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PubMed2004

Targeted knockouts of Physcomitrella lacking plant-specific immunogenic N-glycans.

Using plants as production factories for therapeutic proteins requires modification of their N-glycosylation pattern because of the immunogenicity of plant-specific sugar residues. In an attempt towards such humanization, we disrupted the genes for alpha1,3-fucosyltransferase and beta1,2-xylosyltransferase in Physcomitrella patens by homologous recombination. The single Deltafuc-t and Deltaxyl-t plants, as well as the double knockout, lacked transcripts of the corresponding genes, but did not differ from the wild-type moss in morphology, growth, development, and ability to secrete a recombinant protein, the human vascular endothelial growth factor VEGF(121), into the culture medium. N-Glycan analysis, however, revealed the absence of 1,3-fucosyl and/or 1,2-xylosyl residues, respectively. Therefore, the modifications described here represent the key step towards the generation of moss lines suitable for the production of plant-made glycosylated biopharmaceuticals with nonallergenic N-glycans.

Journal Article↗

PubMed2006

Transgenic expression and recovery of biologically active recombinant human insulin from Arabidopsis thaliana seeds.

The increased incidence of diabetes, coupled with the introduction of alternative delivery methods that rely on higher doses, is expected to result in a substantial escalation in the demand for affordable insulin in the future. Limitations in the capacity and economics of production will make it difficult for current manufacturing technologies to meet this demand. We have developed a novel expression and recovery technology for the economical manufacture of biopharmaceuticals from oilseeds. Using this technology, recombinant human precursor insulin was expressed in transgenic plants. Plant-derived insulin accumulates to significant levels in transgenic seed (0.13% total seed protein) and can be enzymatically treated in vitro to generate a product with a mass identical to that of the predicted product, DesB(30)-insulin. The biological activity of this product in vivo and in vitro was demonstrated using an insulin tolerance test in mice and phosphorylation assay performed in a mammalian cell culture system, respectively.

Animals↗

PubMed2005

Formulations of hydrogels and lipogels with vitamin E.

Vitamin E, a topically administered antioxidant, reduces erythema, photoaging, photocarcinogenesis, edema, and skin hypersensitivity associated with exposure to ultraviolet B (UVB) radiation. Virgin olive oil, which also has antioxidant properties, reduces the number of, and delays the onset of skin cancer induced by UVB radiation when used after sunbathing. Topical use after sunbathing of formulations that contain virgin olive oil and vitamin E may therefore reduce the number and delay the onset of UVB-related skin cancer in humans. We designed formulations of gels with olive oil (lipogels) and hydrogels containing 2% tocopherol. The formulations were optimized on the basis of rheological, organoleptic, biopharmaceutical, and cosmetic criteria. Different formulae for hydrogels with vitamin E were ideal for application after exposure to solar radiation because of their good organoleptic properties. Vitamin E lipogels are of potential use in cosmetics such as locally acting anti-aging treatments because of the antioxidant effects of vitamin E.

Journal Article↗

PubMed2006

Molecular medicine, the Medicare drug benefit, and the need for cost control.

The implementation of Medicare Part D, although successful in improving access to prescription drugs for millions of beneficiaries, will lead to a marked escalation in the cost of the Medicare program. An important component of the rise in costs will be specialty pharmaceuticals, including a group of drugs that are self-administered and that cost at least 1,000 dollars/month. The rate of growth in expenditures on specialty pharmaceuticals has been 34% per year. Although all these drugs confer benefits, the degree of benefit varies from dramatic (e.g., imatinib for chronic myelogenous leukemia) to cost-effective (e.g., tumor necrosis factor-alpha blockers for rheumatoid arthritis) to more modest (e.g., disease-modifying drugs used in multiple sclerosis). Historically, when costs within the Medicare program have risen, Congress has enacted price controls, as it did with hospitalization, physician services, and outpatient care. The Medicare Modernization Act (MMA) currently prohibits such an approach. Resorting instead to competition from generic drugs will be of little utility, because there is currently no mechanism to allow biogeneric drugs and patents in the biopharmaceutical industry to limit competition. Controlling the cost of the Medicare Part D program, as dramatically illustrated by the case of specialty pharmaceuticals, will require patent reform, giving the Food and Drug Administration jurisdiction over biogenerics, and amending the MMA to allow the Centers for Medicare and Medicaid Services to institute price controls.

