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PubMed2003

The influence of chitosan on in vitro properties of Eudragit RS microspheres.

Eudragit RS microspheres containing chitosan hydrochloride were prepared by the solvent evaporation method using acetone/liquid paraffin solvent system and their properties were compared with Eudragit RS microspheres without chitosan, prepared in our previous study. Different stirring rates were applied (400-1200 rpm) and drug content, Higuchi dissolution rate constant, surface and structure characteristics of the microspheres were determined for each size fraction. An increase in average particle size with a reduction of stirring rate appeared in limited interval in both series. The average particle size of microspheres without chitosan, prepared at the same stirring rate, was smaller. Pipemidic acid content increased with increasing fraction particle size, but not with increasing stirring rate as it was observed for microspheres without chitosan. We presume that high pipemidic acid content in larger microspheres is a consequence of cumulation of undissolved pipemidic acid particles in larger droplets during microspheres preparation procedure. Pipemidic acid release was faster from microspheres with chitosan and no correlation between Higuchi dissolution rate constant and stirring rate or fraction particle size was found, though it existed in the system without chitosan. Structure and surface characteristics of microspheres observed by scanning electron microscope (SEM) were not changed significantly by incorporation of chitosan. But in contrast with microspheres without chitosan, the surface of chitosan microspheres was more porous after three hours of dissolution. It is supposed that the influence of particle size fraction and stirring rate on release characteristics is expressed to a great extent through porosity and indirectly through total effective surface area, but the incorporation of highly soluble component i.e. chitosan salt hides these effects on drug release. In conclusion, changes in biopharmaceutical properties due to varying stirring rate and fraction particle size exhibited the same direction as those reported for the microspheres without chitosan, although they are less expressed because of increased experimental variability, likely caused by chitosan.

Acrylic Resins↗

PubMed2002

[Development and application of an Internet-based educational system to share pharmaceutical case reports between pharmacists].

For pharmacists to enhance skill of pharmaceutical cares, it is necessary to learn many instructive clinical cases, which include drug-related incidences and checks of medication errors by pharmacists. However, these cases tend to be kept in each facility and there is no access to the cases for outside pharmacists. Therefore, we aimed to develop an internet-based educational system to gather such cases, append educational commentaries by university staffs, and share them between pharmacists. An exclusive site was set up on the world wide web (WWW) homepage of the Section of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University (http://seizai.phar.kyushu-u.ac.jp) on November 2000. Browsing was limited to registered pharmacists. Any pharmacist can be freely registered. Cases were collected via WWW-forms in the site. After educational commentaries and elucidation were appended, the cases were distributed to the registered pharmacists by e-mails and WWW pages. Many applications for membership have been sent from around Japan to have more than 50 members per month, and many cases have been contributed. These cases were distributed weekly by e-mail magazines. The developed system enabled us to share many educational cases of drug-related problems all over the country. This system could contribute to pharmacists to enhance their skills of pharmaceutical cares.

Education, Pharmacy, Continuing↗

PubMed2006

Glycosylation variant analysis of recombinant human tissue plasminogen activator produced in urea-cycle-enzyme-expressing Chinese hamster ovary (CHO) cell line.

Tissue plasminogen activator (tPA) was produced in ornithine transcarbamoylase (OTC) cells by introducing the tPA gene into OTC cells. OTC cells were originally derived from Chinese hamster ovary (CHO) cells and express the first two enzymes of the urea cycle, carbamoyl phosphate synthetase I (CPS I) and OTC. To investigate glycosylation variants, tPA variants produced in serum-supplemented culture medium of OTC-tPA cells were separated by lysine-Sepharose 4B chromatography. Unlike in previous studies that used lysine-Sepharose chromatography, two peaks were identified to correspond to eluted glycosylation variants type I and II and type II and the percentages of the type I and type II variants were found to be 23% and 77%, respectively. The biological activities of the type I and II and type II variants were twofold that of the Third International tPA Standard (98/714) produced in the CHO cell line, and the activity of type II variant was 12.6% higher than that of the type I and II variants. These results demonstrate that tPA produced in urea-cycle-enzyme-producing OTC cells have a very high biological activity and the percentage of type II variant which is very valuable for the biopharmaceutical industry is higher than that of any report using CHO cells.

