware, magnetic and electromagnetic fields are created around the exposed products with power levels greater than Federal Communications Commission-regulated limits. The in vitro test results on more than 100

Natural Products as a Foundation for Drug Discovery

PubMed Central

Beutler, John A.

2009-01-01

Natural products have contributed to the development of many drugs for diverse indications. While most U.S. pharmaceutical companies have reduced or eliminated their in-house natural product groups, new paradigms and new enterprises have evolved to carry on a role for natural products in the pharmaceutical industry. Many of the reasons for the decline in popularity of natural products are being addressed by the development of new techniques for screening and production. This overview aims to inform pharmacologists of current strategies and techniques that make natural products a viable strategic choice for inclusion in drug discovery programs. PMID:20161632

Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products.

PubMed

Zou, Peng; Tyner, Katherine; Raw, Andre; Lee, Sau

2017-09-01

Iron carbohydrate colloid drug products are intravenously administered to patients with chronic kidney disease for the treatment of iron deficiency anemia. Physicochemical characterization of iron colloids is critical to establish pharmaceutical equivalence between an innovator iron colloid product and generic version. The purpose of this review is to summarize literature-reported techniques for physicochemical characterization of iron carbohydrate colloid drug products. The mechanisms, reported testing results, and common technical pitfalls for individual characterization test are discussed. A better understanding of the physicochemical characterization techniques will facilitate generic iron carbohydrate colloid product development, accelerate products to market, and ensure iron carbohydrate colloid product quality.

Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study

PubMed Central

Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

2016-01-01

Background Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Objective Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Methods Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. Results One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). Conclusions The results suggest that nonexpert annotation might be a feasible option for comprehensive

Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study.

PubMed

Hochheiser, Harry; Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

2016-04-11

Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). The results suggest that nonexpert annotation might be a feasible option for comprehensive labeling of annotated PDDIs across a broader

9 CFR 112.6 - Packaging biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Packaging biological products. 112.6 Section 112.6 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... if seal is broken.” (d) Diluent for the following products need not be packaged with the final...

9 CFR 112.6 - Packaging biological products.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Packaging biological products. 112.6 Section 112.6 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF... if seal is broken.” (d) Diluent for the following products need not be packaged with the final...

78 FR 23273 - Determination That the OXYCONTIN (Oxycodone Hydrochloride) Drug Products Covered by New Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-18

... Hydrochloride) Drug Products Covered by New Drug Application 20-553 Were Withdrawn From Sale for Reasons of... was often abused by manipulating the product to defeat its extended-release mechanism, causing the... example, by crushing the product to sprinkle it onto food or to administer it through a gastric tube. As...

Platform for Rapid Delivery of Biologics and Drugs to Ocular Cells and Tissues Following Combat Associated Trauma

DTIC Science & Technology

2013-09-01

death pathways such as apoptosis subsequent to acute trauma as soon as possible, ideally by self- administration of a drug or a biologic that can be... Drugs to Ocular Tissues Including Retina and Cornea . Mol Ther, 2007;16(1):107- 14. 3. Read SP, Cashman SM, and Kumar-Singh R: POD...1 AD_________________ Award Number: W81XWH-12-1-0374 TITLE: Platform for Rapid Delivery of Biologics and Drugs to Ocular Cells

Molecular approaches towards development of purified natural products and their structurally known derivatives as efficient anti-cancer drugs: current trends.

PubMed

Saha, Santu Kumar; Khuda-Bukhsh, Anisur Rahman

2013-08-15

Several natural products and their derivatives, either in purified or structurally identified form, exhibit immense pharmacological and biological properties, some of them showing considerable anticancer potential. Although the molecular mechanisms of action of some of these products are yet to be elucidated, extensive research in this area continues to generate new data that are clinically exploitable. Recent advancement in molecular biology, high throughput screening, biomarker identifications, target selection and genomic approaches have enabled us to understand salient interactions of natural products and their derivatives with cancer cells vis-à-vis normal cells. In this review we highlight the recent approaches and application of innovative technologies made to improve quality as well as efficiency of structurally identified natural products and their derivatives, particularly in small molecular forms capable of being used in "targeted therapies" in oncology. These products preferentially involve multiple mechanistic pathways and overcome chemo-resistance in tumor types with cumulative action. We also mention briefly a few physico-chemical features that compare natural products with drugs in recent natural product discovery approaches. We further report here a few purified natural products as examples that provide molecular interventions in cancer therapeutics to give the reader a glimpse of the current trends of approach for discovering useful anticancer drugs. © 2013 Elsevier B.V. All rights reserved.

"New drug" designations for new therapeutic entities: new active substance, new chemical entity, new biological entity, new molecular entity.

PubMed

Branch, Sarah K; Agranat, Israel

2014-11-13

This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations. Chemical, biological, and innovative drugs are addressed in turn. The terms new chemical entity (NCE), new molecular entity (NME), new active substance (NAS), and new biological entity (NBE) as applied in worldwide jurisdictions are clarified. Differences between them are explored through case studies showing why new drugs have different periods of exclusivity in different jurisdictions or none at all. Finally, this Perspective recommends that in future, for the purpose of new drug compilations, NME is used for a new chemical drug, NBE for a new biological drug, and the combined designation NTE should refer to either an NME or an NBE.

Drug tendering: drug supply and shortage implications for the uptake of biosimilars

PubMed Central

Dranitsaris, George; Jacobs, Ira; Kirchhoff, Carol; Popovian, Robert; Shane, Lesley G

2017-01-01

Due to the continued increase in global spending on health care, payers have introduced a number of programs, policies, and agreements on pharmaceutical pricing in order to control costs. While incentives to increase generic drug use have achieved significant savings, other cost-containment measures are required. Tendering is a formal procedure to purchase medications using competitive bidding for a particular contract. Although useful for cost containment, tendering can lead to decreased competition in a given market. Consequently, drug shortages can occur, resulting in changes to treatment plans to products that may have lower efficacy and/or an increased risk of adverse effects. Therefore, care must be taken to ensure that tendering does not negatively impact patient care or the health care system. A large and expanding portion of total pharmaceutical expenditure is for biologic therapies. These agents have revolutionized the treatment of many diseases, including cancer and inflammatory conditions; however, patient access to biologic drugs can be limited due to availability, insurance coverage, and cost. As branded biologic therapies reach the end of patent- and data-protection periods, biosimilars are being approved as lower-cost alternatives. Biosimilars are products that are highly similar to the originator product with no clinically meaningful differences in terms of safety, purity, or potency. As more biosimilars receive regulatory approval and adoption increases, these therapies are expected to have an impact on global health care spending and should result in overall savings. However, the use of tendering to maximize the potential benefits of biosimilars has varied across the world. Therefore, the objectives of this review are to examine the drug-tendering process and its implications on drug supply and drug shortages, as well as to describe biosimilars and how tendering may influence their uptake. PMID:29033595

A primer of drug safety surveillance: an industry perspective. Part II: Product labeling and product knowledge.