Aged↗

PubMed2006

The CssRS two-component regulatory system controls a general secretion stress response in Bacillus subtilis.

Bacillus species are valuable producers of industrial enzymes and biopharmaceuticals, because they can secrete large quantities of high-quality proteins directly into the growth medium. This requires the concerted action of quality control factors, such as folding catalysts and 'cleaning proteases'. The expression of two important cleaning proteases, HtrA and HtrB, of Bacillus subtilis is controlled by the CssRS two-component regulatory system. The induced CssRS-dependent expression of htrA and htrB has been defined as a protein secretion stress response, because it can be triggered by high-level production of secreted alpha-amylases. It was not known whether translocation of these alpha-amylases across the membrane is required to trigger a secretion stress response or whether other secretory proteins can also activate this response. These studies show for the first time that the CssRS-dependent response is a general secretion stress response which can be triggered by both homologous and heterologous secretory proteins. As demonstrated by high-level production of a nontranslocated variant of the alpha-amylase, AmyQ, membrane translocation of secretory proteins is required to elicit this general protein secretion stress response. Studies with two other secretory reporter proteins, lipase A of B. subtilis and human interleukin-3, show that the intensity of the protein secretion stress response only partly reflects the production levels of the respective proteins. Importantly, degradation of human interleukin-3 by extracellular proteases has a major impact on the production level, but only a minor effect on the intensity of the secretion stress response.

Bacillus subtilis↗

PubMed2005

Modeling and Monte Carlo simulations in oral drug absorption.

Drug dissolution, release and uptake are the principal components of oral drug absorption. All these processes take place in the complex milieu of the gastrointestinal tract and they are influenced by physiological (e.g. intestinal pH, transit time) and physicochemical factors (e.g. dose, particle size, solubility, permeability). Due to the enormous complexity issues involved, the models developed for drug dissolution and release attempt to capture their heterogeneous features. Hence, Monte Carlo simulations and population methods have been utilized since both dissolution and release processes are considered as time evolution of a population of drug molecules moving irreversibly from the solid state to the solution. Additionally, mathematical models have been proposed to determine the effect of the physicochemical properties, solubility/dose ratio and permeability on the extent of absorption for regulatory purposes, e.g. biopharmaceutics classification. The regulatory oriented approaches are based on the tube model of the intestinal lumen and apart from the drug's physicochemical properties, take into account the formulation parameters the dose and the particle size.

Administration, Oral↗

PubMed2005

Antibody engineering: facing new challenges in cancer therapy.

Antibody-based therapeutics are beginning to realize the promise enclosed in their early denomination as magic bullets. Initial disappointment has turned into clinical and commercial success, and engineered antibodies currently represent over 30% of biopharmaceuticals in clinical trials. Recent structural and functional data have allowed the design of a new generation of therapeutic antibodies, with strategies ranging from complement-mediated and antibody-dependant cellular cytotoxicity enhancement to improved cytotoxic payloads using toxins, drugs, radionucleids and viral delivery. This review considers the structure of different types of recombinant antibodies, their mechanism of action and how their efficacy has been increased using a broad array of approaches. We will also focus on the additional benefits offered by the use of gene therapy methods for the in vivo production of therapeutic antibodies.

Animals↗

PubMed1996

Scrapie: the risk of its introduction and effects on trade.