Animals↗

PubMedDate not supplied

Baculovirus and insect cell gene expression: review of baculovirus biotechnology.

The BEVS continues to evolve as a powerful, flexible tool for molecular biology, protein function, and biomedical research. Future developments offer the promise of replacement of hazardous chemical insecticides with environmentally safe biopesticides, construction of baculovirus vectors which encode genes for specific post-translational modifications, and establishment of efficient, stably transformed insect cell lines. FDA approval of BEVS-produced products offer the prospect of new biopharmaceuticals, in particular human therapeutics and vaccines, to improve human health and increase the quality of life for millions of people.

Animals↗

PubMed2005

Sticking to the knitting: CIHR, innovation and Canadian biotech.

The novel proposal outlined by Glenn Brimacombe suggests that the federal government directly participate in funding incremental venture capital investment in Canadian biotechnology, with the goal of facilitating commercialization of Canadian biotechnology and health sciences intellectual property. In this way, they suggest, the economic development benefits of the Canadian current investment in health sciences will be increased. The proposal is based on two premises that need further evaluation: (1) the biotechnology sector in Canada presently underperforms in terms of value creation; (2) this underperformance is due to inadequate venture capital investment. It is the author's view that, although several measures do suggest relative system underperformance, this is likely due to structural differences rather than inadequate venture capital investment. The absence of large, integrated, global biopharmaceutical firms based in Canada, the large number of very small biotech firms and the absence of a clear federal policy mandate supporting technology transfer and underinvestment in public sector funded basic research may all be contributory factors. Given the Canadian biotech sector's current efficiency at creating value from limited public investment in basic science, increasing the core CIHR budget might be an even better investment opportunity for limited incremental funding.

Biotechnology↗

PubMedDate not supplied

An overview of immunomodulatory intervention in rheumatoid arthritis.

In recent years there has been exceptional progress in the development of immunomodulatory interventions for the treatment of rheumatoid arthritis (RA). Part of the impetus for the creation of novel therapies for RA has come from a growing appreciation of the substantial morbidity and mortality that this chronic, progressive disease causes for affected patients. In addition, there has been the realization that currently available therapeutics are suboptimal as regards both their efficacy and tolerability. The development of newer therapies has been facilitated by two factors; a greater understanding of the immunopathogenesis of RA and progress in biotechnology that has allowed the creation of specific inhibitors and other agents. Myriad studies performed by investigators throughout the world have helped delineate the immunologic basis of RA. It appears that various components of the immune system are involved in the initiation and propagation of this systemic inflammatory disease. T-cells, and in particular activated CD4(+) 'memory' T-cells, serve a central role in orchestrating the immune response that underlies rheumatoid inflammation. Other cells, including monocytes, fibroblasts, B-cells, dendritic cells, mast cells and neutrophils also contribute significantly to various aspects of disease. Adhesion molecules mediate many intercellular interactions, thus contributing to activities such as the accrual of cells within the synovium and the activation of cells. Cytokines, small peptides that exert numerous inflammatory activities and cause many of the signs and symptoms of RA, play a crucial role. Indeed, RA may be considered a disorder of 'cytokine dysregulation' in that the activity of proinflammatory cytokines such as TNF-alpha and IL-1 is enhanced, and overwhelms the effects of antiinflammatory factors. Finally, a host of other inflammatory mediators are involved in the disease process. Thus, many components of the immune response may be attractive therapeutic targets for immunomodulatory intervention in RA. Advances in biotechnology have permitted the creation of specific inhibitors of distinct components of the immune system. Monoclonal antibodies (MAbs) have been created to target various cell surface molecules and cytokines. At first, most MAbs were murine in origin, which can present problems as regards immunogenicity. More recently, progress in molecular biologic techniques has allowed the synthesis of hybrid antibodies that are partly human. Such techniques have also allowed the creation of cytokine receptors coupled to immunoglobulin molecules, and other constructs. These agents can be modified to provide optimal characteristics in terms of half-life, immunogenicity and specificity, and this is an exciting area of new development. Progress has also been made in molecular-based agents that directly modify the genes or gene products for specific targets. To date, a number of trials assessing novel immunomodulatory therapies have been undertaken. In some cases, such as with inhibitors of TNF-alpha, the results have been dramatic and exciting. Further development and refinement may allow the introduction of these agents into the clinic in the foreseeable future, and will provide an important area for further research. In other cases, for example with therapies targeting CD4(+) molecules, the results have not been as promising as was hoped. Nevertheless, critical analysis of the results of these studies has provided insights into the pathogenesis of RA which may prove quite valuable for future trials. A number of agents are being studied actively at the present time, and it is hoped that they too may generate novel therapies for, and a greater understanding of, this difficult disease. The future for immunomodulatory intervention in RA looks very promising. Greater understanding of the intricacies of the immune response that underlie this disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. This should allow the clinician truly to modify the disease and achieve tangible improvements in the lives of RA patients.