PubMed

Allan, M C

1992-01-01

To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part II of this series discusses specific issues regarding product labeling, such as developing the labeling, changing the labeling, and the legal as well as commercial ramifications of the contents of the labeling. An adverse event report scenario is further analyzed and suggestions are offered for maintaining the product labeling as an accurate reflection of the drug safety surveillance data. This article also emphasizes the necessity of product knowledge in adverse event database management. Both scientific and proprietary knowledge are required. Acquiring product knowledge is a part of the day-to-day activities of drug safety surveillance. A knowledge of the history of the product may forestall adverse publicity, as shown in the illustration. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered

Participation of Women and Sex Analyses in Late-Phase Clinical Trials of New Molecular Entity Drugs and Biologics Approved by the FDA in 2007–2009

PubMed Central

Poon, Rita; Khanijow, Keshav; Umarjee, Sphoorti; Yu, Monica; Zhang, Lei; Parekh, Ameeta

2013-01-01

Abstract Background Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007–2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. Methods New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. Results Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. Conclusion Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007–2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998–2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics

[Biologics - nomenclature and classification].

PubMed

Eichbaum, Christine; Haefeli, Walter E

2011-11-01

Biological medicines are a heterogeneous group of drugs that are produced by living organisms using genetic or biological technology. Unlike chemically derived small molecules biologics are structurally complex making characterization and manufacturing difficult. Moreover, biological medicines show a great variety concerning their clinical use. To appropriately consider these particularities, there are other standards and guidelines for approval of similar derivatives of biologics, the so-called biosimilars or follow-on biologics. In contrast to a generic medicinal product containing a chemically identical active ingredient, a biosimilar is only expected to be similar to the innovator drug. Nowadays, monoclonal antibodies, fragments of antibodies, and fusion proteins manufactured by recombinant procedures play an important role. They have been used in many specialties for diagnostic and therapeutic purposes and are subject to continuous further development and improvement. Their nomenclature is based on a classification by the WHO which allows drawing conclusions for class of substance, origin, and pharmacological target.

21 CFR 357.850 - Labeling of deodorant drug products for internal use.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Labeling of deodorant drug products for internal... HUMAN USE Deodorant Drug Products for Internal Use § 357.850 Labeling of deodorant drug products for... drug, if any, and identifies the product as a “deodorant for internal use” or as a “colostomy or...

21 CFR 357.850 - Labeling of deodorant drug products for internal use.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Labeling of deodorant drug products for internal... HUMAN USE Deodorant Drug Products for Internal Use § 357.850 Labeling of deodorant drug products for... drug, if any, and identifies the product as a “deodorant for internal use” or as a “colostomy or...

21 CFR 357.850 - Labeling of deodorant drug products for internal use.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Labeling of deodorant drug products for internal... HUMAN USE Deodorant Drug Products for Internal Use § 357.850 Labeling of deodorant drug products for... drug, if any, and identifies the product as a “deodorant for internal use” or as a “colostomy or...

21 CFR 357.850 - Labeling of deodorant drug products for internal use.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Labeling of deodorant drug products for internal... HUMAN USE Deodorant Drug Products for Internal Use § 357.850 Labeling of deodorant drug products for... drug, if any, and identifies the product as a “deodorant for internal use” or as a “colostomy or...

21 CFR 357.850 - Labeling of deodorant drug products for internal use.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Labeling of deodorant drug products for internal... HUMAN USE Deodorant Drug Products for Internal Use § 357.850 Labeling of deodorant drug products for... drug, if any, and identifies the product as a “deodorant for internal use” or as a “colostomy or...

The evolving landscape of drug products containing nanomaterials in the United States

NASA Astrophysics Data System (ADS)

D'Mello, Sheetal R.; Cruz, Celia N.; Chen, Mei-Ling; Kapoor, Mamta; Lee, Sau L.; Tyner, Katherine M.

2017-07-01

The Center for Drug Evaluation and Research (CDER) within the US Food and Drug Administration (FDA) is tracking the use of nanotechnology in drug products by building and interrogating a technical profile of products containing nanomaterials submitted to CDER. In this Analysis, data from more than 350 products show an increase in the submissions of drug products containing nanomaterials over the last two decades. Of these, 65% are investigational new drugs, 17% are new drug applications and 18% are abbreviated new drug applications, with the largest class of products being liposomal formulations intended for cancer treatments. Approximately 80% of products have average particle sizes of 300 nm or lower. This analysis identifies several trends in the development of drug products containing nanomaterials, including the relative rate of approvals of these products, and provides a comprehensive overview on the landscape of nanotechnology application in medicine.

Random laser in biological tissues impregnated with a fluorescent anticancer drug

NASA Astrophysics Data System (ADS)

Lahoz, F.; Martín, I. R.; Urgellés, M.; Marrero-Alonso, J.; Marín, R.; Saavedra, C. J.; Boto, A.; Díaz, M.

2015-04-01

We have demonstrated that chemically modified anticancer drugs can provide random laser (RL) when infiltrated in a biological tissue. A fluorescent biomarker has been covalently bound to tamoxifen, which is one of the most frequently used drugs for breast cancer therapy. The light emitted by the drug-dye composite is scattered in tissue, which acts as a gain medium. Both non-coherent and coherent RL regimes have been observed. Moreover, the analysis of power Fourier transforms of coherent RL spectra indicates that the tissues show a dominant random laser cavity length of about 18 µm, similar to the average size of single cells. These results show that RL could be obtained from other drugs, if properly marked with a fluorescent tag, which could be appealing for new forms of combined opto-chemical therapies.

