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PubMed2006

AgBase: a functional genomics resource for agriculture.

BACKGROUND: Many agricultural species and their pathogens have sequenced genomes and more are in progress. Agricultural species provide food, fiber, xenotransplant tissues, biopharmaceuticals and biomedical models. Moreover, many agricultural microorganisms are human zoonoses. However, systems biology from functional genomics data is hindered in agricultural species because agricultural genome sequences have relatively poor structural and functional annotation and agricultural research communities are smaller with limited funding compared to many model organism communities. DESCRIPTION: To facilitate systems biology in these traditionally agricultural species we have established "AgBase", a curated, web-accessible, public resource http://www.agbase.msstate.edu for structural and functional annotation of agricultural genomes. The AgBase database includes a suite of computational tools to use GO annotations. We use standardized nomenclature following the Human Genome Organization Gene Nomenclature guidelines and are currently functionally annotating chicken, cow and sheep gene products using the Gene Ontology (GO). The computational tools we have developed accept and batch process data derived from different public databases (with different accession codes), return all existing GO annotations, provide a list of products without GO annotation, identify potential orthologs, model functional genomics data using GO and assist proteomics analysis of ESTs and EST assemblies. Our journal database helps prevent redundant manual GO curation. We encourage and publicly acknowledge GO annotations from researchers and provide a service for researchers interested in GO and analysis of functional genomics data. CONCLUSION: The AgBase database is the first database dedicated to functional genomics and systems biology analysis for agriculturally important species and their pathogens. We use experimental data to improve structural annotation of genomes and to functionally characterize gene products. AgBase is also directly relevant for researchers in fields as diverse as agricultural production, cancer biology, biopharmaceuticals, human health and evolutionary biology. Moreover, the experimental methods and bioinformatics tools we provide are widely applicable to many other species including model organisms.

Agriculture↗
PubMed2005

Investigation of oral bioavailability and brain distribution of the Ind(8)-Val conjugate of indinavir in rodents.

Protease inhibitors are successfully used for the treatment of acquired immune deficiency syndrome (AIDS) although their biopharmaceutical characteristics are not optimal. Prodrugs have therefore been synthesized to increase protease inhibitor bioavailability and brain distribution. Among several compounds tested, a valine derivative of indinavir (Ind(8)-Val) showed promising characteristics using an in-vitro Caco-2 cell model. The objective of this study was to further investigate this compound using in-situ and in-vivo approaches. The pharmacokinetics of indinavir (Ind) and Ind(8)-Val were investigated in rats after intravenous and oral administration. Free indinavir resulting from in-vivo hydrolysis of Ind(8)-Val could not be detected in the plasma of rats receiving Ind(8)-Val. Furthermore Ind(8)-Val bioavailability was only 32% on average compared with 76% for indinavir, and effective permeability coefficients determined with a single-pass intestinal perfusion method were close to 25x10(6)cms(-1) for the two compounds. Brain-to-plasma concentration ratios in the post equilibrium phase after intravenous administration to mice were 9.7+/-8.1% for indinavir and 2.5+/-2.7% for Ind(8)-Val. In conclusion, the promising biopharmaceutical characteristics of Ind(8)-Val suggested from previous in-vitro experiments with the Caco-2 cell model were not confirmed by in-situ and in-vivo experiments.

Administration, Oral↗
PubMed2004

Solvation of drugs as a key for understanding partitioning and passive transport exemplified by NSAIDs.

Passive transport properties of drug molecules are of utmost importance for their pharmacological and biopharmaceutical effectiveness. Diffusion in different media and through lipid bilayers is in many cases the rate-determining step for the distribution in the body. In the present review an attempt is made to demonstrate the importance of solvation of drug molecules for the diffusion and partition/distribution in phases of different lipophilicity. Different approaches known in the literature to describe solvation of compounds with flexible conformation are discussed as well as the experimental methods to directly measure the energy of solvation. NSAIDs are chosen as an example of a class of drugs of different molecular structures that have already been studied thoroughly in many aspects, and a set of aliphatic alcohols can be used as a model for compartments of different lipophilic/hydrophilic properties. Thermodynamic characteristics of solvation of the drug molecules yielded by independent classical experimental methods (Gibbs energy, enthalpic and entropic terms of Gibbs energy) are studied in order to better understand diffusion and distribution properties. Correlations between in-vitro-data (partition coefficient, enthalpy of solvation) with biopharmaceutically relevant characteristics (plasma half-life) are also discussed.