Journal Article↗

PubMed2026

4D-DIA proteomics reveals distinct proteolytic landscapes induced by mechanical stress, Agrobacterium, and a viral capsid precursor.

Nicotiana benthamiana is a widely used platform for plant molecular farming, yet recombinant protein yields are frequently compromised by the host's innate defense mechanisms, particularly proteolytic degradation. While the general effects of Agroinfiltration are known, the distinct contributions of mechanical injury, bacterial perception, and product-specific stress remain poorly resolved. Here we utilized high-depth 4D-DIA proteomics to dissect the host response across three dimensions: physical stress (buffer infiltration), pathogen-associated stress (Agrobacterium), and product-associated stress (GFP vs. the FMDV capsid precursor P1_2A). We demonstrate that buffer infiltration is not a neutral event but an independent inducer of cell wall remodeling and oxidative stress. By filtering out these background effects, we defined a core Agrobacterium-responsive proteome characterized by a growth-defense trade-off. We also expanded the known protease repertoire of N. benthamiana to 1,505 enzymes through improved genomic annotation. We found that the expression of the FMDV capsid precursor P1_2A was associated with a distinct and more pronounced protease profile compared to soluble GFP, characterized by the upregulation of subtilases and cysteine proteases. These findings suggest that host proteolytic responses vary with the recombinant cargo, a factor worth considering when designing engineering strategies for the production of complex biopharmaceuticals in plants.

Proteomics↗

PubMedDate not supplied

The shifting functional balance of patents and drug regulation.

Patents are often portrayed as the necessary reward to compensate pharmaceutical firms for the huge costs and risks associated with Food and Drug Administration (FDA)-mandated clinical trials of new drugs. But the relationship between the patent system and other regulation of drugs is more complex than this simple formulation suggests. Drug regulation operates in tandem with patents to make proprietary products profitable, and patents themselves increasingly threaten to limit profitability by diverting profits elsewhere. At the same time, resistance to high drug prices is prompting new state and federal regulatory initiatives that threaten to reduce the value of drug patents. The distinctive intertwining of patents with other regulatory regimes and the shifting role of patents in the biopharmaceutical sector call into question how this singular success story for innovation policy will play out in the future.

Drug Approval↗

PubMed2004

Inducible gene expression in mammalian cells and mice.

Inducible expression of desired transgenes in mammalian cells and animals is a current priority in basic and applied research, biopharmaceutical manufacturing, gene therapy, and tissue engineering, as well as in drug discovery. Among the most prominent human-compatible transgene control technologies are engineered promoter/transactivator configurations that adjust heterologous target gene transcription in response to clinically licensed antibiotics (tetracyclines, streptogramins, macrolides). In this chapter we provide a detailed case study on macrolide-inducible expression of the human model glycoprotein SEAP (human placental secreted alkaline phosphatase) in transgenic Chinese hamster ovary (CHO) cell cultures or following implantation of microencapsulated CHO cells into mice.

Animals↗

PubMed2006

Chloroplast genetic engineering via organogenesis or somatic embryogenesis.

