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PubMed2003

Validating the hen as a bioreactor for the production of exogenous proteins in egg white.

Increased demand for the production of human biopharmaceuticals in transgenic organisms has led to an intensive effort to develop the hen as a bioreactor producing exogenous proteins in egg white via transgenesis. To date, however, robust methods for transgenic modification of the avian genome have been lacking. We have used a replication-defective retroviral vector derived from avian leukosis virus (ALV) to generate transgenic chickens expressing bacterial beta-lactamase secreted into serum and egg whites through several generations. Expression was driven by the ubiquitous cytomegalovirus (CMV) promoter. Here we describe results from a transgenic lineage (Harvey et al., 2002a,b) in which (1) the transgene was stably transmitted from a G1 founder male (5657) through several generations without silencing, (2) the protein was biologically active, and (3) the level of expression in egg whites was doubled in a G3 homozygote.

Animals↗

PubMed2006

Receptor-mediated oral delivery of a bioencapsulated green fluorescent protein expressed in transgenic chloroplasts into the mouse circulatory system.

Oral delivery of biopharmaceutical proteins expressed in plant cells should reduce their cost of production, purification, processing, cold storage, transportation, and delivery. However, poor intestinal absorption of intact proteins is a major challenge. To overcome this limitation, we investigate here the concept of receptor-mediated oral delivery of chloroplast-expressed foreign proteins. Therefore, the transmucosal carrier cholera toxin B-subunit and green fluorescent protein (CTB-GFP), separated by a furin cleavage site, was expressed via the tobacco chloroplast genome. Polymerase chain reaction (PCR) and Southern blot analyses confirmed site-specific transgene integration and homoplasmy. Immunoblot analysis and ELISA confirmed expression of monomeric and pentameric forms of CTB-GFP, up to 21.3% of total soluble proteins. An in vitro furin cleavage assay confirmed integrity of the engineered furin cleavage site, and a GM1 binding assay confirmed the functionality of CTB-GFP pentamers. Following oral administration of CTB-GFP expressing leaf material to mice, GFP was observed in the mice intestinal mucosa, liver, and spleen in fluorescence and immunohistochemical studies, while CTB remained in the intestinal cell. This report of receptor-mediated oral delivery of a foreign protein into the circulatory system opens the door for low-cost production and delivery of human therapeutic proteins.

Administration, Oral↗

PubMed1994

Augmentation of alveolar macrophage phagocytic activity by granulocyte colony stimulating factor and interleukin-1: influence of splenectomy.

The use of cytokines and other naturally occurring substances as biopharmaceuticals for modulating the host response to trauma and infection offers new therapeutic possibilities. Cytokine pretreatment protects animals in a variety of experimental models, including splenectomized mice following pneumococcal aerosol challenge. Since splenectomy appears to affect alveolar macrophage function, we postulated that pretreatment with interleukin 1 (IL-1) and granulocyte colony stimulating factor (G-CSF) improved survival in mice following aerosol challenge of live pneumococci by activating alveolar macrophages. Alveolar macrophage bactericidal and phagocytic function was slightly, but consistently, depressed following splenectomy. Interleukin-1 and G-CSF pretreatment had pronounced effects on macrophage phagocytic and bactericidal activity, and these effects were quite different depending upon whether the mice were eusplenic or asplenic. Splenectomy augmented the effects of IL-1 on alveolar macrophage bactericidal function compared with eusplenic mice (p < 0.001), while more pronounced effects on macrophage function following G-CSF treatment were seen in mice with intact spleens (p < 0.001). The use of cytokines and other substances to modify the host response to infection has great potential. Individuals with deficits such as splenectomy will have a different net response to therapy. It is important that we be able to predict these responses accurately in most patients in order to use these substances more effectively.

Animals↗

PubMed1994

The Pharmacokinetics of Once-Daily Diltiazem SR (Sustained-Release) in Young Versus Elderly Hypertensive Patients.