Examination of the Regulatory Frameworks Applicable to Biologic Drugs (Including Stem Cells and Their Progeny) in Europe, the U.S., and Australia: Part I—A Method of Manual Documentary Analysis

PubMed Central

Savic, Snezana; Siegel, Evan; Atkinson, Kerry; Tasic, Ljiljana

2012-01-01

Recent development of a wide range of regulatory standards applicable to production and use of tissues, cells, and other biologics (or biologicals), as advanced therapies, indicates considerable interest in the regulation of these products. The objective of this study was to analyze and compare high-tier documents within the Australian, European, and U.S. biologic drug regulatory environments using qualitative methodology. Cohort 1 of the selected 18 high-tier regulatory documents from the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and the Therapeutic Goods Administration (TGA) regulatory frameworks were subject to a manual documentary analysis. These documents were consistent with the legal requirements for manufacturing and use of biologic drugs in humans and fall into six different categories. Manual analysis included a terminology search. The occurrence, frequency, and interchangeable use of different terms and phrases were recorded in the manual documentary analysis. Despite obvious differences, manual documentary analysis revealed certain consistency in use of terminology across analyzed frameworks. Phrase search frequencies have shown less uniformity than the search of terms. Overall, the EMA framework's documents referred to “medicinal products” and “marketing authorization(s),” the FDA documents discussed “drug(s)” or “biologic(s),” and the TGA documents referred to “biological(s).” Although high-tier documents often use different terminology they share concepts and themes. Documents originating from the same source have more conjunction in their terminology although they belong to different frameworks (i.e., Good Clinical Practice requirements based on the Declaration of Helsinki, 1964). Automated (software-based) documentary analysis should be obtained for the conceptual and relational analysis. PMID:23283551

21 CFR 355.70 - Testing procedures for fluoride dentifrice drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Testing procedures for fluoride dentifrice drug... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ANTICARIES DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Testing Procedures § 355.70 Testing procedures for fluoride dentifrice drug products. (a) A fluoride dentifrice drug...

21 CFR 355.70 - Testing procedures for fluoride dentifrice drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Testing procedures for fluoride dentifrice drug... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ANTICARIES DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Testing Procedures § 355.70 Testing procedures for fluoride dentifrice drug products. (a) A fluoride dentifrice drug...

21 CFR 355.70 - Testing procedures for fluoride dentifrice drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Testing procedures for fluoride dentifrice drug... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ANTICARIES DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Testing Procedures § 355.70 Testing procedures for fluoride dentifrice drug products. (a) A fluoride dentifrice drug...

Biological drugs for the treatment of psoriasis in a public health system

PubMed Central

Lopes, Luciane Cruz; Silveira, Miriam Sanches do Nascimento; de Camargo, Iara Alves; Barberato, Silvio; Del Fiol, Fernando de Sá; Osorio-de-Castro, Claudia Garcia Serpa

2014-01-01

OBJECTIVE To analyze the access and utilization profile of biological medications for psoriasis provided by the judicial system in Brazil. METHODS This is a cross-sectional study. We interviewed a total of 203 patients with psoriasis who were on biological medications obtained by the judicial system of the State of Sao Paulo, from 2004 to 2010. Sociodemographics, medical, and political-administrative characteristics were complemented with data obtained from dispensation orders that included biological medications to treat psoriasis and the legal actions involved. The data was analyzed using an electronic data base and shown as simple variable frequencies. The prescriptions contained in the lawsuits were analyzed according to legal provisions. RESULTS A total of 190 lawsuits requesting several biological drugs (adalimumab, efalizumab, etanercept, and infliximab) were analyzed. Patients obtained these medications as a result of injunctions (59.5%) or without having ever demanded biological medication from any health institution (86.2%), i.e., public or private health services. They used the prerogative of free legal aid (72.6%), even though they were represented by private lawyers (91.1%) and treated in private facilities (69.5%). Most of the patients used a biological medication for more than 13 months (66.0%), and some patients were undergoing treatment with this medication when interviewed (44.9%). Approximately one third of the patients discontinued treatment due to worsening of their illness (26.6%), adverse drug reactions (20.5%), lack of efficacy, or because the doctor discontinued this medication (13.8%). None of the analyzed medical prescriptions matched the legal prescribing requirements. Clinical monitoring results showed that 70.3% of the patients had not undergone laboratory examinations (blood work, liver and kidney function tests) for treatment control purposes. CONCLUSIONS The plaintiffs resorted to legal action to get access to biological medications

Genetics of rheumatoid arthritis contributes to biology and drug discovery.

PubMed

Okada, Yukinori; Wu, Di; Trynka, Gosia; Raj, Towfique; Terao, Chikashi; Ikari, Katsunori; Kochi, Yuta; Ohmura, Koichiro; Suzuki, Akari; Yoshida, Shinji; Graham, Robert R; Manoharan, Arun; Ortmann, Ward; Bhangale, Tushar; Denny, Joshua C; Carroll, Robert J; Eyler, Anne E; Greenberg, Jeffrey D; Kremer, Joel M; Pappas, Dimitrios A; Jiang, Lei; Yin, Jian; Ye, Lingying; Su, Ding-Feng; Yang, Jian; Xie, Gang; Keystone, Ed; Westra, Harm-Jan; Esko, Tõnu; Metspalu, Andres; Zhou, Xuezhong; Gupta, Namrata; Mirel, Daniel; Stahl, Eli A; Diogo, Dorothée; Cui, Jing; Liao, Katherine; Guo, Michael H; Myouzen, Keiko; Kawaguchi, Takahisa; Coenen, Marieke J H; van Riel, Piet L C M; van de Laar, Mart A F J; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Bridges, S Louis; Zhernakova, Alexandra; Toes, Rene E M; Tak, Paul P; Miceli-Richard, Corinne; Bang, So-Young; Lee, Hye-Soon; Martin, Javier; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Rantapää-Dahlqvist, Solbritt; Arlestig, Lisbeth; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Eyre, Steve; Bowes, John; Barton, Anne; de Vries, Niek; Moreland, Larry W; Criswell, Lindsey A; Karlson, Elizabeth W; Taniguchi, Atsuo; Yamada, Ryo; Kubo, Michiaki; Liu, Jun S; Bae, Sang-Cheol; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Gregersen, Peter K; Raychaudhuri, Soumya; Stranger, Barbara E; De Jager, Philip L; Franke, Lude; Visscher, Peter M; Brown, Matthew A; Yamanaka, Hisashi; Mimori, Tsuneyo; Takahashi, Atsushi; Xu, Huji; Behrens, Timothy W; Siminovitch, Katherine A; Momohara, Shigeki; Matsuda, Fumihiko; Yamamoto, Kazuhiko; Plenge, Robert M

2014-02-20

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Implementation of mechanism of action biology-driven early drug development for children with cancer.

