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PubMed2002

Exceptional economic returns on investments in medical research.

The United States will invest nearly US$70 billion (US$260 per capita) on medical research this year, more than half of which will be sponsored by the biopharmaceutical industry. This investment has been shown to provide major gains in basic, disease-oriented and patient-oriented research. It also provides a huge economic return on investment--whether measured in terms of jobs created, health costs saved, or the dollar value of lives saved. Australia, whose investment in medical research is less than 10% that of the United States, should increase its national commitment.

Australia↗

PubMed1999

Prodrug approaches to the improved delivery of peptide drugs.

Undesirable pharmaceutical and biopharmaceutical properties, which include low water solubility, poor stability, and low permeability through biological membrane barriers, often hinder the clinical development of biologically active peptides. Finding solutions to these problems is a contemporary issue in developing clinically the vast number of biologically active peptides as drugs. In recent years, significant progress has been made in developing prodrug approaches for the improvement of the water solubility, stability, and membrane permeability of peptides. For improving water solubility, the focus has been on the bioreversible introduction of ionizable functional groups to peptides, which helps to increase the polarity and thus water solubility of the peptide drugs. For improving stability, efforts have focused on stabilizing peptides against exopeptidase-mediated hydrolysis by bioreversibly masking the terminal carboxyl and/or amino groups. For improving permeability through biological barriers, recent efforts have focused on both improving the lipophilicity of a peptide in order to facilitate its passive permeation through biological membranes and conjugation of a peptide to a carrier which allows for the active transport of the peptide-carrier conjugate. Many of the prodrug systems developed recently have the potential to be used clinically for the delivery of peptide drugs to the desired site of action.

Animals↗

PubMed1999

Recent advances in the understanding of the molecular biology of hemophilia A: possible implications towards a more effective therapeutic regime.

Hemophilic care was revolutionized in the late 50's, when factor VIII (FVIII) substitution therapy became accessible. Since then, plasma-derived FVIII preparations with varying degrees of purity have been widely used. The availability of such products has resulted in a great improvement of life quality and life expectancy of affected people. However, FVIII concentrates have been involved in the transmission of blood borne viruses like HIV and HCV. The tremendous development of molecular biology techniques, in association with modern biotechnology has allowed the large-scale production of first generation biopharmaceuticals such as recombinant FVIII, for clinical purposes. In parallel, intense research has revealed the genetic basis of hemophilia A, many aspects of FVIII biosynthesis and the biological function of FVIII. Synergistic efforts between genetic engineering and biotechnology have the potential to develop second generation products and therapeutic strategies based solely on "protein engineering". Integration of basic research results in new treatment concepts should allow the rational design of FVIII molecules endowed with improved functional properties. Such molecules may be highly beneficial in the development of future strategies in FVIII inhibitor therapy and in FVIII somatic gene therapy.

Animals↗

PubMed1984

P & T Committee formulary requests: criteria for admission.

The criteria for P & T Committee members to consider when adding or deleting a product to the formulary are discussed. Although each institution will require and develop different standards that reflect the characteristics of the patient population they serve, two general sets of factors should be studied. The anticipated needs of the institution and the therapeutic application of the medication in consideration must be identified. Furthermore, the characteristics of the drug, including pharmacokinetics, biopharmaceutics, and cost must be clearly defined. The P & T Committee formulary decisions are critical in ensuring high-quality, cost-effective health care.

Decision Making↗

PubMed1999

Gene therapy in the world and in Switzerland.

Until the mid-seventies, biology used to be taught as an interesting, yet rather "useless" discipline in our high schools. The advent of molecular biology has drastically changed this image. Now, applied molecular genetics has been shown to have the potential to revolutionize many aspects of our life, including the paradigms of medicine. In a first phase, gene knowledge has allowed medical diagnosis with previously unimaginable precision. In a second wave, gene transfer in micro-organisms has produced a plethora of biopharmaceuticals. This decade has seen the third era of molecular medicine, in which direct gene transfer into humans is being developed. This article comments on the most recent developments and concepts in the field of human gene transfer (also called "gene therapy"). Some essential methods are briefly presented and a great deal of attention is devoted to the technical hurdles still to be overcome in achieving efficient and safe gene therapy protocols. The final paragraph attempts to clear up some myths and misunderstandings that are commonly propagated when people talk or think about gene therapy. The purpose of this article will be fulfilled if at the end the reader is convinced that gene therapy is not necessarily dedicated exclusively to hereditary disorders, that Switzerland undertaken an intensive and competitive experimental effort in this direction, that gene therapy has already proven its efficacy and has great potential, but that it will take a couple of decades before some applications are routinely used in the clinic.

