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At least 1,063 records · Page 59Linked to original sources

PubMed2005

Adventitial dysfunction: an evolutionary model for understanding atherosclerosis.

Endothelial and smooth muscle dysfunctions are widely implicated in the pathogenesis of atherosclerosis. Modern mechanical and pharmacologic treatments aim to remodel abnormalities of the vessel intima and media. We hypothesize that adventitial dysfunction comprises the dominant source of atherosclerosis by originating many endothelial and smooth muscle abnormalities. The autonomic nervous system innervates the adventitia, and autonomic dysfunction induces many end-organ dysfunctions including inflammation and thrombosis. The link between diabetes and atherosclerosis may operate through adventitial autonomic neuropathy. Smoking may promote atherosclerosis by inducing adventitial autonomic dysfunction related to nicotine-mediated compensatory upregulation of sympathetic bias independent of endothelial injury induced by purported tobacco toxins. While hypertension is thought to cause atherosclerosis, the two conditions may instead represent independent consequences of autonomic dysfunction. The link between aging and atherosclerosis may operate through adventitial dysfunction induced by autonomic dysregulations. Exercise may ameliorate atherosclerosis by restoring adventitial autonomic function, thereby normalizing adventitial regulation of medial and intimal biology. Feed-forward adventitial vascular baroreceptor and chemoreceptor dysregulation may further exacerbate atherosclerosis as intimal plaque interferes with these sensors. Since penetrating external physical injury likely represented a dominant selective force during evolution, the adventitia may be preferentially equipped with sensors and response systems for vessel trauma. The convergent response of adrenergia, inflammation, and coagulation, which is adaptive for physical trauma, may be maladaptive today when different stressors trigger the cascade. Endoluminal therapies including atherectomy, angioplasty, and stent deployment involve balloon expansion that traumatizes all layers of the vessel wall. These interventions may paradoxically reinitiate the cascade of atherogenesis that begins with adventitial dysfunction and leads to restenosis. Methods to reduce adventitial trauma, a maladaptive trigger of adventitial dysfunction, may reduce the risk of restenosis. We envision novel mechanical and biopharmaceutical solutions that target the adventitia to prevent or treat atherosclerosis including novel drug delivery strategies, exo-stents that wrap vessels, and neuromodulation of vessels.

Animals↗

PubMed2005

Virus-encoded chemokine receptors--putative novel antiviral drug targets.

Large DNA viruses, in particular herpes- and poxviruses, have evolved proteins that serve as mimics or decoys for endogenous proteins in the host. The chemokines and their receptors serve key functions in both innate and adaptive immunity through control of leukocyte trafficking, and have as such a paramount role in the antiviral immune responses. It is therefore not surprising that viruses have found ways to exploit and subvert the chemokine system by means of molecular mimicry. By ancient acts of molecular piracy and by induction and suppression of endogenous genes, viruses have utilized chemokines and their receptors to serve a variety of roles in viral life-cycle. This review focuses on the pharmacology of virus-encoded chemokine receptors, yet also the family of virus-encoded chemokines and chemokine-binding proteins will be touched upon. Key properties of the virus-encoded receptors, compared to their closest endogenous homologs, are interactions with a wider range of chemokines, which can act as agonists, antagonists and inverse agonists, and the exploitation of many signal transduction pathways. High constitutive activity is another key property of some--but not all--of these receptors. The chemokine receptors belong to the superfamily of G-protein coupled 7TM receptors that per se are excellent drug targets. At present, non-peptide antagonists have been developed against many chemokine receptors. The potentials of the virus-encoded chemokine receptors as drug targets--ie. as novel antiviral strategies--will be highlighted here together with the potentials of the virus-encoded chemokines and chemokine-binding proteins as novel anti-inflammatory biopharmaceutical strategies.

Animals↗

PubMed2007

Carisbamate (RWJ-333369).