PubMed

Pearson, Andrew D J; Herold, Ralf; Rousseau, Raphaël; Copland, Chris; Bradley-Garelik, Brigid; Binner, Debbie; Capdeville, Renaud; Caron, Hubert; Carleer, Jacqueline; Chesler, Louis; Geoerger, Birgit; Kearns, Pamela; Marshall, Lynley V; Pfister, Stefan M; Schleiermacher, Gudrun; Skolnik, Jeffrey; Spadoni, Cesare; Sterba, Jaroslav; van den Berg, Hendrick; Uttenreuther-Fischer, Martina; Witt, Olaf; Norga, Koen; Vassal, Gilles

2016-07-01

An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies. Recent large-scale sequencing by International Genome Consortium and Paediatric Cancer Genome Project has further shown that the genetic and epigenetic repertoire of driver mutations in specific childhood malignancies differs from more common adult-type malignancies. To bring about much needed change, a Paediatric Platform, ACCELERATE, was proposed in 2013 by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents and the European Society for Paediatric Oncology. The Platform, comprising multiple stakeholders in paediatric oncology, has three working groups, one with responsibility for promoting and developing high-quality MoA-informed paediatric drug development programmes, including specific measures for adolescents. Key is the establishment of a freely accessible aggregated database of paediatric biological tumour drug targets to be aligned with an aggregated pipeline of drugs. This will enable prioritisation and conduct of early phase clinical paediatric trials to evaluate these drugs against promising therapeutic targets and to generate clinical paediatric efficacy and safety data in an accelerated time frame. Through this work, the Platform seeks to ensure that potentially effective drugs, where the MoA is known and thought to be relevant to paediatric

21 CFR 640.103 - The final product.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false The final product. 640.103 Section 640.103 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS... manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. [38...

21 CFR 640.103 - The final product.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true The final product. 640.103 Section 640.103 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS... manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. [38...

Success rates for product development strategies in new drug development.

PubMed

Dahlin, E; Nelson, G M; Haynes, M; Sargeant, F

2016-04-01

While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008

Predicting Drug Use at Electronic Music Dance Events: Self-Reports and Biological Measurement

ERIC Educational Resources Information Center

Johnson, Mark B.; Voas, Robert A.; Miller, Brenda A.; Holder, Harold D.

2009-01-01

Most information on the prevalence of drug use comes from self-report surveys. The sensitivity of such information is cause for concern about the accuracy of self-report measures. In this study, self-reported drug use in the last 48 hr is compared to results from biological assays of saliva samples from 371 young adults entering clubs. The…

Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease

PubMed Central

Calcul, Laurent; Zhang, Bo; Jinwal, Umesh K; Dickey, Chad A; Baker, Bill J

2013-01-01

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia, affecting more than 5.4 million people in the USA. Although the cause of AD is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. Drug discovery for AD based on the cholinergic and amyloid theories have not been effective. In this article we summarize tau-based natural products as AD therapeutics from a variety of biological sources, including the anti-amyloid agent curcumin, isolated from turmeric, the microtubule stabilizer paclitaxel, from the Pacific Yew Taxus brevifolia, and the Streptomyces-derived Hsp90 inhibitor, geldanamycin. The overlooked approach of clearing tau aggregation will most likely be the next objective for AD drug discovery. PMID:22924511

21 CFR 601.21 - Products under development.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Products under development. 601.21 Section 601.21...) BIOLOGICS LICENSING Biologics Licensing § 601.21 Products under development. A biological product undergoing development, but not yet ready for a biologics license, may be shipped or otherwise delivered from one State...

21 CFR 601.21 - Products under development.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Products under development. 601.21 Section 601.21...) BIOLOGICS LICENSING Biologics Licensing § 601.21 Products under development. A biological product undergoing development, but not yet ready for a biologics license, may be shipped or otherwise delivered from one State...

Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery.

PubMed

Thomford, Nicholas Ekow; Senthebane, Dimakatso Alice; Rowe, Arielle; Munro, Daniella; Seele, Palesa; Maroyi, Alfred; Dzobo, Kevin

2018-05-25

The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compound" has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review

Drug industry in "depression".

PubMed

Almog, Dov M

2005-01-01

The productivity crisis in pharmaceuticals is an important problem that should be seriously addressed by academic scientists and NIH administrators. It is true that most academic scientists avidly practice the reductionist approach and tend to neglect the big picture. However, in light of the crisis, that should change. To stimulate such a change, scientists should see publications addressing big picture issues, and specifically publications which present analyses of the productivity crisis in pharmaceuticals. Although the public media recently published a series of articles reporting the crisis, so far, the peer-reviewed professionaljournals tended to avoid the issue. There seems to be a consensus that there is no successful drug discovery without reasonable biology. The Drug industry in "Depression" paper provides an opportunity to balance the picture and entice discussions on the relationships between academic research practices, NIH policies, and success in drug discovery. Academia and the drug industry must adopt a unified biomedical research approach rather than a multitude of what appears to be unrelated reduction methodologies, especially the basic science/biology end of it.

Lessons from innovation in drug-device combination products.

PubMed

Couto, Daniela S; Perez-Breva, Luis; Saraiva, Pedro; Cooney, Charles L

2012-01-01

Drug-device combination products introduced a new dynamic on medical product development, regulatory approval, and corporate interaction that provide valuable lessons for the development of new generations of combination products. This paper examines the case studies of drug-eluting stents and transdermal patches to facilitate a detailed understanding of the challenges and opportunities introduced by combination products when compared to previous generations of traditional medical or drug delivery devices. Our analysis indicates that the largest barrier to introduce a new kind of combination products is the determination of the regulatory center that is to oversee its approval. The first product of a new class of combination products offers a learning opportunity for the regulator and the sponsor. Once that first product is approved, the leading regulatory center is determined, and the uncertainty about the entire class of combination products is drastically reduced. The sponsor pioneering a new class of combination products assumes a central role in reducing this uncertainty by advising the decision on the primary function of the combination product. Our analysis also suggests that this decision influences the nature (pharmaceutical, biotechnology, or medical devices) of the companies that will lead the introduction of these products into the market, and guide the structure of corporate interaction thereon. Copyright © 2011 Elsevier B.V. All rights reserved.

21 CFR 211.94 - Drug product containers and closures.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drug product containers and closures. 211.94 Section 211.94 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Control of...

21 CFR 211.94 - Drug product containers and closures.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drug product containers and closures. 211.94 Section 211.94 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Control of...

21 CFR 211.94 - Drug product containers and closures.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drug product containers and closures. 211.94 Section 211.94 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Control of...

21 CFR 211.94 - Drug product containers and closures.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drug product containers and closures. 211.94 Section 211.94 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Control of...

21 CFR 211.94 - Drug product containers and closures.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drug product containers and closures. 211.94 Section 211.94 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Control of...

21 CFR 26.4 - Product coverage.

Code of Federal Regulations, 2011 CFR

2011-04-01

.... Products regulated by the Food and Drug Administration's Center for Biologics Evaluation and Research or... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Product coverage. 26.4 Section 26.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL MUTUAL RECOGNITION OF...

21 CFR 26.4 - Product coverage.

Code of Federal Regulations, 2010 CFR

2010-04-01

.... Products regulated by the Food and Drug Administration's Center for Biologics Evaluation and Research or... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Product coverage. 26.4 Section 26.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL MUTUAL RECOGNITION OF...

[Development of Fluorescence Resonance Energy Transfer Sensor for Determination of Adenosine Monophosphate in Biological Drug].