New Zealand and Australia are fortunate in that they are among the few sheep rearing countries free from scrapie, despite cases in imported sheep in the 1950s. The importance of sheep rearing in the Australasian economies, and the difficulties involved in importing sheep without risking the introduction of scrapie, has meant that there have been very few importations of new blood lines in the last 40 years, and those that have been imported have been through stringent programs designed to ensure freedom from scrapie. While scrapie can be a cause of significant wastage in some sheep rearing situations, its major threat to Australasia is probably to the developing biopharmaceutical industries which, since the emergence of bovine spongiform encephalopathy, have benefitted from an international demand for products guaranteed to be derived from livestock free from the transmissible spongiform encephalopathies. This paper outlines one method which has been used to assess the risk of introducing scrapie as the result of importation of sheep and discusses the difficulty in ascertaining what constitutes an acceptable risk.

Animals↗

PubMed1977

Effect of a second solubilizate on the partition coefficient of drugs in micellar solution and their permeation rate across an artificial membrane.

The distribution of a solubilizate between micelles and the aqueous phase does not obey a simple partition law when a second solubilizate species is present. Alterations of the apparent partition coefficient cannot be explained in terms of a simple displacement mechanism, following the interaction of both solubilizates with the same site of the micelle. A non linear increase in solubilizate association to micelles following an increase in surfactant concentration is observed in the presence of a second solubilizate. A depression in the cloud point temperature follows the addition of a second species and is such that cannot be interpreted as a simple additive effect. Alteration of the apparent partition coefficient in a miscellar solution has an effect on the permeation rate of the solubilizate across an artificial membrane. Biopharmaceutical implications are discussed.

Benzoates↗

PubMed1997

Human jejunal effective permeability and its correlation with preclinical drug absorption models.

This review focuses on intestinal permeability measurements in humans and various aspects of in-vivo transport mechanisms. In addition, comparisons of human data with preclinical models and the blood-brain barrier is discussed. The regional human jejunal perfusion technique has been validated by several crucial points. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. We have also shown that it is possible to determine the effective permeability (Peff) for carrier-mediated transported compounds, and to classify them according to the proposed Biopharmaceutical Classification System (BCS). Furthermore, it is possible to predict human in-vivo permeability using preclinical permeability models, such as in-situ perfusion of rat jejunum, the Caco-2 model and excized intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. It is also suggested that it is possible to roughly estimate the permeability of the blood-brain barrier using measurements of intestinal permeability, even if the quantitative role of efflux of P-glycoprotein(s) in-vivo still remains to be clarified. Finally, the data obtained in-vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in-vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It is also important to study the effect of anti-transport mechanisms, such as efflux by P-glycoprotein(s), and gut wall metabolism, for example CYP 3A4, on the bioavailability.

Animals↗

PubMed2006

Rapid identification of P-glycoprotein substrates and inhibitors.

Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on time-consuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [3H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Degradation of ginsenosides in humans after oral administration.

Even though the degradation of ginsenosides has been thoroughly studied in animals and in vitro using acids, enzymes, and intestinal bacteria, knowledge concerning the systemic availability of ginsenosides and their degradation products in humans is generally lacking. Therefore, the attention in this article is focused on the identification of ginsenosides and their hydrolysis products reaching the systemic circulation in man. This is of great importance in understanding clinical effects, preventing herb-drug interactions, and optimizing the biopharmaceutical properties of ginseng preparations. Using a sensitive mass spectrometric method, which is specific for the identification of ginsenosides in complex biological matrices, the degradation pathway of ginsenosides in the gastrointestinal tract of humans could be elucidated following the oral administration of ginseng. Within the frame of a pilot study, human plasma and urine samples of two subjects were screened for ginsenosides and their possible degradation products. In general, the urine data coincided well with the plasma data. In both volunteers the same hydrolysis products, which are not originally present in the Ginsana extract (Pharmaton S.A., Lugano, Switzerland) ingested, were identified in plasma and urine. It was shown that two hydrolysis products of the protopanaxatriol ginsenosides, namely G-Rh1 and G-F1 may reach the systemic circulation. In addition, compound-K, the main intestinal bacterial metabolite of the protopanaxadiol ginsenosides, was detected in plasma and urine. These products are probably responsible for the action of ginseng in humans. In opposition to previous reports, G-Rb1 was identified in plasma and urine of one subject.