Gene Transfer Techniques↗

PubMedDate not supplied

Application of bacteriophages as surrogates for mammalian viruses: a case for use in filter validation based on precedents and current practices in medical and environmental virology.

Infectivity-based assays are the assays of choice for the detection of pathogenic mammalian viruses. While it is intuitively appropriate to conduct testing and validation studies with the known viral burden or a closely related mammalian species, logistic considerations often dictate otherwise. Consequently, bacteriophages have served as suitable surrogates for mammalian viruses in both medical and environmental virology applications. The wide range of bacteriophages available offers a powerful analytical tool amenable to several different applications: filter validation studies (where removal is based on size exclusion), investigations into virus contamination control issues, evaluation of barrier materials, etc. There is a considerable body of evidence to suggest and support the use of bacteriophages as surrogates for mammalian viruses. Use of appropriately sized bacteriophages provides an innocuous, efficacious and expeditious method for economical testing and validation of viral clearance capabilities of virus removal filters, thus facilitating performance of filter validation studies in biopharmaceuticals under product- and process-specific conditions in an overall effort towards ensuring the virological safety of biologicals. This paper discusses the limitations associated with mammalian virus assays and provides a rationale for the use of bacteriophages as surrogates for mammalian viruses. Data from published literature documenting applicability of bacteriophages in filter validation studies, especially when removal is based on size exclusion, is reviewed along with examples of studies from the fields of medical and environmental virology.

Bacteriophages↗

PubMedDate not supplied

Identification of bacteria in water for pharmaceutical use.

Different systems for the obtention of water used in Biopharmaceutical Industry were characterized from the bacteriological point of view. Determination of aerobic mesophilic microorganisms was performed; as well as the isolation of contaminant microorganisms for what the techniques of membrane filtration was used. For the identification of the more representative species there were made conventional biochemical tests and quick systems: API. The results show that water serving as tap water for purification systems fulfill with the microbiological requirements to this kind of water. All the isolated microorganisms were gram-negative bacteria characteristics of this environment: Pseudomonas putida, Xanthomonas maltophilia, Aeromonas salmonicida ssp. salmonicida, Flavimonas coryzihabitans and Acinetobacter iwoffi. The ultrafiltration and distillation tested systems fulfill with the established microbiological limits, except for deionization and distilled water storing systems. The isolation showed that approximately the 76.9% were of Gram-negative bacteria, the 14.6% of Gram-positive cocci and the 8.5% Gram-positive sporulated bacilli. The most representative genus of purified water were: Pseudomonas, with the higher percent of incidence, Staphylococcus, Bacillus, Flavobacterium, Sphingomonas, Aeromonas and Agrobacterium.

Bacteria, Aerobic↗

PubMed2000

Studies on gynaecological hydrophilic lactic acid preparations. Part 3: Effects of chitosan on the properties of methylcellulose gels.

Methylcellulose gels comprising lactic acid, similarly to its water solutions, have pH values between 2.0 and 2.6, i.e. out of the physiological range. Addition of Chitosan enables preparation of gels with pH values from 2.2 to 4.9 similar to the natural vagina pH range, 3.8-4.4. The absolute viscosity of the gels, ranging from 27 up to 700 mPa.s, depends on chemical composition and on excess of lactic acid used. Measurement of adhesion enabled the selection of gels which remain located at the point of application under simulated biopharmaceutical conditions. The behavior of those preparations in the true environment of the vagina needs to be verified in vivo.

Adhesiveness↗

PubMedDate not supplied

Comparative in vitro evaluation of nimesulide-containing preparations on the Italian market.