The objective of this open-label, outpatient, parallel-group investigation was to compare the single-dose and steady-state pharmacokinetic profiles of young (n = 12; x = 41 ± 6 years) and elderly (n = 12; X = 69 ± 4 years) hypertensive patients following administration of a once-daily formulation of diltiazem. The study was comprised of two phases. The first phase was a lead-in phase used to establish hypertensive status. In the second phase, patients were administered a single- and multiple-daily dose regimen of 240 mg of diltiazem SR. Plasma samples were obtained at selected times and analyzed for diltiazem using a specific and sensitive HPLC assay. Biopharmaceutic parameter estimates were determined and analyzed for statistical differences. Qualitatively similar concentration-time profiles were observed between groups, suggesting similar release characteristics of the sustained-release formulation. However, significantly higher overall concentrations of diltiazem were observed following single-dose administration in the elderly, possibly as a result of an age-related decrease in the apparent oral clearance of diltiazem. A further reduction in the apparent oral clearance of diltiazem with multiple-dose administration was observed in the elderly resulting in even higher than projected concentrations of diltiazem. Thus, greater oral systemic availability of diltiazem in the elderly hypertensive patients may warrant closer clinical monitoring and possibly a reduction in dosage.

Journal Article↗

PubMedDate not supplied

The effect of food on the bioavailability of ebastine.

Two studies were performed to characterize the influence of food on the bioavailability of the current formulation of ebastine tablets. Study 1 was an open label, randomized, three-period, crossover food effect study where 18 healthy male volunteers received 10 mg ebastine after an overnight fast, a low-fat breakfast, and a high-fat breakfast. Study 2 was an open label, randomized, two period crossover food effect study where 12 healthy male volunteers received 20 mg ebastine after both an overnight fast and a high-fat breakfast. Plasma samples were obtained at selected times and analyzed for ebastine and carebastine, the active metabolite of ebastine, using a validated high-performance liquid chromatography assay. Biopharmaceutic parameters for carebastine, area under the plasma concentration-time curves (AUC (0-infinity)), and maximum plasma concentrations (C ( max ) ), were estimated using noncompartmental techniques and analyzed for statistical differences. AUC (0-infinity) and C(max estimates were 40%-50% and 30%-40% higher under fed conditions as compared with fasting conditions. The time to reach maximum concentrations (T(max)), the terminal elimination rate (K(e) ), and the half-life (t(1/2) ) were not significantly altered by the ingestion of a low-fat or high-fat meal. Statistical analyses of the natural logarithmic transformed data for AUC ((0-infinity) and C(max) also demonstrated significant differences between fasted and fed (low-fat and high-fat) conditions. This indicates that food had a statistically significant effect on the rate and extent of carebastine formation. Therefore, it may be concluded that administration with food maximizes the bioavailability of carebastine.

Adult↗

PubMed2001

Antituberculosis drugs and new drug development.

Tuberculosis affects more than 8 million people and has serious repercussions on economic, psychologic, and social status. Since its declaration as a global emergency in 1993 by the World Health Organization, significant development in the treatment and control of tuberculosis has been the implementation of the short-course directly observed treatment along with fixed dose combinations of existing drugs. However, the currently available therapeutic regimens have inherent disadvantages of long treatment duration, patient noncompliance, and risk of drug resistance. Hence, new antituberculosis drugs that are potent, are active against resistant strains and latent forms, and reduce the treatment period are needed to combat this disease. In this review, the authors discuss new chemical entities that in their opinion have a potential to become new antituberculosis drugs. This article emphasizes the role of biopharmaceutics and pharmacokinetics as an indispensable part in the development of new antituberculosis drugs to overcome the common hurdles such as exorbitant cost, time, and attrition rate involved in the process.

Animals↗

PubMed2003

Transdermal testosterone for women: a new physiological approach for androgen therapy.