Administration, Oral↗

PubMed2002

Coming of age: anti-cytokine therapies.

Although cytokines are critical in maintaining normal physiology, excessive production of these proteins can lead to pathological consequences. Inhibitors of cytokine production or action are therefore widely investigated as potential therapeutic agents in a variety of immune and inflammatory diseases. Indeed, the successful application of inhibitors of tumor necrosis factor-alpha in rheumatoid arthritis and Crohn's disease heralds the great therapeutic potential of biopharmaceutical agents to counteract cytokine activities. Emerging opportunities for new therapeutics, as well as the challenges we face in their use and development, are described in this review.

Animals↗

PubMed2004

Characterization of coliphage PR772 and evaluation of its use for virus filter performance testing.

Virus filtration is a key clearance unit operation in the manufacture of recombinant protein, monoclonal antibody, and plasma-derived biopharmaceuticals. Recently, a consensus has developed among filter manufacturers and end users about the desirability of a common nomenclature and a standardized test for classifying and identifying virus-retentive filters. The Parenteral Drug Association virus filter task force has chosen PR772 as the model bacteriophage to standardize nomenclature for large-pore-size virus-retentive filters (filters designed to retain viruses larger than 50 to 60 nm in size). Previously, the coliphage PR772 (Tectiviridae family) has been used in some filtration studies as a surrogate for mammalian viruses of around 50 to 60 nm. In this report, we describe specific properties of PR772 critical to the support of its use for the standardization of virus filters. The complete genomic sequence of virulent phage PR772 was determined. Its genome contains 14,946 bp with an overall G+C content of 48.3 mol%, and 32 open reading frames of at least 40 codons. Comparison of the PR772 nucleotide sequence with the genome of Tectiviridae family prototype phage PRD1 revealed 97.2% identity at the DNA level. By dynamic light-scattering analysis, its hydrodynamic diameter was measured as 82 +/- 6 nm, consistent with use in testing large-virus-retentive filters. Finally, dynamic light-scattering analysis of PR772 preparations purified on CsCl gradients showed that the phage preparations are largely monodispersed. In summary, PR772 appears to be an appropriate model bacteriophage for standardization of nomenclature for larger-pore-size virus-retentive filters.

Biotechnology↗

PubMed2001

High-Pressure Biotechnology in Medicine and Pharmaceutical Science.

High-pressure (HP) biotechnology is an emerging technique initially applied for food processing and more recently in pharmaceutical and medical sciences. Pressure can stabilize enzymes and modulate both their activity and specificity. HP engineering of proteins may be used for enzyme-catalyzed synthesis of fine chemicals, pharmaceuticals, and production of modified proteins of medical or pharmaceutical interest. HP inactivation of biological agents is expected to be applicable to sterilization of fragile biopharmaceuticals, or medical compounds. The enhanced immunogenicity of some pressure-killed bacteria and viruses could be applied for making new vaccines. Finally, storage at subzero temperatures without freezing is another potential application of HP for cells, animal tissues, blood cells, organs for transplant, and so forth.

Journal Article↗

PubMed1991

Potency assessment of topical corticoids in the vasoconstrictor assay and on tuberculin-induced inflammation.