Carisbamate (RWJ-333369) is a novel neuromodulator, initially developed by SK Biopharmaceuticals (Fairlawn, NJ), under development by Johnson & Johnson Pharmaceutical Research and Development (La Jolla, CA). Carisbamate displays high potency in a broad range of rodent seizure models at doses well below those that produce CNS toxicity. Its mechanism of action has not been elucidated. Acute and chronic nonclinical toxicological studies have not revealed any significant abnormalities other than dose-related CNS toxicity. It is extensively metabolized, chiefly through glucuronidation and oxidation of the aliphatic side chain. There is little evidence of CYP metabolism. It has linear pharmacokinetics. Its clearance is increased by carbamazepine and to a lesser degree by oral contraceptives. Carisbamate slightly increases the clearance of valproic acid and lamotrigine. The most common adverse events in humans are headaches, dizziness, and somnolence, generally mild to moderate, occurring at doses of 1000 mg/day or more. A recently completed phase 2 study for adjunctive use in partial onset seizures showed efficacy at a dose that was well tolerated.

Animals↗

PubMed2004

In vitro protein refolding by chromatographic procedures.

In vitro protein refolding is still a bottleneck in both structural biology and in the development of new biopharmaceuticals, especially for commercially important polypeptides that are overexpressed in Escherichia coli. This review focuses on protein refolding methods based on column procedures because recent advances in chromatographic refolding have shown promising results.

Chaperonins↗

PubMed2004

Purification and characterization of a recombinant version of human alpha-fetoprotein expressed in the milk of transgenic goats.

Alpha-Fetoprotein (AFP) is a 68 kDa glycoprotein expressed at high levels by the fetal liver and yolk with transcription repressed to very low levels after birth. Transfer of fetal AFP through the placenta into the circulation of the mother is correlated with remission of rheumatoid arthritis, multiple sclerosis, and other autoimmune disorders. AFP is therefore under development as a biopharmaceutical for the treatment of autoimmune diseases. The clinical evaluation of AFP requires the production of hundreds of grams of highly purified and biologically active protein. We have produced goats that express a form of the human AFP transgene under the control of the beta-casein promoter. In this form of rhAFP, the single N-linked glycosylation site was removed by mutagenesis (N233Q). Here, we describe a purification protocol for this recombinant human (rh)AFP from the milk of these transgenic goats. A three-column procedure was developed to produce gram quantities of highly purified rhAFP. Near- and far-UV circular dichroism spectra of human umbilical cord blood AFP and rhAFP were essentially identical, suggesting that the structure is not affected by removal of the glycosylation site. Furthermore, the cell binding and pharmacokinetics of purified rhAFP were similar to human AFP isolated from cord blood. Our results demonstrate that an active form of rhAFP can be produced on industrial scale by expression in transgenic goat milk.

Animals↗

PubMed2006

High-level expression of human lactoferrin in the milk of goats by using replication-defective adenoviral vectors.

The expression of human lactoferrin in the mammary gland is an attractive approach to diminish its current production cost. Previous attempts to produce lactorferrin in the milk of transgenic animals resulted in very high cost and uncertain results. In this paper, we have directly infused replication-defective adenovirus encoding human lactoferrin cDNA into the mammary gland of goats via the teat canal. In this way, we obtained a high level of expressed human lactoferrin up to 2g/L in the milk of goats. The milk serum was collected from the infected mammary gland 48 h post-infection and subjected to a 10% SDS-PAGE and Western blotting. A approximately 80-kDa protein was visualized after viral vector infection. Our results demonstrate that intraductal injection of recombinant replication-defective adenovirus vectors may provide a very useful tool for large-scale production of recombinant proteins of biopharmaceutical interest.

Adenoviridae↗

PubMed2005

Flavones and flavone synthases.

Within the secondary metabolite class of flavonoids which consist of more than 9000 known structures, flavones define one of the largest subgroups. Their natural distribution is demonstrated for almost all plant tissues. Various flavone aglyca and their O- or C-glycosides have been described in the literature. The diverse functions of flavones in plants as well as their various roles in the interaction with other organisms offer many potential applications, not only in plant breeding but also in ecology, agriculture and human nutrition and pharmacology. In this context, the antioxidative activity of flavones, their use in cancer prevention and treatment as well as the prevention of coronary heart disease should be emphasized. The therapeutic potential of flavones makes these compounds valuable targets for drug design, including recombinant DNA approaches. The biosynthesis of flavones in plants was found to be catalyzed by two completely different flavone synthase proteins (FNS), a unique feature within the flavonoids. The first, FNS I, a soluble dioxygenase, was only described for members of the Apiaceae family so far. The second, FNS II, a membrane bound cytochrome P450 enzyme, has been found in all other flavone accumulating tissues. This phenomenon is particularly of interest from the evolutionary point of view concerning the flavone biosynthesis and functions in plants. Recently, FNS I and FNS II genes have been cloned from a number of plant species. This now enables detailed biochemical and molecular characterizations and also the development of direct metabolic engineering strategies for modifications of flavone synthesis in plants to improve their nutritional and/or biopharmaceutical value.