Nimesulide is a quite popular non-steroidal anti-inflammatory drug (NSAID), which has been demonstrated to preferentially inhibit cycloxygenase-2 (COX-2), thus exerting milder gastrointestinal and renal side effects. Apart from the original products (Aulin and Mesulid), several copy and generic nimesulide-containing preparations are presently available on the Italian market. Generics are defined by the World Health Organization (WHO) as interchangeable multi-source pharmaceutical products and, according to international regulatory issues, their bioequivalence to an already marketed reference product has to be proven. Due to its physico-chemical properties, and in particular to the low solubility, nimesulide appears to be a critical molecule from a biopharmaceutical point of view. On the basis of these premises, the aim of the present work was to perform a comparative evaluation of tablets in vitro behaviour for the best-selling copy (Sulidamor) and generic (Nimesulide Dorom) in reference to the original products. The results provided by the dissolution test pointed out statistically significant differences in the in vitro behaviour displayed by the original products on one hand and by the copy as well as generic preparations in exam on the other.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Studies on gynaecological hydrophilic lactic acid preparations. Part 4: Effects of polyvinyl pyrrolidone K-90 on properties of methylcellulose gels.

In continuing the investigation of the binding of lactic acid with basic polymers polyvinyl pyrrolidone K-90 (PVP) was used. Use of PVP in mixtures with lactic acid in experimentally determined and calculated proportions allowed the preparation of gels with pH 3.8-4.4, i.e. maintaining the physiological conditions in the vagina. The viscosity of the methylcellulose gels increases proportionally to the amount of the PVP--lactic acid complex added. Examination of the gels in the biopharmaceutical model, which simulated the physiological conditions of the vagina, allowed determination of the mobility of the preparations in patients.

Gels↗

PubMed2001

[In vitro models of intestinal and alveolar epithelium cultures in pharmaceutical research].

The progress of modern bio- and information-technology has made an enormous impact on the development of new drugs: At the one hand, computer-aided drug design and automated high-throughput screening has enormously facilitated the chemical synthesis of new drug candidates. At the other hand, the number of macromolecular biopharmaceuticals, such as peptides, proteins, antisense agents or gene vectors is continuously increasing. Whether or not such new entities can indeed be developed to safe and efficient medicines, is largely determined by the question, if these molecules are able to reach their actual target (receptor) within the patient"s body. Often, biological barriers, such as the mucosal epithelium of the gastrointestinal tract cannot be passed. In vitro test systems based on human epithelial cells may help to determine those candidate drugs which are well absorbed after oral application. Moreover, such cell culture models are helpful tools for the discovery for new delivery routes for those molecules, which cannot be administered by oral application. In this context, there is an increasing interest in the pulmonary delivery of drugs, as well as in the development of cell culture systems to model the blood-air barrier represented by the alveolar epithelium.

Animal Testing Alternatives↗

PubMed2001

[In vitro permeability studies as a substitute for in vivo studies--which requirements have to be met?].

In order to reduce costs and shorten time-to-market, the permeability of drug substances can be characterized by in vitro techniques including the use of cell and tissue models. It is required to apply appropriate quality standards similar to those used in animal or clinical studies. The Caco-2 cell model is a well-established and recognized in vitro technique in research, industry and in the drug discovery sector. However, the lack of standardized operating is reflected in the heterogeneity of the data acquired using this model. Using the Caco-2 cell model as an example, this paper demonstrates how to test the suitability of a cell culture model for conducting drug permeability studies. The procedures involve not only the characterization of cell morphology but also functional assessment of the model and the periodic testing of monolayer permeability. Both the useful comparison of permeability data and the reliable prediction of in vivo permeability require prior classification of the in vitro permeability in accordance with the FDA"s Biopharmaceutics Classification System (BCS).

Animal Testing Alternatives↗

PubMed2001

Branded versus generic clozapine: bioavailability comparison and interchangeability issues.