Animals↗
PubMed1999

Colorimetric protein assay techniques.

There has been an increase in the number of colorimetric assay techniques for the determination of protein concentration over the past 20 years. This has resulted in a perceived increase in sensitivity and accuracy with the advent of new techniques. The present review considers these advances with emphasis on the potential use of such technologies in the assay of biopharmaceuticals. The techniques reviewed include Coomassie Blue G-250 dye binding (the Bradford assay), the Lowry assay, the bicinchoninic acid assay and the biuret assay. It is shown that each assay has advantages and disadvantages relative to sensitivity, ease of performance, acceptance in the literature, accuracy and reproducibility/coefficient of variation/laboratory-to-laboratory variation. A comparison of the use of several assays with the same sample population is presented. It is suggested that the most critical issue in the use of a chromogenic protein assay for the characterization of a biopharmaceutical is the selection of a standard for the calibration of the assay; it is crucial that the standard be representative of the sample. If it is not possible to match the standard with the sample from the perspective of protein composition, then it is preferable to use an assay that is not sensitive to the composition of the protein such as a micro-Kjeldahl technique, quantitative amino acid analysis or the biuret assay. In a complex mixture it might be inappropriate to focus on a general method of protein determination and much more informative to use specific methods relating to the protein(s) of particular interest, using either specific assays or antibody-based methods. The key point is that whatever method is adopted as the 'gold standard' for a given protein, this method needs to be used routinely for calibration.

Colorimetry↗
PubMed1994

How a collaborative task force can assist in managing biotechnology products.

The rapid expansion of biotechnology-derived pharmaceuticals into the health care system presents new challenges and concerns in formulary selection, development of usage guidelines, and budgeting. A DUE/QA pharmacy network and a hospital association in a metropolitan area formed a Biotechnology Task Force, whose goals included: developing a forum for practitioners and administrators to exchange information; applying a strategy for evaluating and predicting usage patterns; promoting educational endeavors; and developing database technology to assist institutions with usage monitoring. The task force successfully educated health care professionals and administrators about the ramifications of biopharmaceuticals. Having this process defined will prove beneficial for future evaluation of other biopharmaceuticals.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

Multiprobe fluorescence imaging and microspectrofluorimetry of cell transformation and differentiation: implications in terms of applied biochemistry and biotechnology.