Chloroplast genetic engineering offers a number of unique advantages, including high-level transgene expression, multigene engineering in a single transformation event, transgene containment via maternal inheritance, lack of gene silencing, position and pleiotropic effects and undesirable foreign DNA. More than 40 transgenes have been stably integrated and expressed via the tobacco chloroplast genome to confer desired agronomic traits or express high levels of vaccine antigens and biopharmaceuticals. Despite such significant progress, this technology has not been extended to other important plant species. For example, Arabidopsis may be an ideal model system for chloroplast functional genomics. The employment of chloroplast transformation technology in Arabidopsis has been hampered by the lack of an efficient and reproducible protocol that provides fertile chloroplast transgenic plants. Transformation of the Arabidopsis chloroplast genome was achieved via organogenesis but the efficiency was at least a 100-fold lower than in tobacco and had the drawback of polyploidy in the leaf tissue that resulted in sterile transgenic plants. This problem can be overcome by adapting procedures that are now available to regenerate plants from both diploid and tetraploid explants via callus. In addition, it is feasible to regenerate Arabidopsis via somatic embryogenesis. Recent breakthroughs in highly efficient plastid transformation of recalcitrant crops such as cotton and soybean have opened the possibility of engineering Arabidopsis plastid genome via somatic embryogenesis. Therefore, protocols of recent improvements in tissue culture, DNA delivery, and the novel vector designs are provided here in order to achieve highly efficient plastid transformation in Arabidopsis.

Arabidopsis↗

PubMed2006

LONG R3IGF-I as a more potent alternative to insulin in serum-free culture of HEK293 cells.

LONG R3IGF-I, an analogue of insulin-like growth factor (IGF)-I, was specifically engineered for use in biopharmaceutical protein production in mammalian cells. LONG R3IGF-I is capable of supporting the growth and survival of Chinese hamster ovary cells in serum-free media at concentrations at least 200-fold lower than required for insulin. LONG R3IGF-I also acts as a more potent growth and survival factor than either insulin or native IGF-I in SF culture of human embryonic kidney (HEK293) cells. To investigate the basis of the enhanced potency of LONG R3IGF-I we have examined the mechanism of action of these mitogens in HEK293 cells. All mitogens tested were found to activate the Type I IGF receptor (IGF-IR) and insulin receptor (IR) in a dose-responsive manner. However, the level of activation of both receptors after stimulation with LONG R3IGF-I, at lower concentrations, was greater than with either insulin or IGF-I. The greater potency of LONG R3IGF-I in activating the IR, despite having a low affinity for IRs, suggests the presence of heterotetrameric IGF-IR/IR dimers. Interestingly, the decrease in IGF-IR activation at higher concentrations of LONG R3IGF-I suggests that the dose-response curve may be bell-shaped.

Cells, Cultured↗

PubMed2003

Delivery strategies for antiparasitics.

Optimisation of drug carrier systems and drug delivery strategies that take into account the peculiarities of individual infectious agents and diseases are key elements of modern drug development. In the following, different aspects of a rational design for antiparasitic drug formulation will be reviewed, covering delivery systems such as nano- and microparticles, liposomes, emulsions and microemulsions, cochleates and bioadhesive macromolecules. Functional properties for each carrier system will be discussed as well as their therapeutic efficacy for parasitic diseases, including leishmaniasis, human African trypanosomiasis, human cryptosporidiosis, malaria and schistosomiasis. Critical issues for the application of drug carrier systems will be discussed, focusing on biopharmaceutical and pathophysiological parameters such as routes of application, improvement of body distribution and targeting intracellularly persisting pathogens.

Administration, Cutaneous↗

PubMed2002

Genaissance pharmaceuticals, inc.

Genaissance Pharmaceuticals, Inc. (Nasdaq: GNSC) is the world leader in the discovery and use of gene variation for the development of personalized medicines. In addition, the company has established partnerships with some of the world's top biopharmaceutical companies. The company has initiated the development of its own pipeline of products -- HAP Clozapine for schizophrenia and HAP Statin for cholesterol management -- utilizing its proprietary genetic markers. The company also markets its technology and clinical development skills to the pharmaceutical industry as a complete solution for improving the development, marketing and prescribing of drugs.

Cooperative Behavior↗

PubMed2002

Variagenics, inc.

Variagenics, Inc. develops molecular diagnostic tests by identifying genetic markers associated with response to cancer therapies, with the goal of optimizing patient care. Toward this end, the company analyzes genetic variations in both normal and tumor cells, including SNPs, haplotypes, loss of heterozygosity, and gene expression levels. The company's approach of analyzing multiple types of genetic variations increases the likelihood of finding significant associations with drug response and successfully developing diagnostics. Variagenics is pursuing marker identification and diagnostic development through both biopharmaceutical collaborations and internal research programs.

Antineoplastic Agents↗

PubMed2004

Functional informatics: convergence and integration of automation and bioinformatics.