Clozapine has been the treatment of choice for patients with refractory schizophrenia. Generic clozapine has recently become available, because of a waiver of the usual criteria for establishing bioequivalence. However, there are biopharmaceutical, bioavailability, and clinical concerns related to the generic formulation raised by both clinicians and academic researchers. We conducted a prospective, randomized, crossover study to evaluate steady-state pharmacokinetics, pharmacodynamics, and tolerability of generic clozapine (Zenith Goldline Pharmaceuticals) versus Clozaril (Novartis Pharmaceuticals) in schizophrenic patients. A preliminary report of the pertinent bioavailability results is presented here. Despite comparable mean plasma concentration-time curves, significant differences were found in the primary pharmacokinetic parameters of the 2 formulations in almost 40% of patients. Such intraindividual differences raise the issue of average bioequivalence versus individual bioequivalence and the implication for interchangeability of different clozapine formulations. The decision to switch a patient from branded to generic clozapine should be made on an individual basis with special emphasis on clinical outcome, and patients should be monitored closely during the transition.

Adult↗

PubMed2001

Compound mixtures in Caco-2 cell permeability screens as a means to increase screening capacity.

The purpose of this investigation was a study of simultaneous permeability measurement using compound mixtures (cassette dosing) as an alternative to single compound evaluation in order to increase the capacity of screens for intestinal drug permeability. Drug transport across Caco-2 monolayers was studied, both in the apical to basolateral and the basolateral to apical direction. The apparent permeability coefficients for ten compounds displaying different intestinal transport mechanisms were determined, first as single compounds and then as components of a mixture. Seven beta-adrenoceptor antagonists and baclofen were analysed simultaneously using reversed phase HPLC with UV detection, D-glucose and mannitol were measured by scintillation counting. The results indicated that the Papp from the mixture as donor phase correlated well with that of the single compounds and merely small changes in the Papp of each compound were observed between the single compound and mixture experiments. This minor variation resulted in a change in rank-order of the poorly permeable compounds in the mixture, however, without affecting their association with the permeability class according to the biopharmaceutics classification system (BCS). It can be concluded that the use of compound mixtures is a suitable method for improving the capacity in permeability screens. Further improvement of the throughput may be expected upon automatisation of permeability measurements using robotics combined with increased selectivity using LC-MS analysis.

Adrenergic beta-Antagonists↗

PubMed2000

[Effects of new antineoplastic agents (dimethoxybenflurone and Oracin) on the cardiovascular system and other parameters in the rabbit in vivo].

Anthracycline derivatives belong among the most effective antineoplastic drugs but their therapeutic use is limited by their side effects--a dose-related cardiotoxicity. The influence of repeated i.v. administration (once weekly, max. 10 weeks) of new antineoplastic agents--dimethoxybenfluron (DMB) (3,9-dimethoxybenfluron hydrochloride, C23H24O4NCl, M.w. 413.9, Institute of Experimental Biopharmaceutics, Czech Academy of Sciences, Hradec Králové, Czech Republic; 12 or 24 mg base/kg) and Oracin (6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H- indeno[1,2c]isoquinoline hydrochloride), C20H19N2O3Cl, M.w. 370.84, Research Institute for Pharmacy and Biochemistry, Prague, Czech Republic; 5 or 10 mg/kg) on cardiovascular, biochemical, haematological and histological parameters were studied in rabbits in vivo. Data obtained in these groups were compared with the group with experimentally induced cardiomyopathy (daunorubicin 50 mg/m2 i.v.) and with the control group (saline 1 ml/kg). Only mild and mostly no significant changes of the cardiovascular parameters (DMB 12 group: PEP:LVET ratio--0.408-0.502, LV dP/dtmax.--1337.0 kPa/s; DMB 24 group: PEP:LVET ratio--0.407-0.433, LV dP/dtmax.--1438.2 kPa/s), biochemical parameters (decrease in natrium, ALP and increase in glucose, GPX and GSH levels) and haematological parameters (increase in erythrocytes and decrease in leukocytes after the larger dose of the drug) were found in the dimethoxybenfluron groups. Repeated administration of the lower dose of Oracin induced only mild and mostly no significant changes of parameters (PEP:LVET ratio--0.393-0.475, LV dP/dtmax.--1092.4 kPa/s) in comparison with the control group. Though significant in some intervals, only a mild oscillation of the PEP:LVET ratio (0.368-0.446), decrease in LV dP/dtmax. (991.2 kPa/s) and--in comparison with control group--significantly higher blood pressure and lower heart rate were found after the higher dose of Oracin. In the most of haematological and biochemical parameters (with the exception of chlorides, protein and albumin levels) no significant changes were present. Histological examination of the heart revealed normal structure of the myocardium including minute changes of myocardium following administration of antineoplastic agents in all groups. Administration of new antineoplastic agents induced mostly mild changes of the followed-up parameters (PEP:LVET ratio, LV dP/dtmax., heart rate, levels of cardiac troponin T, survival of animals, haematological and biochemical parameters); the values of parameters were mostly significantly different from those in rabbits with daunorubicin-induced cardiomyopathy. On the basis of our results it is possible to conclude that the administration of dimethoxybenflurone and Oracin did not induce signs of cardiotoxicity in rabbits in vivo. This observation is considered to be important from the viewpoint of possible further clinical use of these new antineoplastic agents.