Antineoplastic Agents↗

PubMed2004

Processing of plasmid DNA with ColE1-like replication origin.

With the increasing utilization of plasmid DNA as a biopharmaceutical drug, there is a rapidly growing need for high quality plasmid DNA for drug applications. Although there are several different kinds of replication origins, ColE1-like replication origin is the most extensively used origin in biotechnology. This review addresses problems in upstream and downstream processing of plasmid DNA with ColE1-like origin as drug applications. In upstream processing of plasmid DNA, regulation of replication of ColE1-like origin was discussed. In downstream processing of plasmid DNA, we analyzed simple, robust, and scalable methods, which can be used in the efficient production of pharmaceutical-grade plasmid DNA.

Bacterial Proteins↗

PubMedDate not supplied

Determinants of eye drop size.

Ophthalmic solutions are available for multidose or single-dose administration in a wide variety of glass and plastic dropper bottles which deliver drops with a volume between 25 and 70 microl. From a biopharmaceutical and economic point of view, however, smaller volumes of 5 to 15 microl should be instilled. In this review, the technical, pharmaceutical, and therapeutic aspects of eye drop formation and delivery are presented. The different types of containers are described and the determinants of eye drop size are discussed, such as the design and physical characteristics of the dropper tip and bottle, the physico-chemical properties of the solution, and the manner in which the patient dispenses the drops. Preferred and alternative instillation techniques and aids to facilitate the administration of eye drops by elderly patients are described.

Chemistry, Pharmaceutical↗

PubMed2004

When biotech proteins go off-patent.

The patents of the first generation of biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins are expiring, opening up the possibility for competitors to introduce biosimilar products. The concept of generics that applies to classical drugs and allows market admission on limited documentation cannot be extrapolated to these "off-patent biologics". Physicochemical characterization, bioassays and animals studies do not predict completely the efficacy and safety of therapeutic proteins. Clinical studies will nearly always be necessary to obtain marketing authorization for off-patent biologics. Immunogenicity is considered to be the main problem with therapeutic proteins. The recent upsurge of pure red cell aplasia (PRCA), a severe form of anemia associated with the use of epoietin-alpha, highlights both the unpredictability and the severe consequences of immunogenicity. A risk-based approach can be used to evaluate the potential induction of antibodies by off-patent biologics.

Animals↗

PubMed2005

Breakthrough in chloroplast genetic engineering of agronomically important crops.

Chloroplast genetic engineering offers several unique advantages, including high-level transgene expression, multi-gene engineering in a single transformation event and transgene containment by maternal inheritance, as well as a lack of gene silencing, position and pleiotropic effects and undesirable foreign DNA. More than 40 transgenes have been stably integrated and expressed using 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 major crops. However, highly efficient soybean, carrot and cotton plastid transformation has recently been accomplished through somatic embryogenesis using species-specific chloroplast vectors. This review focuses on recent exciting developments in this field and offers directions for further research and development.

Crops, Agricultural↗

PubMed2006

Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells.

Recombinant proteins form an increasingly large part of the portfolio of biopharmaceutical companies. Production of these often complex transgenic proteins is achieved predominantly in mammalian cell lines but the process is hampered by low yields and unstable expression. Some of these problems are caused by gene silencing at the level of chromatin - so-called epigenetic gene silencing. Here, we describe approaches, which have emerged during the past few years, designed to interfere with epigenetic gene silencing with the aim of enhancing and stabilizing transgene expression. These include targeting histones, the inclusion of specific DNA elements and targeting sites of high gene-expression. We conclude that employing epigenetic gene regulation tools, in combination with further process optimization, might represent the next step forward in the production of therapeutic proteins.

Animals↗

PubMed2006

Harnessing phage and ribosome display for antibody optimisation.