Transdermal testosterone patches and topically applied gels have become well accepted for the treatment of testosterone deficiency in men and are currently being developed in appropriate dosage strengths for androgen therapy in women. The furthest developed among these products is an investigational testosterone matrix patch which is now in phase III clinical trials for the treatment of sexual dysfunction in oophorectomized and naturally menopausal women. This review article discusses the biopharmaceutical rationale for the transdermal delivery of testosterone to women, illustrates and quantitatively analyzes the pharmacokinetics and metabolism of the testosterone matrix patch and a recently investigated testosterone gel, and summarizes the efficacy and safety data that have been reported in phase II studies of the testosterone matrix patch in surgically menopausal women with sexual dysfunction and HIV-infected women with the AIDS wasting syndrome. The different effects of oral and transdermal estrogen therapy (ET) on the concentrations of total and free testosterone attained with the testosterone matrix patch are contrasted. Although still in development, transdermal testosterone therapy appears to be a promising new approach for providing physiologically based androgen therapy to women.

Administration, Cutaneous↗

PubMed2006

Peptide display on Potato virus X: molecular features of the coat protein-fused peptide affecting cell-to-cell and phloem movement of chimeric virus particles.

The potexvirus Potato virus X (PVX) can be modified genetically to generate chimeric virus particles (CVPs) carrying heterologous peptides fused to coat protein (CP) subunits. A spontaneous PVX mutant expressing a truncated, but functional, form of the CP has been isolated. With the aim of exploiting this virus to display peptides useful for vaccine formulations, two novel viral expression vectors based on pPVX201 (bearing the wild-type PVX genome) were constructed encoding the truncated CP. Both vectors were able to produce infectious virus particles in planta and were used to insert a panel of sequences encoding peptides of biopharmaceutical interest as N-terminal fusions to the truncated cp gene. The analysis of infection progression induced by the different constructs enabled identification of two important structural features of the fused peptide, namely tryptophan content and isoelectric point, critically affecting the formation of PVX CVPs and virus movement through the plant. These results are discussed in view of the rising interest in engineered plant viruses for development of peptide-based epitope vaccines.

Capsid Proteins↗

PubMed2000

Correcting for noncompliance and dependent censoring in an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests.

AIDS Clinical Trial Group (ACTG) randomized trial 021 compared the effect of bactrim versus aerosolized pentamidine (AP) as prophylaxis therapy for pneumocystis pneumonia (PCP) in AIDS patients. Although patients randomized to the bactrim arm experienced a significant delay in time to PCP, the survival experience in the two arms was not significantly different (p = .32). In this paper, we present evidence that bactrim therapy improves survival but that the standard intent-to-treat comparison failed to detect this survival advantage because a large fraction of the subjects either crossed over to the other therapy or stopped therapy altogether. We obtain our evidence of a beneficial bactrim effect on survival by artificially regarding the subjects as dependently censored at the first time the subject either stops or switches therapy; we then analyze the data with the inverse probability of censoring weighted Kaplan-Meier and Cox partial likelihood estimators of Robins (1993, Proceedings of the Biopharmaceutical Section, American Statistical Association, pp. 24-33) that adjust for dependent censoring by utilizing data collected on time-dependent prognostic factors.

AIDS-Related Opportunistic Infections↗

PubMed1980

Comparative single-dose kinetics and effects of four sulfonylureas in healthy volunteers.

The single-dose kinetics and effects of tolbutamide (500 mg), chlorpropamide (250 mg), glibenclamide (5 mg) and glipizide (5 mg) were compared in 7 healthy male volunteers by measurements of serum concentrations of the drugs and of plasma insulin and blood glucose. The drugs were administered both on an empty stomach and together with a standardized breakfast. The concentrations of tolbutamide and chlorpropamide were measured by gas chromatography, those of glipizide with high-pressure liquid chromatography, those of glibenclamide and insulin by radioimmunoassay and those of glucose by the hexokinase method. Glipizide and glibenclamide were more potent inducers of insulin release and blood glucose reduction than tolbutamide and chlorpropamide. As the concentrations of the former two drugs were in the range of nmol/l and those of the latter two in the mumol/l range, the findings support the notion that the intrinsic activity of the two second-generation sulfonylureas is at least 1 000 times greater than that of the two first-generation drugs. Glipizide seemed to be a more potent and more rapid insulin releaser than glibenclamide, but this may be secondary to biopharmaceutic differences between the two preparations. The bioavailability of glipizide was apparently greater than that of glibenclamide. Both glibenclamide (t 1/2 = 1.8 h) and glipizide (t 1/2 = 4.3 h) showed much shorter elimination half-lives than tolbutamide (7 h) and chlorpropamide (34 h). It seems probable, however, that these half-lives are not fully informative as to the duration of action of the drugs.

