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PubMed2001

ALX-0600 (NPS Allelix Corp).

NPS Allelix (formerly Allelix Biopharmaceuticals) is developing the glucagon-like peptide 2 (GLP-2) analog ALX-0600 for the potential treatment of gastrointestinal diseases, including short bowel disease. GLP stimulates the growth of the lining of the small intestine, thus increasing the absorptive area of the intestine [214370], [315107]. ALX-0600 also has potential for mucositis associated with cancer chemotherapy and inflammatory bowel disease [331459]. During the third quarter of 1999, a pilot phase II trial began for short bowel syndrome (SBS) [331459]. ALX-0600 began pivotal phase II trials in 2000 following the completion of the pilot trial which was designed to measure the safety, tolerability, and any other drug-related improvements in nutrient absorption and physical changes in the gut of a small number of patients with SBS. Allelix hopes to bring this drug to the market by 2001 [341519]. Allelix filed an application to the FDA for Orphan Drug designation in the third quarter of 1999 [331459]; in August, the designation was approved [377524]. As of November 1998, Allelix was in discussions with a potential marketing partner for worldwide development and marketing [305000]. In August 1998, the USPTO issued a notice of allowance to Allelix for its basic patent containing claims covering the composition and medical uses of ALX-0600 and related GI drug candidate compounds [2946571.

Amino Acid Sequence↗

PubMed2001

[Results of creating domestic medicinal forms of antineoplastic agents at the N. N. Blokhin Cancer Research Center of the Russian Academy of Medical Sciences].

Since there is a rise in morbidity and mortality rates due to malignant neoplasms, their drug therapy along with radiation and surgical methods remains a burning problem of modern medicine. Empirical and rational approaches to searching for new drugs have given rise to cancer agents that are widely used in clinical practice today. By taking into account the chemical and biological features of experimentally chosen active cytostatics, emphasis should be laid on the particular importance of development of effective dosage forms of antitumor substances by conducting chemical analytical, pharmacological engineering, biopharmaceutical, and pharmacokinetic studies. The purpose of the present paper is to assess the retrospective and present status of studies to design dosage forms of cancer drugs in our and foreign countries, and to pool the results of the author's own studies in designing dosage forms of antitumor substances from classes of chloroethylamines, nitrosoalkyl ureas, complex metal compounds, anthracene diones, antibiotics of plant origin, etc.

Academies and Institutes↗

PubMed2001

The influence of selected bioadhesive polymers on physical-chemical properties of stomatological dressing.

Dressings made from polyvinyl alcohol (PAV) and Hydroxypropylmethylcellulose (HPMC) with the addition of glycerol (GLY) differ in adhesiveness and the time of wash out in water, both characteristics depended on polymer and GLY concentration. The research on the release speed which is applied in topical therapy of chlorhexidine digluconate antiseptic in biopharmaceutical model proved the existence of close to rectilinear relation between the amount of released substance and release time for selected formulations.

Adhesiveness↗

PubMedDate not supplied

A method for the rapid detection of microbial contaminants in animal cell culture processes.

The early detection of microbial contamination is an important issue in the production of biopharmaceuticals using animal cell culture systems. A new method, based on the ChemScan RDI analyser, was evaluated for the rapid detection and enumeration of low concentrations of microorganisms within a large population of animal cells and in cell culture media. The method was tested with suspension cell cultures and is applicable to adherent cell cultures. In both cases, the method uses an initial step to eliminate the animal cells followed by collection and fluorescent labelling of the viable microbial contaminants on a filter membrane. Total counts of the viable microorganisms were obtained after analysis of the membrane by the ChemScan RDI analyser. The results showed that the ChemScan RDI detected individual bacterial cells after filtration of the pre-treated animal cell culture. The detection limit of the ChemScan RDI was less than 10 bacteria/ml in cell culture containing 10(6) mammalian cells/ml and one bacterium in 500 ml of cell culture medium. A strong correlation between the standard plate count and the ChemScan RDI was observed, even at low bacterial concentrations. The total time for each analysis was less than two hours.

Animals↗

PubMed2002

Value of antimicrobials in the prevention and treatment of tuberculosis in the United States.