The dichotomy of cellular transformation versus differentiation does not preclude the hypothesis of a unified underlying mechanism that can switch either way as a result of growth factors, cell-membrane receptors, secondary messengers, integrating switch kinases and/or nuclear receptors. Its study for biopharmaceutical and biotechnological applications requires a methodology capable of dealing with such pleiotropy. In the multiprobe-multiparameter approach, one must remain wary of cumulative toxic effects and misinterpretations. 'Smart' instrumentation does not mean 'smart' probes. It turns out that the cell's own endogenous probes, the fluorescent coenzymes, may be akin to 'smart' probes, open to study in situ of many-fold interrelated pathways in cell energetics and dynamics. Resolution at the micro- and even nano-compartment levels is not altogether impossible. Thus an innovative search in terms of what may be called 'intracellular reconnaissance with fluorescent probes and biopharmaceuticals' necessitates recourse to multiple tentative probings along the pleiotropic mechanisms as far in resolution as one can go. Among the characteristic findings using this approach are: (i) morphometric alterations in the mitochondria and melanosomes of melanoma cells treated with azelaic acid; (ii) deregulation of mitochondrial control and extramitochondrial metabolism in similarly treated cells; (iii) considerable acceleration of NAD(P) transient kinetics in atractylate-treated L sarcoma cells; (iv) alterations of mitochondria and Golgi in fusion-deficient myoblasts; (v) tentative recognition of beta-glucosidase deficiency in Gaucher disease cells by the use of fluorescent and fluorogenic lysosomal probes; and (vi) UVA-induced accumulation of Schiff bases (a kind of accelerated photo-aging) in yeast and kidney epithelial cells. Because these studies utilize probing at whatever points along the concerned pathways become accessible, at first glance they may look disconnected. What and where is the connecting thread, for instance, between studying melanoma metabolism, melanosome morphometry, hepatocyte organelle morphogenesis and transformation, myotube organelle morphogenesis and fusion-non-fusion, and lysosomal activity in gene-deficient cells? In the mapping of the regulatory and deregulatory mechanisms involved in the switching of differentiation or transformation, each of the above topics carries an information content towards resolution of the pleiotropic puzzle. The integration of such information with increasing resolution and access to intracellular microdomains may ultimately allow focus on the precise target, the switch from differentiation to transformation or vice versa.

Animals↗
PubMed1999

Elimination of serum from cell culture medium.

Growth of continuous cell lines for preparing biopharmaceuticals in the absence of animal serum has been attempted by many organizations to improve process and product quality, prevent exposure to adventitious agents, and reduce costs. Literature surveys suggest that substantial academic studies on serum-free medium have been pursued for many decades, with varying levels of success for different cell types and cell lines in terms of achieving cell growth while retaining cell function. Industrial research proceeded for at least three decades. Recent work with CHO cells and with some hybridomas has been successful in providing the basis for serially propagating cells on a large scale in suspension in the total absence of serum, while preserving the ability to prepare biopharmaceuticals. In some cases, this can be achieved not only without serum, but also without the use of other animal-derived proteins.

Animals↗
PubMed2000

Supercritical fluid precipitation of recombinant human immunoglobulin from aqueous solutions.

Supercritical carbon dioxide was used as an antisolvent for producing recombinant human immunoglobulin G (rIgG) particulate powders. Liquid carbon dioxide (CO(2)) was premixed with ethanol to create a single-phase, modified supercritical fluid (SCF). The modified SCF was then vigorously mixed with a pharmaceutically acceptable, aqueous formulation of rIgG, and the mixture was immediately atomized into a pressurized vessel where rapid expansion of the modified SCF extracted the aqueous phase, resulting in precipitation of the protein powder. The process was reproducible, and resulting powder products were characterized by their aqueous solubilities, and the spectroscopic profile, molecular integrity, and antigen binding activity of the individual soluble fractions. Molecular integrity was assessed via size-exclusion high-performance liquid chromatography (SEC), whereas antigen binding activity was determined using an enzyme-linked immunosorbent assay (ELISA). Attempts to characterize particle size and morphology were confounded due to the extremely deliquescent nature of the powders, causing them to absorb moisture rapidly and become gummy. Operational conditions were optimized to a point which yielded powders that were completely soluble, and had ultraviolet (UV) spectroscopic and SEC profiles indistinguishable from those of the reference standard starting solution from which the powders were derived. Antigen binding activities of the powders, however, were </=50% of expected levels, revealing the need for improvement of this SCF processing approach for rIgGs. From this study, two important conclusions were drawn: (1) Biopharmaceutical product quality assessments must include definitive activity analyses, because profound activity losses, such as those suffered here by the rIgGs, may not be revealed when using standard physicochemical analyses alone; and, (2) A more comprehensive understanding and control of the range of SCF processing effects, particularly on aqueous-based macromolecular protein therapeutics, is necessary for SCF precipitation to gain full acceptance as a viable option for secondary manufacturing of biopharmaceutical powders.

Biotechnology↗
PubMed2002

[Crystalline modifications and polymorphism changes during drug manufacture].