PubMed

Dong, Ling-yu; Du, Hong-ming; Wang, Peng; Wang, Li-yun; Li, Yi-ke; Zhai, Hong; Feng, Ting; Wang, Xiang-feng; Zhu, Qiao-you; Xie, Meng-xia

2015-11-01

The biological drug of the calf-blood dialysate has various pharmacological effects. It can promote the oxygen and glucose uptake for the hypoxia cells, and has beneficial effects on the malfunction of the blood circulation and trophic disturbances in the brain, and the impairment of peripheral blood circulation. Furthermore, it is favorable to wound healing and can regulate the central nervous system. Adenosine monophosphate (AMP) is a main active ingredient of the biological drug. In this report, a fluorescence resonance energy transfer (FRET) sensor has been developed with β-CD-capped ZnS QDs as energy donor and 3-hydroxyflavone (3-HF) as energy acceptor. The results showed that AMP can lead to the fluorescence quenching of the FRET sensor at 526 nm, and the Stern-Volmer curve between the fluorescence quenching and the concentrations of AMP present a satisfactory linearity with the correlation coefficient of 0.996. The developed sensor has successfully applied for determination of the AMP in the biological drug.

21 CFR 341.76 - Labeling of bronchodilator drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Labeling of bronchodilator drug products. 341.76 Section 341.76 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... prescription drug for asthma unless directed by a doctor.” (4) Drug interaction precaution. “Do not use if you...

21 CFR 341.76 - Labeling of bronchodilator drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Labeling of bronchodilator drug products. 341.76 Section 341.76 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... prescription drug for asthma unless directed by a doctor.” (4) Drug interaction precaution. “Do not use if you...

78 FR 57397 - Over-the-Counter Ophthalmic Drug Products-Emergency Use Eyewash Products; Announcement of Public...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-18

...) emergency first aid eyewash drug products, including the components of these products, and the conditions... A. Product Overview OTC emergency first aid eyewash drug products (EE products) are typically water... emergency first aid treatment of chemical burns (including acid and alkali burns). FDA stated in the call...

Yeast synthetic biology toolbox and applications for biofuel production.

PubMed

Tsai, Ching-Sung; Kwak, Suryang; Turner, Timothy L; Jin, Yong-Su

2015-02-01

Yeasts are efficient biofuel producers with numerous advantages outcompeting bacterial counterparts. While most synthetic biology tools have been developed and customized for bacteria especially for Escherichia coli, yeast synthetic biological tools have been exploited for improving yeast to produce fuels and chemicals from renewable biomass. Here we review the current status of synthetic biological tools and their applications for biofuel production, focusing on the model strain Saccharomyces cerevisiae We describe assembly techniques that have been developed for constructing genes, pathways, and genomes in yeast. Moreover, we discuss synthetic parts for allowing precise control of gene expression at both transcriptional and translational levels. Applications of these synthetic biological approaches have led to identification of effective gene targets that are responsible for desirable traits, such as cellulosic sugar utilization, advanced biofuel production, and enhanced tolerance against toxic products for biofuel production from renewable biomass. Although an array of synthetic biology tools and devices are available, we observed some gaps existing in tool development to achieve industrial utilization. Looking forward, future tool development should focus on industrial cultivation conditions utilizing industrial strains. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis

PubMed Central

Emery, Paul; Sebba, Anthony; Huizinga, Tom W J

2013-01-01

Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral disease-modifying antirheumatic drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX. PMID:23918035

Administration costs of intravenous biologic drugs for rheumatoid arthritis.

PubMed

Soini, Erkki J; Leussu, Miina; Hallinen, Taru

2013-01-01

Cost-effectiveness studies explicitly reporting infusion times, drug-specific administration costs for infusions or real-payer intravenous drug cost are few in number. Yet, administration costs for infusions are needed in the health economic evaluations assessing intravenously-administered drugs. To estimate the drug-specific administration and total cost of biologic intravenous rheumatoid arthritis (RA) drugs in the adult population and to compare the obtained costs with published cost estimates. Cost price data for the infusions and drugs were systematically collected from the 2011 Finnish price lists. All Finnish hospitals with available price lists were included. Drug administration and total costs (administration cost + drug price) per infusion were analysed separately from the public health care payer's perspective. Further adjustments for drug brand, dose, and hospital type were done using regression methods in order to improve the comparability between drugs. Annual expected drug administration and total costs were estimated. A literature search not limited to RA was performed to obtain the per infusion administration cost estimates used in publications. The published costs were converted to Finnish values using base-year purchasing power parities and indexing to the year 2011. Information from 19 (95%) health districts was obtained (107 analysable prices out of 176 observations). The average drug administration cost for infliximab, rituximab, abatacept, and tocilizumab infusion in RA were €355.91; €561.21; €334.00; and €293.96, respectively. The regression-adjusted (dose, hospital type; using semi-log ordinary least squares) mean administration costs for infliximab and rituximab infusions in RA were €289.12 (95% CI €222.61-375.48) and €542.28 (95% CI €307.23-957.09). The respective expected annual drug administration costs were €2312.96 for infliximab during the first year, €1879.28 for infliximab during the forthcoming years, and �

Description of Patients Treated with Biologic Drugs as First-Line Systemic Therapy in the BIOBADADERM Registry Between 2008 and 2016.

PubMed

Carretero Hernández, G; Ferrándiz, C; Rivera Díaz, R; Daudén Tello, E; de la Cueva-Dobao, P; Gómez-García, F J; Herrera-Ceballos, E; Belinchón Romero, I; López-Estebaranz, J L; Alsina Gibert, M; Sánchez-Carazo, J L; Ferrán Farrés, M; González Quesada, A; Carrascosa Carrillo, J M; Llamas-Velasco, M; Mendiola Fernández, M V; Ruiz Genao, D; Muñoz Santos, C; García-Doval, I; Descalzo, M A

2018-06-07

Biologic drugs are usually prescribed as second-line treatment for psoriasis, that is, after the patient has first been treated with a conventional psoriasis drug. There are, however, cases where, depending on the characteristics of the patient or the judgement of the physician, biologics may be chosen as first-line therapy. No studies to date have analyzed the demographics or clinical characteristics of patients in this setting or the safety profile of the agents used. The main aim of this study was to characterize these aspects of first-line biologic therapy and compare them to those observed for patients receiving biologics as second-line therapy. We conducted an observational study of 181 patients treated in various centers with a systemic biologic drug as first-line treatment for moderate to severe psoriasis between January 2008 and November 2016. All the patients were registered in the Spanish Registry of Adverse Events Associated with Biologic Drugs in Dermatology. The characteristics of the first- and second-line groups were very similar, although the patients receiving a biologic as first-line treatment for their psoriasis were older. No differences were observed for disease severity (assessed using the PASI) or time to diagnosis. Hypertension, diabetes, and liver disease were all more common in the first-line group. There were no differences between the groups in terms of reasons for drug withdrawal or occurrence of adverse effects. No major differences were found between patients with psoriasis receiving biologic drugs as first- or second-line therapy, a finding that provides further evidence of the safety of biologic therapy in patients with psoriasis. Publicado por Elsevier España, S.L.U.