Therapeutic antibodies have become a major driving force for the biopharmaceutical industry; therefore, the discovery and development of safe and efficacious antibody leads have become competitive processes. Phage and ribosome display are ideal tools for the generation of such molecules and have already delivered an approved drug as well as a multitude of clinical candidates. Because they are capable of searching billions of antibody variants in tailored combinatorial libraries, they are particularly applicable to potency optimisation. In conjunction with targeted, random or semi-rational mutagenesis strategies, they deliver large panels of potent antibody leads. This review introduces the two technologies, compares them with respect to their use in antibody optimisation and highlights how they can be exploited for the successful and efficient generation of putative drug candidates.

Antibodies↗

PubMed2006

Granulocyte and granulocyte macrophage colony-stimulating factors as therapy in human and veterinary medicine.

Granulocyte colony-stimulating factors (G-CSFs) and granulocyte macrophage colony-stimulating factors (GM-CSFs) are endogenous cytokines that regulate granulocyte colonies and play a major role in the stimulation of granulopoiesis (neutrophils, basophils and eosinophils) and in the regulation of microbicidal functions. There are numerous pathological conditions in which neutrophils are decreased, the most common being neutropenia associated with cancer chemotherapy, which increases the risk of serious microbial infections developing with the potential for high morbidity and mortality. New methods in molecular biology have led to the identification and cloning of CSF genes and biopharmaceutical production. Since then, CSFs have been widely used for the prevention and treatment of neutropenia associated with cancer chemotherapy, for mobilising haematopoietic cell precursors, and for other neutropenia-related pathologies. This review focuses on the use of CSFs within both human and veterinary medicine. Clinical applications, pharmacology, tolerability and the potential role of these factors in veterinary medicine are considered.

Animals↗

PubMed2005

Preventing transmission: plant-derived microbicides and mucosal vaccines for reproductive health.

Exclusion of infectious agents from mucosal surfaces of the reproductive tract is a key objective of microbicides and mucosal vaccines. With mucosal antibodies as a common mechanism of exclusion, parallel development of passive and active immunization strategies is an opportunity to determine and achieve protective antibody concentrations in the female reproductive tract. Recognizing that access to sexual and reproductive health products will require low-cost and high-capacity production technologies, the emerging tools of plant biotechnology for complex biopharmaceutical production are crucial. Unfortunately, few preclinical or clinical studies have been completed to date with plant-derived agents intended for reproductive health.

Animals↗

PubMed2006

State of the art in developing allergen vaccines in Cuba: prospects of novel adjuvanted vaccines.

Standardized allergen vaccines have been developed and registered as biopharmaceutical products in Cuba. Three different vaccines were obtained from the most relevant allergenic mite species: Dermatophagoides pteronvssinus, Dermatophagoides siboney, and Blomia tropicalis. Immuno-analytical methods based on murine monoclonal antibodies and human IgE antibodies were developed for assessing allergenic potency, composition, and stability. Preclinical and clinical studies showed efficacy and safety in diagnostic prick-tests and subcutaneous immunotherapy in asthmatic patients. New approaches are now undertaken in order to develop new adjuvanted formulations based on liposomes or proteoliposomes from Neisseria meningitidis, and purified allergens; aiming to overcome the drawbacks of conventional immunotherapy.

Adjuvants, Immunologic↗

PubMed2005

16S rRNA gene probe quantitates residual host cell DNA in pharmaceutical-grade plasmid DNA.

The development and widespread use of DNA-based vaccination against infectious pathogens have been a great triumph of medical science. Quality control of DNA vaccines as biopharmaceutical productions is a problem to solve. Residual genomic DNA of engineering bacteria has been identified as a potential risk factor, so whose level must be controlled under the regulatory standards. We report a dot-blot hybridization method to detect residual host cell DNA in purified DNA vaccines. The assay utilizes PCR amplified and digoxigenin-labeled Escherichia coli 16S rRNA gene as probe. The sensitivity of the dot-blot hybridization assay with E. coli 16S rRNA gene probe was evaluated in comparison with single copy UidR gene probe. The optimized dot-blot hybridization assay had both low background and a suitable sensitivity, detecting 10 pg of residual E. coli DNA. The method is suitable in the routine use of measuring the levels of residual E. coli DNA in the pharmaceutical-grade DNA vaccine.

DNA↗

PubMed2006

Chapter 23: International Standard reagents for harmonization of HPV serology and DNA assays--an update.

International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority.

Humans↗