OBJECTIVE: To estimate the economic value of antimicrobials for the prevention and treatment of tuberculosis in the United States from 1954 through 1997. DESIGN: Published sources were used to estimate the burden of illness (direct medical costs, reductions in quality of life, and years of life lost) from active tuberculosis (TB) cases diagnosed between 1954 and 1997. Published literature concerning the pre-antimicrobial incidence rate and treatment of TB were extrapolated to estimate the burden of illness that would have occurred in the absence of antimicrobials. RESULTS: Between 1954 and 1997, the use of antimicrobials reduced the number of newly diagnosed cases of active TB by 32% (relative to the number that would have occurred in the absence of antimicrobials), the number of mortalities by 81%, the number of life-years lost by 87%, and the cost of medical treatment by 76%. The total financial burden of illness over this time period (including the value of lost life-years) was reduced from $894 billion (in 1997 dollars) to $128 billion. CONCLUSION: TB antimicrobials had a substantial health impact in the US from 1954 to 1997. This quantitative assessment of the economic impact of innovative biopharmaceutical products demonstrates the importance of continuing medical innovation.

Antibiotics, Antitubercular↗

PubMed2002

Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.

PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. Results of Phase I and Phase II clinical studies in patients with CML in blast crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized. The basis for marketing approval and postmarketing commitments by the pharmaceutical company are discussed. RESULTS: Toxicology studies in the rat, dog, and monkey show the hematological, renal, and hepatobiliary toxicity of imatinib. Pharmacokinetic studies in patients with CML demonstrate 98% imatinib bioavailability. The elimination half-lives of the parent drug and the major active metabolite, CGP74588, from plasma are approximately 18 and 40 h, respectively. Approximately 81% of the drug is eliminated in 7 days, 68% in the feces and 13% in the urine. Cytochrome P-450 3A4 is the main enzyme responsible for imatinib metabolism. Phase I and II clinical studies were conducted. The Phase I study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000 mg/day. Dose-limiting toxicity was not observed. The three Phase II studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP patients received 400 mg/day imatinib, whereas CML-AP and CML-BC patients generally received 600 mg/day imatinib. Primary study endpoints were cytogenetic response rate (CML-CP) and hematological response rate (CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients was 49%. The hematological response rate of CML-AP and CML-BC patients was 63 and 26%, respectively. The most common imatinib adverse events were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver enzymes and/or bilirubin were reported in 27 patients (2.6%). CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known as STI-571 and Glivec), manufactured and distributed by Novartis Pharmaceuticals, East Hanover, NJ, was approved by the United States Food and Drug Administration for the treatment of CML in three clinical settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food and Drug Administration's review of the New Drug Application.

Antineoplastic Agents↗

PubMed2002

Structural genomics: bridging functional genomics and structure-based drug design.

Considerable advances in structural genomics have been witnessed in the last year. Several pilot studies have begun to report their initial results, and new centers have been funded to join the endeavor. The legacies of the genome sequencing efforts, namely high-throughput molecular biology and whole-organism genome sequences, have been integrated as front-end modules for structural genomics pipelines. Impressive advances have been made in NMR spectroscopy and X-ray crystallography. New methods in structural bioinformatics and computational chemistry have been published that provide the means to exploit the wealth of new information in drug discovery. Not surprisingly, the biopharmaceutical industry has been quick to recognize the benefits of these new developments and has begun to adopt them. This article reviews recent results from structural genomics initiatives and the potential applications of new information and technologies in the drug discovery process.

Drug Design↗

PubMed2002

XTL-001. XTL Pharmaceuticals.

XTL-001, a combination of two human high-affinity monoclonal antibodies with affinity to different regions of the HBV surface antigen (HBsAg), is under development by XTL Biopharmaceuticals as a potential passive immunotherapy for HBV infection. An IND for XTL-001 was submitted in the third quarter of 1998 and was approved by the FDA in March 1999. It has been anticipated that the use of two antibodies against different viral determinants would lower the probability of viral escape mutants. XTL-001 showed viral neutralization activity in the Trimera model for HBV infection and was several thousand-fold more active than current antibody-based therapies. XTL has anticipated that XTL-001 will be used as a combination therapy with existing drugs. In March 2002, Roberton Stephens predicted a 2006 launch for XTL-001, with sales expected to reach at least US$100 million.

Animals↗

PubMed2002

[Modification of Chinese hamster ovary cells].

Chinese hamster ovary cells (CHO) are preferable to prokaryotic, yeast or insect cells as hosts for biopharmaceutical production due to the products are more similar to their natural conformation. However, CHO cells confront tremendous difficulties when cultured in large scale such as mal-adaptation to serum-free medium, apoptosis and over-growth without limitation. So in addition to optimizing CHO system in respect of medium, environment and expression vector, modification of CHO cells themselves has drawn more and more attention. Here the main progress in CHO-modification is reviewed.