Indicators of club management practices and biological measurements of patrons' drug and alcohol use.

PubMed

Byrnes, Hilary F; Miller, Brenda A; Johnson, Mark B; Voas, Robert B

2014-12-01

Electronic music and dance events in nightclubs attract patrons with heavy alcohol/drug use. Public health concerns are raised from risks related to these behaviors. Practices associated with increased risk in these club settings need to be identified. The relationship between club management practices and biological measures of patrons' alcohol/drug use is examined. Observational data from 25 events across six urban clubs were integrated with survey data (N = 738 patrons, 42.8% female) from patrons exiting these events, 2010-2012. Five indicators of club management practices were examined using mixed model regressions: club security, bar crowding, safety signs, serving intoxicated patrons, and isolation. Analyses revealed that serving intoxicated patrons and safety signs were related to substance use. Specifically, serving intoxicated patrons was related to heavy alcohol and drug use at exit, while safety signs were marginally related to less exit drug use. CONCLUSIONS/IMPORTANCE: Findings indicate observable measures in nightclubs provide important indicators for alcohol/drug use, suggesting practices to target. Study strengths include the use of biological measures of substance use on a relatively large scale. Limitations and future directions are discussed.

Indicators of Club Management Practices and Biological Measurements of Patrons’ Drug and Alcohol Use

PubMed Central

Byrnes, Hilary F.; Miller, Brenda A.; Johnson, Mark B.; Voas, Robert B.

2015-01-01

Background Electronic Music Dance Events in nightclubs attract patrons with heavy alcohol/drug use. Public health concerns are raised from risks related to these behaviors. Practices associated with increased risk in these club settings need to be identified. Objectives The relationship between club management practices and biological measures of patrons’ alcohol/drug use is examined. Methods Observational data from 25 events across 6 urban clubs were integrated with survey data (N=738 patrons, 42.8% female) from patrons exiting these events, 2010–2012. Five indicators of club management practices were examined using mixed model regressions: club security, bar crowding, safety signs, serving intoxicated patrons, and isolation. Results Analyses revealed that serving intoxicated patrons and safety signs were related to less substance use. Specifically, serving intoxicated patrons was related to heavy alcohol and drug use at exit, while safety signs were marginally related to less exit drug use. Conclusions/Importance Findings indicate observable measures in nightclubs provide important indicators for alcohol/drug use, suggesting practices to target. Study strengths include the use of biological measures of substance use on a relatively large scale. Limitations and future directions are discussed. PMID:24832721

Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases.

PubMed

Zha, Weibin

2018-04-01

The growing use of natural products in cardiovascular (CV) patients has been greatly raising the concerns about potential natural product-CV drug interactions. Some of these may lead to unexpected cardiovascular adverse effects and it is, therefore, essential to identify or predict potential natural product-CV drug interactions, and to understand the underlying mechanisms. Drug transporters are important determinants for the pharmacokinetics of drugs and alterations of drug transport has been recognized as one of the major causes of natural product-drug interactions. In last two decades, many CV drugs (e.g., angiotensin II receptor blockers, beta-blockers and statins) have been identified to be substrates and inhibitors of the solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters, which are two major transporter superfamilies. Meanwhile, in vitro and in vivo studies indicate that a growing number of natural products showed cardioprotective effects (e.g., gingko biloba, danshen and their active ingredients) are also substrates and inhibitors of drug transporters. Thus, to understand transporter-mediated natural product-CV drug interactions is important and some transporter-mediated interactions have already shown to have clinical relevance. In this review, we review the current knowledge on the role of ABC and SLC transporters in CV therapy, as well as transporter modulation by natural products used in CV diseases and their induced natural product-CV drug interactions through alterations of drug transport. We hope our review will aid in a comprehensive summary of transporter-mediated natural product-CV drug interactions and help public and physicians understand these type of interactions. Copyright © 2017. Published by Elsevier B.V.

21 CFR 341.74 - Labeling of antitussive drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Labeling of antitussive drug products. 341.74 Section 341.74 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... years of age. Drug interaction precaution. “Do not use in a child who is taking a prescription monoamine...

21 CFR 341.74 - Labeling of antitussive drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Labeling of antitussive drug products. 341.74 Section 341.74 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... years of age. Drug interaction precaution. “Do not use in a child who is taking a prescription monoamine...

Predicting drug use at electronic music dance events: self-reports and biological measurement.

PubMed

Johnson, Mark B; Voas, Robert A; Miller, Brenda A; Holder, Harold D

2009-06-01

Most information on the prevalence of drug use comes from self-report surveys. The sensitivity of such information is cause for concern about the accuracy of self-report measures. In this study, self-reported drug use in the last 48 hr is compared to results from biological assays of saliva samples from 371 young adults entering clubs. The relationship between self-reports and drug presence in oral fluid was determined for three substances as follows: cocaine, marijuana, and amphetamine. Forty-one percent of the participants with drugs detected in their oral fluids reported no use in the last 48 hr. The significance of these results is discussed.

A survey of the concentrations of eleven metals in vaccines, allergenic extracts, toxoids, blood, blood derivatives and other biological products.

PubMed

May, J C; Rains, T C; Maienthal, F J; Biddle, G N; Progar, J J

1986-10-01

Approximately 85 samples of injectable biological products regulated by the Center for Drugs and Biologics of the United States Food and Drug Administration were surveyed for the presence of 11 elements, namely aluminum, arsenic, barium, cadmium, chromium, lead, mercury, selenium, thallium and zinc, by flame and flameless methods of atomic absorption spectrometry and flame emission spectrometry. The range of products tested included whole blood, red cells, plasma, normal serum albumin, antihemophilic factor, and other products derived from blood; allergenic extracts including honey bee venom and house dust allergenic extracts; vaccines such as measles virus vaccine and typhoid vaccine; and tetanus toxoid. The metal concentrations found in the majority of these products were low or undetectable. The metal levels varied from manufacturer to manufacturer, product and lot-to-lot of the same manufacturer's products. House dust allergenic extracts had the highest concentrations of arsenic (2.4 ppm), cadmium (0.28 ppm), chromium (0.6 ppm) and lead (1.5 ppm) found in the study. A high zinc concentration (24 ppm) in an immune serum globulin was attributed to the zinc-containing rubber stopper in contact with the product. A range of 0.36-3.30 ppm aluminum was found for seven 25% normal serum albumin samples from seven manufacturers. Values of 8.2, 17 and 18 ppm aluminum were found in one manufacturer's 25% normal serum albumin. These aluminum values appeared to be the result of an anomaly in this manufacturer's production that has not been repeated to date.