More than half of the pharmaceutical compounds exhibit polymorphism or pseudopolymorphism, e.g., they exist as more than one crystalline structure (true polymorphs, hydrates, solvates) or as more or less amorphous products. As such, they show at the solid state different physicochemical properties (melting point, transition point, plasticity, solubility, hygroscopicity, chemical reactivity), which in turn may affect the technological and biopharmaceutical properties of active ingredients or excipients (compactibility, dissolution rate, bioavailability, pharmacological activity, stability). When considering a chemically well-defined compound, one may find one or another crystalline state or polymorphic form according to the source or batch considered. One may also observe changes in technological or biopharmaceutical properties that are due to polymorphic transformations arising from the mechanical or heat treatment or from the environmental conditions (solvent-mediated reactions, desolvation) undergone by the product or the dosage form. The present article presents the fundamental aspects related to the above-mentioned phenomena and reviews both classical and recent examples from the literature reporting transformations during milling or grinding, tabletting, preparation of drug suspensions, granulation, dissolution or release tests, stability trials, spray drying, freeze-drying or preparation of adsorbates or complexes.

Chemistry, Pharmaceutical↗
PubMed1990

Cell banking.

The use of cultured cells (diploid strains or continuous cell lines) to produce biopharmaceuticals provides a level of standardization to the manufacturing process that cannot be attained by the more traditional methods of biological extraction from animal or human fluids, tissues, or primary cells. The key to this advantage is the ability to cryopreserve the production cell line as a master cell bank. This bank serves as the common starting source of a given product for the lifetime of the manufacture of that product. Since the MCB is the common and only starting source, it can be exhaustively characterized with regard to contamination by adventitious and endogenous agents. Assays can be developed for cellular components that are potential contaminants of the product. The removal of these components during product purification can be validated and their removal confirmed by rigorous quality control. In conclusion, characterized cell banks are central to the standardization of biopharmaceutical manufacturing processes and give rise to the production of high-quality products not attainable by the traditional methods of extraction of product from sources which are continually changing.

Animals↗
PubMed1992

[The therapeutic utilization of magnesium: medical consequences].

To optimize a pharmaceutical formulation, one has to take into account physicochemical, biopharmaceutical, therapeutical and technological properties of the active principle. These properties are investigated in the PREFORMULATION phase. The authors envisage dosage form (capsule) of magnesium and describe two aspects of the active principle: therapeutic and biopharmaceutic.

Animals↗
PubMed1999

Transmissible Spongiform Encephalopathies. Managing risk in mammalian organs, cells and sera. 15-16 March 1999, San Diego, CA, USA.

The aim of this conference was to review the risks posed by potential contamination of biopharmaceutical products with the causal agents of Transmissible Spongiform Encephalopathies (TSEs). These agents have become of particular concern with the BSE epidemic in the UK and with a proposed link between BSE and a new variant form of Creutzfeldt-Jakob disease (nvCJD) which occurs at significantly higher incidence in the UK. The conference particularly focused on the potential for contamination of products derived from human blood, where donors are clinically diagnosed as being infected with either classical CJD or nvCJD. Manufacturing steps, with the potential for the removal of TSE agents, were also discussed, along with the strategies available for demonstrating the effectiveness of such steps. Early diagnosis of TSE infection still represents the most effective strategy for the prevention of TSE contamination of biopharmaceutical products, and progress towards the development of assays with sufficient sensitivity to detect TSE contamination either in the raw start material or in donors was discussed.

Journal Article↗
PubMed1999

Therapeutic innovation.

The small but very focused meeting of 60 delegates from academia, small biopharmaceutical companies and large pharmaceutical companies aimed to give an overview of current R&D approaches in the cardiovascular disease area. Most of the new therapeutic approaches were presented by small biopharmaceutical companies and addressed disease targets in the vasculature for the following indications: thrombosis; atherosclerosis; restenosis; hyperlipidemia; and hypertension. Cardiac disease targets were addressed in the following indications: congestive heart failure (CHF); chronic angina; reperfusion injury; and atrial arrhythmia. The technologies presented included small molecule drugs, protein drugs and gene therapeutics as well as vaccines and an integrated target definition platform. The therapeutic approaches were complemented by the presentation of two innovative diagnostic products for thrombosis and stroke related brain injury.