Animals↗

PubMed2000

[Therapeutic Effects on Chemotherapy-Induced Granulocytopenia in Hematologic Malignacies, a Comparison Between Lishengsu and Filgrastim]

A multi-center, open controlled study was performed to observe the effects of Lishengsu, a rhG-CSF preparation manufactured by Beijing Shuanglu Biopharmaceutical Co., Ltd. on chemotherapy-induced granulocytopenia in patients with hematological malignancies. The results showed the total response rates were similar between Lishengsu- and Filgrastim-treated groups (98.8% vs 100%), recovery of peripheral ANC and WBC was also similar between the two groups, with the peaks appeared both at the 12th day after rhG-CSF treatment. No differences were observed in the duration for ANC to recover to normal level between Lishengsu- and Filgrastim-treated groups (7 and 8 days respectively). Our results indicated Lishengsu is as effective as Filgrastim in accelerating the recovery of chemotherapy-induced granulocytopenia.

Journal Article↗

PubMed2003

Safety of foods derived from genetically modified plants.

Biopharmaceuticals have been available for clinical use for nearly three decades, but foods derived from agribiotechnology have been available for just under a decade. Controversy surrounding foods from genetically modified (GM) plants has focused primarily upon their allergenicity, with lesser concerns about antibiotic resistance genes. Concerns are related to possible environmental impacts on non-human species, including effects on non-target species (e.g., butterflies) and on the development of so-called "super weeds." Food allergies are no more prevalent in foods from GM plants than in conventional foods. Further, the use of antibiotics in the development of GM plants does not pose a significant risk to the human population. Foods from the current GM plant products have been shown not to pose any detrimental effects to humans, and, in fact, nutritionally enhanced products are being developed. GM foods are subjected globally to intense regulatory scrutiny, and extensive data have been provided consistently to regulatory agencies in the United States on a voluntary basis, with mandatory reporting of data soon to be in force. Existing environmental concerns appear to be unjustified on the basis of existing data and experience.

Consumer Product Safety↗

PubMed2002

Physicochemical properties of stomatological dressings on the basis of biodegradable nonionic polymers.

The properties of polyvinyl alcohol (PVA), such as the ability to form membranes, good relative bioadhesiveness, the ability to mix with other polymers, biodegradability, swelling in water, lead to an assumption that the polymer may be used effectively as a carrier of the active substance onto the mucous membranes, what has led us to undertake present studies [1-4]. They revealed that depending on the degree of polyalcohol hydrolysis, the dressings made on the basis of PVA and methylcellulose (MC) with the addition of hydrophilic substances were characterised by distinct rheological properties and released the active substance in various ways. The studies on the kinetics of the release of a locally applied antiseptic, chlorhexidine digluconate, in biopharmaceutical model provided evidence of close to rectilinear relationship between the amount of released substance and the time of release for selected formulations.

Adhesives↗

PubMed1990

High performance isoelectric focusing using capillary electrophoresis instrumentation.

High performance isoelectric focusing in capillaries provides rapid, high resolution separation of proteins based on their isoelectric points. Results can be obtained in a matter of minutes with little or no sample preparation. The technique requires the use of coated capillaries to reduce electroendosmosis so that stable, focused zones can be attained. Once focused, protein zones may be mobilized by the addition of salt to the catholyte or anolyte buffer. On-tube UV monitoring enables direct detection of sample components during mobilization with mass sensitivity equal to that of silver staining. The linear relationship between mobilization time and isoelectric point allows the technique to be used for estimation of protein pI. Demonstrated applications include separation of proteins in biological fluids with possible clinical applications, and characterization of biopharmaceutical proteins and monoclonal antibodies.

Capillary Action↗

PubMed1992

Genetic manipulation of milk proteins and its consequences for the dairy industry.

Genetic selection of cattle by selective breeding patterns dates back to prehistoric times and has resulted in the diversity of breeds we see today. Selection in New Zealand has been for fat production earlier in the century, and more recently for protein production as well as fat. There is a lot of interest today in the naturally occurring variants of the milk proteins, as these can confer interesting differences in the molecular behaviour of the proteins as well as being correlated with compositional differences in the milk. Genetic modification holds great promise for the future in the dairy industry, but present constraints due to cost, lack of basic knowledge, and difficulty in producing genetically-modified calves, mean that only the biopharmaceutical area is likely to be affected in the near future. Coupled to this is an apparent lack of acceptance of food from genetically-modified animals by consumers. It will therefore need a change in public attitude as well as some development in science and technology before dairy products from genetically modified cattle become a commercial reality.