21 CFR 201.312 - Magnesium sulfate heptahydrate; label declaration on drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Magnesium sulfate heptahydrate; label declaration... Drug Products § 201.312 Magnesium sulfate heptahydrate; label declaration on drug products. Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or...

21 CFR 201.312 - Magnesium sulfate heptahydrate; label declaration on drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Magnesium sulfate heptahydrate; label declaration... Drug Products § 201.312 Magnesium sulfate heptahydrate; label declaration on drug products. Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or...

21 CFR 201.312 - Magnesium sulfate heptahydrate; label declaration on drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Magnesium sulfate heptahydrate; label declaration... Drug Products § 201.312 Magnesium sulfate heptahydrate; label declaration on drug products. Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or...

21 CFR 201.312 - Magnesium sulfate heptahydrate; label declaration on drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Magnesium sulfate heptahydrate; label declaration... Drug Products § 201.312 Magnesium sulfate heptahydrate; label declaration on drug products. Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or...

21 CFR 201.312 - Magnesium sulfate heptahydrate; label declaration on drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Magnesium sulfate heptahydrate; label declaration... Drug Products § 201.312 Magnesium sulfate heptahydrate; label declaration on drug products. Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or...

Stem cell biology and drug discovery

PubMed Central

2011-01-01

There are many reasons to be interested in stem cells, one of the most prominent being their potential use in finding better drugs to treat human disease. This article focuses on how this may be implemented. Recent advances in the production of reprogrammed adult cells and their regulated differentiation to disease-relevant cells are presented, and diseases that have been modeled using these methods are discussed. Remaining difficulties are highlighted, as are new therapeutic insights that have emerged. PMID:21649940

Production of drug nanosuspensions: effect of drug physical properties on nanosizing efficiency.

PubMed

Liu, Tao; Müller, Rainer H; Möschwitzer, Jan P

2018-02-01

Drug nanosuspension is one of the established methods to improve the bioavailability of poorly soluble drugs. Drug physical properties aspect (morphology, solid state, starting size et al) is a critical parameter determining the production efficiency. Some drug modification approaches such as spray-drying were proved to improve the millability of drug powders. However, the mechanism behind those improved performances is unclear. This study is to systematically investigate the influence of those physical properties. Five different APIs (active pharmaceutical ingredients) with different millabilities, i.e. resveratrol, hesperetin, glibenclamide, rutin, and quercetin, were processed by standard high pressure homogenization (HPH), wet bead milling (WBM), and a combinative method of spray-drying and HPH. Smaller starting sizes of certain APIs could accelerate the particle size reduction velocity during both HPH and WBM processes. Spherical particles were observed for almost all spray-dried powders (except spray-dried hesperetin) after spray-drying. The crystallinity of some spray-dried samples such as rutin and glibenclamide became much lower than their corresponding unmodified powders. Almost all spray-dried drug powders after HPH processes could lead to smaller nanocrystal particle size than unmodified APIs. The modified microstructure instead of solid state after spray-drying explained the potential reason for improved nanosizing efficiency. In addition, the contribution of starting size on the production efficiency was also critical according to both HPH and WBM results.

Synthetic Biology for Therapeutic Applications

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

Abil, Zhanar; Xiong, Xiong; Zhao, Huimin

Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders.

Synthetic Biology for Therapeutic Applications

DOE PAGES

Abil, Zhanar; Xiong, Xiong; Zhao, Huimin

2014-08-06

Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders.

Synthetic Biology Guides Biofuel Production

PubMed Central

Connor, Michael R.; Atsumi, Shota

2010-01-01

The advancement of microbial processes for the production of renewable liquid fuels has increased with concerns about the current fuel economy. The development of advanced biofuels in particular has risen to address some of the shortcomings of ethanol. These advanced fuels have chemical properties similar to petroleum-based liquid fuels, thus removing the need for engine modification or infrastructure redesign. While the productivity and titers of each of these processes remains to be improved, progress in synthetic biology has provided tools to guide the engineering of these processes through present and future challenges. PMID:20827393

21 CFR 357.150 - Labeling of anthelmintic drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Section 357.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE... milligrams of pyrantel base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram...

21 CFR 357.150 - Labeling of anthelmintic drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Section 357.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE... milligrams of pyrantel base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram...

21 CFR 357.150 - Labeling of anthelmintic drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Section 357.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE... milligrams of pyrantel base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram...

21 CFR 357.150 - Labeling of anthelmintic drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Section 357.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE... milligrams of pyrantel base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram...

21 CFR 357.150 - Labeling of anthelmintic drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Section 357.150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE... milligrams of pyrantel base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram...

9 CFR 118.3 - Movement of detained biological products; Termination of detention.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Movement of detained biological... VECTORS DETENTION; SEIZURE AND CONDEMNATION § 118.3 Movement of detained biological products; Termination of detention. Except as provided in paragraphs (a) and (b) of this section, no biological product...

Scientific and Regulatory Considerations for Generic Complex Drug Products Containing Nanomaterials.

PubMed

Zheng, Nan; Sun, Dajun D; Zou, Peng; Jiang, Wenlei

2017-05-01

In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

PubMed

Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

2016-11-10

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

21 CFR 680.2 - Manufacture of Allergenic Products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Manufacture of Allergenic Products. 680.2 Section 680.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS § 680.2 Manufacture of Allergenic Products. (a...

21 CFR 680.2 - Manufacture of Allergenic Products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Manufacture of Allergenic Products. 680.2 Section 680.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS § 680.2 Manufacture of Allergenic Products. (a...

21 CFR 680.2 - Manufacture of Allergenic Products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Manufacture of Allergenic Products. 680.2 Section 680.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS § 680.2 Manufacture of Allergenic Products. (a...

21 CFR 680.2 - Manufacture of Allergenic Products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Manufacture of Allergenic Products. 680.2 Section 680.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS § 680.2 Manufacture of Allergenic Products. (a...

Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs.