The topical anti-inflammatory activity of potent and very potent corticoids was studied in normal and inflamed skin using the vasoconstriction assay and tuberculin-induced inflammation in four double-blind intraindividual comparison trials. Instrumental techniques in addition to visual scores and several time points were applied to get better insight into the reliability of the models and the sensitivity of the different variables. Beta-methasone-17-valerate and two concentrations of prednicarbate were used as potent corticoids, clobetasol-17-propionate, betamethasone-17,21-dipropionate and different biopharmaceutical forms of desoximetasone (DOM) as very potent corticoids. Visual scores, the reactive skin hyperemia after arterial occlusion and skin colorimetry were used to quantify vasoconstriction; erythema scores, surface area of infiltration and changes in skin colorimetry, skin blood flow and skin temperature for the tuberculin reaction. The time courses of blanching (n = 20) and of the tuberculin reaction (n = 10) were described by orthogonal polynomials and the coefficients were statistically analyzed by nonparametric tests, the discriminative variables in tuberculin inflammation in addition by the parametric multiple analysis of variance. Important differences in the release rates of corticoids demand several assessment times and not just one as often used. The potency ranking may otherwise be misleading. In general, ointments released corticoids slowlier than the cream which in turn liberated slowlier than the gels. The DOM gel declined rapidly after an apparent peak at 5.5 h in terms of its blanching effect, but was nevertheless comparable after once-daily application to other very potent corticoids in its activity against delayed-type inflammation. Such differences may explain discrepancies found for some corticoid preparations between their blanching response and clinical efficacy. The more potent a corticoid the more the erythema is reduced, the less pronounced the cell infiltration and the more delayed the peak seems from 24 to 48 h in the tuberculin reaction. The inflammatory response is diminished in the following manner: very potent greater than potent corticoids; erythema greater than infiltration. Visual scores were the most reliable parameters in normal and inflamed skin and they correlated well with skin colorimetry which shows greater variability. Reactive hyperemia after arterial occlusion gave poor results in terms of ranking in the vasoconstriction assay as did resting skin blood flow in inflamed skin. Changes in the temperature of inflamed skin are sensitive enough to discriminate the active drugs from the controls, but have a somewhat different time course, reflecting perhaps a higher impact of the amount of mediator release in the early phase relative to the cell invasion in the later phase.

Administration, Topical↗

PubMedDate not supplied

Nanotechnologies in protein delivery.

The growth rate for biotech drugs, namely proteins, peptides, and oligonucleotides, is dictated by the parallel progresses in biotechnology and nanotechnology. Actually, biotechnology techniques have expanded enormously the arsenal of therapeutically useful peptides and proteins making these products of primary interest for future pharmaceutical market. Nevertheless, the exploitation of protein and peptide drugs is strictly related to the development of innovative delivery systems which should provide for controlled, prolonged, or targeted delivery, improved stability during storage and delivery, reduced adverse effects, increased bioavailability, improved patient compliance and allow for administration through the desired route and cope with cost-containment therapeutic protocols. Colloidal formulations ideally possess the physicochemical and biopharmaceutical requisites for protein delivery. Pharmaceutical nanotechnology is a tool of techniques applied to design, develop and produce these systems. It involves the investigation of innovative materials and production procedures for preparation of a variety of nanosized dosage forms, which range from solid nanoparticles to soluble bioconjugates. The research and development of innovative tailor made protein delivery systems, which must be designed according to the drug candidate pharmacological and physicochemical properties, is one of the primary aim of modern pharmaceutical technology. Therefore, as an unmet need exists for technologies that combine innovative drug delivery solutions, a close un-prejudicial interaction between academic and industrial researchers as well as business thought leaders is required.

Coated Materials, Biocompatible↗

PubMed1983

Transdermal absorption of nitroglycerin from microseal drug delivery (MDD) system.

A recent important advance in biopharmaceutics has been the utilization of controlled delivery of drugs to the systemic circulation through the intact skin. With the conventional tablet and capsule dosage forms, the amount of drug absorbed through the gastrointestinal (GI) tract varies depending on the quantity and types of food in the stomach, on the GI motility and transit time. Acid and/or alkaline labile drugs may be deactivated prior to absorption from the GI tract while some drugs also get deactivated by GI microbial flora. In the case of drugs with a high hepatic extraction ratio, the absorbed drug may be largely deactivated by first-pass metabolism before reaching the systemic circulation. Drug absorption through the GI tract can therefore result in variable and/or unpredictable blood levels. Some of this variability can be minimized by administering controlled-release tablet or capsule formulations. However, these dosage forms cannot eliminate the inherent variability associated with first-pass metabolism.

Administration, Topical↗