Adult↗

PubMed2003

Validation of fermentation processes.

The ability to prepare consistent biopharmaceutical products depends extensively on possession of banked and characterized cell substrates and on development of production processes which can be validated. While the attributes that define cell characterization have been extensively detailed by ICH and the regulatory agencies in the past decade, little has been specified regarding process validation for biological processes. The extent to which validation concepts can be applied to biological processes varies depending on the nature of the process, the nature of the product, and the level of knowledge regarding the relationship between process parameters and product quality. Expectations concerning the rigour of the validation programme should be adjusted accordingly. There is no single approach that is appropriate for all processes and products. At a minimum, there should be an attempt to define which process parameters are critical, and to focus the attention of validation efforts on these parameters.

Biotechnology↗

PubMed2003

Validation of sterilizing grade filtration.

Validation consideration of sterilizing grade filters, namely 0.2 micron, changed when FDA voiced concerns about the validity of Bacterial Challenge tests performed in the past. Such validation exercises are nowadays considered to be filter qualification. Filter validation requires more thorough analysis, especially Bacterial Challenge testing with the actual drug product under process conditions. To do so, viability testing is a necessity to determine the Bacterial Challenge test methodology. Additionally to these two compulsory tests, other evaluations like extractable, adsorption and chemical compatibility tests should be considered. PDA Technical Report # 26, Sterilizing Filtration of Liquids, describes all parameters and aspects required for the comprehensive validation of filters. The report is a most helpful tool for validation of liquid filters used in the biopharmaceutical industry. It sets the cornerstones of validation requirements and other filtration considerations.

Drug Industry↗

PubMed2003

The high road to success: how investing in ethics enhances corporate objectives.

There is a growing gap between the tidal wave of information emerging from the Human Genome Project and other molecular biology initiatives, and the clinical research needed to transform these discoveries into new diagnostics and therapeutics. While genomics-based technologies are being rapidly integrated into pharmaceutical R&D, many steps in the experimental process are still reliant on traditional surrogate model systems whose predictive power about human disease is incomplete or inaccurate. There is a growing trend underway in the research community to introduce actual human disease understanding as early as possible into discovery, thereby improving accuracy of results throughout the R&D continuum. Such an approach (known as clinical genomics: the large scale study of genes in the context of actual human disease) requires the availability of large quantities of ethically and legally sourced, high-quality human tissues with associated clinical information.Heretofore, no source could meet all of these requirements. Ardais Corporation was the first to address this need by pioneering a systematized, standardized network for the collection, processing, dissemination and research application of human tissue and associated clinical information, all of which rest on the highest ethical standards. Based on a novel model of collaboration between industry and the academic/medical community, Ardais has created procedures, structures, technologies, and information tools that collectively compromise a new paradigm in the application of human disease to biomedical research. Ardais now serves as a clinical genomics resource to dozens of academic researchers and biopharmaceutical companies, providing products and services to accelerate and improve drug discovery and development.

Advisory Committees↗

PubMed1992

Effects of fermentation on product consistency.

A variety of different fermentation processes has been successfully employed to produce consistent protein-based biopharmaceuticals from genetically engineered animal cells. Chinese hamster ovary (CHO) cells were genetically modified to produce recombinant human soluble CD4, tissue plasminogen activator (tPA) or erythropoietin (EPO). Soluble CD4 was collected from extended perfused fermentations of several months' duration, during which some quantitative loss of DNA copy level, mRNA expression level, and fermentation titer were observed. In one extended run, a novel contaminant appeared in intermediates purified from later harvests. However, in all cases, the final soluble CD4 product was consistent in terms of purity and potency. Evaluation of genetic stability for tPA examined both biological traits at the cellular level as well as potency, purity and structure of product derived from cells at various levels of in vitro age; no significant cell age effects were observed. Similarly, evaluation of the EPO product showed that genetically-determined and process-determined traits such as potency, tryptic peptide mapping, and sialylation were consistent from lot to lot. These data exemplified how process design, process validation, and in-process and quality control assays can be used effectively to ensure the consistency of recombinant products derived from cell culture fermentations.

Animals↗