Journal Article↗
PubMed2006

In vitro - in vivo correlation: from theory to applications.

A key goal in pharmaceutical development of dosage forms is a good understanding of the in vitro and in vivo performance of the dosage forms. One of the challenges of biopharmaceutics research is correlating in vitro drug release information of various drug formulations to the in vivo drug profiles (IVIVC). Thus the need for a tool to reliably correlate in vitro and in vivo drug release data has exceedingly increased. Such a tool shortens the drug development period, economizes the resources and leads to improved product quality. Increased activity in developing IVIVCs indicates the value of IVIVCs to the pharmaceutical industry. IVIVC can be used in the development of new pharmaceuticals to reduce the number of human studies during the formulation development as the main objective of an IVIVC is to serve as a surrogate for in vivo bioavailability and to support biowaivers. It supports and/or validates the use of dissolution methods and specification settings. This is because the IVIVC includes in vivo relevance to in vitro dissolution specifications. It can also assist in quality control for certain scale-up and post-approval changes (SUPAC). With the proliferation of modified-release products, it becomes necessary to examine the concept of IVIVC in greater depth. Investigations of IVIVC are increasingly becoming an integral part of extended release drug development. There must be some in vitro means of assuring that each batch of the same product will perform identically in vivo. This review article represents the FDA guidance, development, evaluation, and validation of an IVIVC to grant biowaivers, and to set dissolution specifications for oral dosage forms, biopharmaceutics classification systems (BCS), BCS biowaivers, application of BCS in IVIVC development and concept of mapping. The importance of dissolution media and methodology and pharmacokinetic studies in the context of IVIVC has been highlighted. The review also covers the literature examples of IVIVCs regarding internal and external validation, compendial dissolution assessment, formulation dependency of IVIVCs, and IVIVCs of pure enantiomers versus racemate drugs. The same principles of IVIVC used for oral extended release products may be applied for non-oral products such as parenteral depot formulations and novel drug delivery systems as well.

Biological Availability↗
PubMed1990

Estimating integrals using quadrature methods with an application in pharmacokinetics.

The estimation of integrals using numerical quadrature is common in many biological studies. For instance, in biopharmaceutical research the area under curves is a useful quantity in deriving pharmacokinetic parameters and in providing a surrogate measure of the total dose of a compound at a particular site. In this paper, statistical issues as separate from numerical issues are considered in choosing a quadrature rule. The class of Newton-Côtes numerical quadrature procedures is examined from the perspective of minimizing mean squared error (MSE). The MSE are examined for a variety of functions commonly encountered in pharmacokinetics. It is seen that the simplest Newton-Côtes procedure, the trapezoidal rule, frequently provides minimum MSE for a variety of concentration-time shapes and under a variety of response variance conditions. A biopharmaceutical example is presented to illustrate these considerations.

Animals↗
PubMedDate not supplied

Inhibition of lipopolysaccharide-induced TNF-alpha production by semisynthetic polymyxin-B conjugated dextran.