Animals↗

PubMed2001

Protein secretion biotechnology using Streptomyces lividans: large-scale production of functional trimeric tumor necrosis factor alpha.

We evaluated the feasibility of large-scale production of biopharmaceuticals expressed as heterologous polypeptides from the Gram-positive bacterium Streptomyces lividans. As a model protein we used murine tumor necrosis factor alpha (mTNFalpha). mTNFalpha fused C-terminally to the secretory signal peptide of the subtilisin-inhibitor protein from Streptomyces venezuelae. Under appropriate fermentation conditions, significant amounts of mature mTNFalpha (80-120 mg/L) can be recovered from spent growth media. Efficient downstream processing allowing rapid purification of mTNFalpha from culture supernatants was developed. Importantly, the protein is recovered from the spent growth medium in its native trimeric state as judged by biophysical analysis. Further, mTNFalpha secreted by S. lividans is significantly more active in an in vitro apoptosis tissue culture assay than a corresponding polypeptide produced in Escherichia coli. This pilot study provides the first validation of S. lividans protein secretion as an alternative bioprocess for large-scale production of oligomeric proteins of potential therapeutic value.

Bioreactors↗

PubMed1997

A method for preserving saliva samples at ambient temperatures.

To facilitate biochemical and biopharmaceutical studies when cold storage is unavailable, we assessed the stability of saliva samples containing preservatives stored at room temperature over a 1-year period. Two preservative mixtures were evaluated: sodium benzoate and citric acid (P1), and ethyl and propyl paraben (P2). Saliva samples were spiked with acetaminophen (APAP) or antipyrine (AP) and stored in preservative-coated vials and examined for concentrations of APAP, AP, melatonin, and cortisol at regular intervals as a function of preservative type and storage duration. Samples were stored at room temperature or at -20 degrees C (positive control) and analyzed periodically for APAP and AP by high-performance liquid chromatography and for melatonin and cortisol by radioimmunoassay. The effectiveness of the preservatives was determined by calculating the value of samples stored at room temperature in terms of percent of control (-20 degrees C) values. P1 effectively maintained the stability of APAP (100%) and AP (100%) for 360 days at room temperature; concentrations in samples at room temperature on day 360 were comparable to those on day 01. P1 also effectively maintained melatonin (100%) and cortisol (95%) concentrations for 180 days at room temperature. P2 preserved AP and cortisol in saliva for 60 days, but APAP for only 14 days.

Acetaminophen↗

PubMed2001

[Marker transport across biological barriers in vitro: comparison of cell culture models for the gastrointestinal barrier, the blood-brain barrier and the alveolar epithelium of the lung].

In order to respond to the flood of new active ingredients currently being generated by combinatorial chemistry or molecular biological synthesis, selection procedures able to filter out rapidly and economically those drug candidates with the highest development potential are required. This necessitates the measurement of fundamental biopharmaceutical parameters very early in the drug development process. Any pharmaceutically active agent must be able to overcome the body's natural protective mechanisms. A broad variety of biological barriers can be simulated in the laboratory by cell monolayer models. Apart from ethical aspects, the advantage of these in vitro test systems is that permeability studies can be performed at high throughput rates under controlled and reproducible conditions. The validity of such a model is ultimately reflected in its ability to accurately predict the behaviour of an active ingredient at the corresponding in vivo barrier.

Animal Testing Alternatives↗