PubMed

Appendino, Giovanni; Minassi, Alberto; Taglialatela-Scafati, Orazio

2014-07-01

Covering: up to December 2013. Over the past decade, there has been a growing transition in recreational drugs from natural materials (marijuana, hashish, opium), natural products (morphine, cocaine), or their simple derivatives (heroin), to synthetic agents more potent than their natural prototypes, which are sometimes less harmful in the short term, or that combine properties from different classes of recreational prototypes. These agents have been named smart drugs, and have become popular both for personal consumption and for collective intoxication at rave parties. The reasons for this transition are varied, but are mainly regulatory and commercial. New analogues of known illegal intoxicants are invisible to most forensic detection techniques, while the alleged natural status and the lack of avert acute toxicity make them appealing to a wide range of users. On the other hand, the advent of the internet has made possible the quick dispersal of information among users and the on-line purchase of these agents and/or the precursors for their synthesis. Unlike their natural products chemotypes (ephedrine, mescaline, cathinone, psilocybin, THC), most new drugs of abuse are largely unfamiliar to the organic chemistry community as well as to health care providers. To raise awareness of the growing plague of smart drugs we have surveyed, in a medicinal chemistry fashion, their development from natural products leads, their current methods of production, and the role that clandestine home laboratories and underground chemists have played in the surge of popularity of these drugs.

Starting of biological disease modifying antirheumatic drugs may be postponed in rheumatoid arthritis patients with multimorbidity

PubMed Central

Armagan, Berkan; Sari, Alper; Erden, Abdulsamet; Kilic, Levent; Erdat, Efe Cem; Kilickap, Saadettin; Kiraz, Sedat; Bilgen, Sule Apras; Karadag, Omer; Akdogan, Ali; Ertenli, Ihsan; Kalyoncu, Umut

2018-01-01

Abstract The objective of this study was to assess the frequency of comorbidities and multimorbidities in rheumatoid arthritis (RA) patients under biologic therapy and their effects on biological disease modifying antirheumatic drugs (DMARDs) choice, timing, and response. Hacettepe University Biologic Registry (HUR-BIO) is single center biological DMARD registry. Cardiovascular, infectious, cancer, and other comorbidities were recorded with face to face interviews. Multimorbidity is defined as >1 comorbidity. Disease duration, initial date of biological DMARDs, initial and overall biological DMARD choice were recorded. Disease activity score-28 (DAS-28) responses were compared to comorbidity presence and multimorbidity. Total of 998 RA patients were enrolled into the study. The mean age was 53.1 (12.5) and mean disease duration (standard deviation [SD]) was 11.7 (7.5) years. At least 1 comorbidity was detected in 689 (69.1%) patients, 375 (37.9%) patients had multimorbidity. Patients had mean 1.36 ± 1.32 comorbidity. The median durations of first biological DMARDs prescription were 60 (3–552) months after RA diagnosis. For multimorbidity patients, the median first biological prescription duration was longer than the duration for patients without multimorbidity (72 [3–552] vs 60 [3–396] months, P < .001). The physicians prescribe tumor necrosis factor inhibitor (TNFi) biological drugs less frequently than other biological DMARDs in patients with at least 1 comorbidity (66.2% vs 74.5%, P = .007) or multimorbidity (34.6% vs 43.5%, P = .006). Patients with comorbidities and multimorbidity achieved DAS-28 remission less frequently than patients without comorbidity (31.6% vs 42.6%, P = .012 and 27.2% vs 39.7%, P = .001, respectively). In real life, physicians may postpone to prescribe biological DMARDs and less frequently choose TNFi biological drugs in patients with multimorbidity. Furthermore, comorbidity may have a negative effect on the

Biological therapies (immunomodulatory drugs), worsening of psoriasis and rebound effect: new evidence of similitude.

PubMed

Teixeira, Marcus Zulian

2016-11-01

Employing the secondary action or adaptative reaction of the organism as therapeutic response, homeopathy uses the treatment by similitude (similia similibus curentur) administering to sick individuals the medicines that caused similar symptoms in healthy individuals. Such homeostatic or paradoxical reaction of the organism is scientifically explained through the rebound effect of drugs, which cause worsening of symptoms after withdrawal of several palliative treatments. Despite promoting an improvement in psoriasis at the beginning of the treatment, modern biological therapies provoke worsening of the psoriasis (rebound psoriasis) after discontinuation of drugs. Exploratory qualitative review of the literature on the occurrence of the rebound effect with the use of immunomodulatory drugs [T-cell modulating agents and tumor necrosis factor (TNF) inhibitors drugs] in the treatment of psoriasis. Several researches indicate the rebound effect as the mechanism of worsening of psoriasis with the use of efalizumab causing the suspension of its marketing authorization in 2009, in view of some severe cases. Other studies also have demonstrated the occurrence of rebound psoriasis with the use of alefacept, etanercept and infliximab. As well as studied in other classes of drugs, the rebound effect of biologic agents supports the principle of similitude (primary action of the drugs followed by secondary action and opposite of the organism). Copyright © 2016 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis

PubMed Central

Tonge, Peter J.; Xie, Lei; Bourne, Philip E.

2009-01-01

The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs. PMID:19578428

Community-Reviewed Biological Network Models for Toxicology and Drug Discovery Applications

PubMed Central

Namasivayam, Aishwarya Alex; Morales, Alejandro Ferreiro; Lacave, Ángela María Fajardo; Tallam, Aravind; Simovic, Borislav; Alfaro, David Garrido; Bobbili, Dheeraj Reddy; Martin, Florian; Androsova, Ganna; Shvydchenko, Irina; Park, Jennifer; Calvo, Jorge Val; Hoeng, Julia; Peitsch, Manuel C.; Racero, Manuel González Vélez; Biryukov, Maria; Talikka, Marja; Pérez, Modesto Berraquero; Rohatgi, Neha; Díaz-Díaz, Noberto; Mandarapu, Rajesh; Ruiz, Rubén Amián; Davidyan, Sergey; Narayanasamy, Shaman; Boué, Stéphanie; Guryanova, Svetlana; Arbas, Susana Martínez; Menon, Swapna; Xiang, Yang

2016-01-01

Biological network models offer a framework for understanding disease by describing the relationships between the mechanisms involved in the regulation of biological processes. Crowdsourcing can efficiently gather feedback from a wide audience with varying expertise. In the Network Verification Challenge, scientists verified and enhanced a set of 46 biological networks relevant to lung and chronic obstructive pulmonary disease. The networks were built using Biological Expression Language and contain detailed information for each node and edge, including supporting evidence from the literature. Network scoring of public transcriptomics data inferred perturbation of a subset of mechanisms and networks that matched the measured outcomes. These results, based on a computable network approach, can be used to identify novel mechanisms activated in disease, quantitatively compare different treatments and time points, and allow for assessment of data with low signal. These networks are periodically verified by the crowd to maintain an up-to-date suite of networks for toxicology and drug discovery applications. PMID:27429547

9 CFR 115.2 - Inspections of biological products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... United States veterinary license number or a United States veterinary permit number or other mark...) When notified to stop distribution and sale of a serial or subserial of a veterinary biological product by the Secretary, veterinary biologics licensees or permittees shall: (1) Stop the preparation...