During episode of severe endotoxemia, concentrations of both lipopolysaccharide and its lipid A-core subfraction are liberated from gram-negative bacteria and become elevated within the systemic circulation. Lipid-A core is the most homogeneous and physiologically toxic segment of the lipopolysaccharide molecule. Polymyxin-B has profound binding avidity for the lipid A-core subfraction of lipopolysaccharide. The mechanism of this binding avidity involves the development of attractive forces between the cationic groups of polymyxin-B and the anionic groups of the lipid A-core moiety of lipopolysaccharide. Complementary attractive forces include hydrophobic interactions which additionally become established between the octylheptanoyl group of polymyxin-B and the saturated carbon chains of the lipid A-core moiety. This paper describes a method for the semisynthetic production of polymyxin-B conjugated dextran in the form of polymyxin-B.ABH.dextran applying the photoreactive crosslinking reagent azidobenzoyl hydrazide (ABH). Molecular design and development of a semisynthetic technique for the conjugation of polymyxin-B to purified dextran fractions was motivated by the pronounced nephrotoxicity associated with this cationic polypeptide antibiotic. Conjugation of polymyxin-B to a relatively large molecular weight carrier compound would increase the overall size of the complex to a degree sufficient to theoretically reduce clearance through glomerular filtration mechanisms. Attributes of such a large molecular weight polymyxin-B conjugated biopharmaceutical would include diminished levels of nephrotoxicity due to a reduction of renal tubular concentrations and a simultaneous prolongation of its intravascular half-life (t (1/2)) and pharmacokinetic profile. Lipopolysaccharide (LPS) binding avidity of polymyxin-B.ABH.dextran was verified by Dot-Blot analysis in conjunction with the application of fluorescein isothiocyanate conjugated E. coli (0.55:B5) LPS (FITC-LPS). Capacity of polymyxin-B.ABH.dextran conjugates to inhibit in vitro LIP-induced synthesis of tumor necrosis factor-alpha (TNF-alpha) was assessed by the application of a tissue culture based biological assay system capable of detecting cytotoxicity mediated by this potent monokine. Semisynthetic conjugates of polymyxin-B.ABH.dextran conjugates (0.6 microns/mL), thereby providing cytoprotectivity (95%; p < or - 0.001. to WEHI 164 clone 13 cell populations relative to untreated reference controls. Since TNF-alpha is currently believed to be the principal endogenous mediator involved in the host's inflammatory response during episodes of endotoxemia, results from these investigations provide a scientific foundation for warranting the elevation of the in vivo efficacy of large molecular weight semisynthetic polymyxin-B conjugates. Results from these investigations may ultimately lead to the application of semisynthetic polymyxin-B.ABH.dextran as a model for the molecular design of semisynthetic production of alternative biopharmaceutical or pharmaceutical agents possessing prophylactic and/or therapeutic efficacy for the management of severe endotoxemia conditions.

Animals↗
PubMed1995

[Bioadhesives: rationale, state of the art and therapeutic potential].

Pharmaceutical research is going on the way to formulate drugs in dosage forms and delivery systems able to improve their biopharmaceutical properties. For some routes of administration, among them the transmucosal ones, such improvements may be reached by increasing the time and the nature of the contact between mucosal tissues and drug dosage forms via chemical or physical bioadhesive links. Biopharmaceutical AFI Study Group efforts were oriented in analyzing the actual state of the art in the field of bioadhesive drug delivery. Rationals of use of drug dosage forms with bioadhesive properties, analytical method of control of bioadhesion (both in vitro and in vivo) and therapeutical potentialities are the matter of this review.

Animals↗
PubMedDate not supplied

Application of total organic carbon analysis to cleaning validation.

Cleaning validation is the process of assuring that cleaning procedures effectively remove residue from manufacturing equipment/facilities below a predetermined level. This is necessary to assure the quality of future products using the equipment, to prevent cross-contamination and as a GMP requirement. Currently, cleaning validation samples are measured using HPLC or spectrophotometric methods of analysis which are often time consuming and subject to a number of interferences. Total Organic Carbon (TOC) analysis is a new method which has previously only been applied to measurement of carbon residues on production surfaces for biopharmaceuticals. We have applied the TOC analysis method to a number of traditional pharmaceutical products including antibiotics, steroids, and antinauseants in addition to biopharmaceuticals. The method offers extremely low detection capability (ppm and ppb), rapid sample analysis time and therefore quick turn-around of production equipment and facilities. TOC analysis is also applicable to on-line analysis. The method allows the measurement of extraneous materials such as process intermediates, cleaning agents, and protein materials not possible by other methods.

Carbon↗