The biopharmaceutical industry is currently being presented with opportunities to improve research and business efficiency via automation and the integration of various systems. In the examples discussed, industrial high-throughput screening systems are integrated with functional tools and bioinformatics to facilitate target and biomarker identification and validation. These integrative functional approaches generate value-added opportunities by leveraging available automation and information technologies into new applications that are broadly applicable to different types of projects, and by improving the overall research and development and business efficiency via the integration of various systems.

Automation↗

PubMed2001

Recombinant antibodies for cancer diagnosis and therapy.

Recombinant antibodies now represent over 30% of biopharmaceuticals in clinical trials, highlighted by the recent approvals for cancer immunotherapy from the FDA which has awoken the biotechnology industry. Sales of these antibodies are increasing very rapidly to a predicted US$ 3 billion per annum worldwide by 2002. Since the development of new therapeutic reagent into commercial product takes 10 years, the recent FDA-approved antibodies are based on early antibody designs which are now considered primitive. Emerging technologies have created a vast range of novel, recombinant, antibody-based reagents which specifically target clinical biomarkers of disease. In the past year, radiolabelling of antibodies has increased their potential for cancer imaging and targeting. Recombinant antibodies have also been reduced in size and rebuilt into multivalent molecules for higher affinity. In addition, antibodies have been fused with many molecules including toxins, enzymes and viruses for prodrug therapy, cancer treatment and gene delivery. Recombinant antibody technology has enabled clever manipulations in the construction of complex antibody library repertoires for the selection of high-affinity reagents against refractory targets. Although phage display remains the most extensively used method, this year high affinity reagents have been isolated using alternative display and selection systems such as ribosome display and yeast display confirming the emergence of new display methods. Furthermore, innovative affinity maturation strategies have been developed to obtain high affinity reagents. This review focuses on developments in the last 12 months and describes the latest developments in the design, production and clinical use of recombinant antibodies for cancer diagnosis and therapy.

Animals↗

PubMed2002

Current prodrug strategies via membrane transporters/receptors.

Prodrug design strategies have been employed to improve the delivery of drugs with undesirable pharmacokinetic properties such as chemical stability and lack of specificity. Targeted prodrug design represents a new strategy for site-directed and efficient drug delivery. Targeting of drugs to transporters and receptors to aid in site-specific carrier-mediated absorption is emerging as a novel and clinically significant approach. Various prodrugs have been successful in achieving the goals of enhanced bioavailability and are, therefore, considered to be an important tool in biopharmaceutics. This review highlights the advances in prodrug design targeted towards membrane transporters/receptors in the past few years.

Acyclovir↗

PubMed2003

Recombinant antibodies for cancer diagnosis and therapy.

Recombinant antibodies currently represent over 30% of biopharmaceuticals in clinical trials, highlighted by the recent Food and Drug Administration (FDA) approvals of Zevalin(TM) (ibritumomab-tiuxetan; IDEC Pharmaceuticals, San Dieago, CA, USA) for cancer radioimmunotherapy and Humira(TM) (adalimumab; Abbott Laboratories, IL, USA) for rheumatoid arthritis. Together, these FDA approvals have excited the biotechnology industry, particularly since sales of recombinant antibodies are increasing rapidly to a predicted US dollar 4 billion per annum worldwide in 2003. To date, 10 engineered therapeutic antibodies have gained FDA approval and many others are in Phase III trials. Many recent FDA-approved antibodies are simple molecular designs that have taken 10 years to be developed into effective therapeutic reagents. Emerging new technologies have created a vast range of recombinant, antibody-based reagents, which specifically target clinical biomarkers of disease. Radiolabelling of antibodies has increased their potential for cancer imaging and targeting. Recombinant antibodies have also been reduced in size and rebuilt into multivalent molecules for higher affinity. In addition, antibodies have been fused with many molecules, including toxins, enzymes, drugs and viruses, for prodrug therapy, cancer treatment and gene delivery. Recombinant antibody technology has enabled clever manipulations in the construction of complex in vitro libraries for the selection of high-affinity reagents against refractory targets. Furthermore, innovative affinity maturation methods have been developed which enable rapid selection of extremely high-affinity reagents. This review focuses on developments in the last 12 months and describes the latest developments in the design, production and clinical use of recombinant antibodies for cancer diagnosis and therapy.

Animals↗