Adult↗

PubMed2004

A review of research related to blood transfusion in Canada, 2000-2002.

The former National Blood Safety Council undertook a comprehensive review of blood transfusion research in Canada for the years 2000 through 2002. Data were acquired by direct contact with agencies which support such research and by searches of the relevant websites. Total grant support increased markedly over the 3-year period, from 4.1 million dollars to 18.5 million dollars. Publicly funded granting agencies, biopharmaceutical companies, the blood services and the province of Ontario were major supporters. Much smaller amounts were granted from charitable organizations. Clinical research attracted the majority of the funding, although a larger number of projects were basic science in nature. Most research was carried out in the provinces of Ontario, Québec and British Columbia. Although we have not assessed the productivity of blood-related research, it appears that substantial amounts of funding were allocated to these projects between 2000 and 2002. These data may provide a helpful perspective to investigators in transfusion medicine elsewhere, who may also be assessing the relative priority given to this field of research in their own countries.

Blood Transfusion↗

PubMed1979

Pharmacokinetics and metabolism of various benzodiazepines used as hypnotics.

1 In the management of insomnia with drugs, any action should be restricted to the duration of the night and residual effects should be absent during the day-time. The intermittent type of drug action desired is fundamentally different from drug treatment where a constant effect is sought. 2 Duration of drug action is dependent on the kinetics of distribution and elimination of the parent drug and its effective metabolites. In addition biopharmaceutical factors, such as those which promote a rapid rate of absorption, are important. 3 These considerations serve as a guide for a review of the kinetics and metabolism of various benzodiazepines.

Anti-Anxiety Agents↗

PubMed1979

Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide.

1. The plasma levels and the urinary excretion of hydrochlorothiazide (HCT) have been studied after administration of single doses of 12.5 and 25 mg of the drug in solution and in combination with 100 mg of the selective beta 1-adrenoreceptor antagonist metoprolol in a rapidly dissolving tablet. 2. Metoprolol did not significantly influence the bioavailability or the time-course of HCT. 3. HCT had no significant effect on the time-course or the plasma levels of metoprolol. The average half-life, 4.4 +/- 0.9 h, is about the same as previously observed for separate doses of this drug. 4. It seems unlikely that repeated doses of the combination product studied will lead to biopharmaceutic or pharmacokinetic interactions of clinical importance.

Biological Availability↗

PubMed1985

Oros controlled-release formulations of metoprolol: an approach to the development of a system for once daily administration.

A combined biopharmaceutical and haemodynamic approach to the development of a metoprolol Oros controlled-release delivery system for once daily administration is reported. Two studies, each involving 18 healthy volunteers, were performed in which twice daily administration of 100 mg conventional metoprolol tartrate tablets was compared with once daily administration of Oros systems containing 190 mg metoprolol fumarate but with different drug release rates. Plasma drug concentrations and beta-adrenoceptor blocking effects were measured over 24 h on days 1 and 5 of each treatment, and pre-dose in the interval between the main study days. The results of the first study with a 19 mg/h Oros system indicated that this rate was too rapid to provide the required response under steady-state dosing conditions. Theoretical calculations based on a one-compartment pharmacokinetic model and input functions for hypothetical Oros systems were then performed to define the optimal release rate for a once daily preparation. The results of the second study confirmed that a 14 mg/h system possessed the required characteristics in that it maintained more uniform beta-adrenoceptor blockade throughout 24 h, and produced pre-dosing plasma concentrations and haemodynamic effects which were identical to those for the conventional tablet twice daily regimen.

Adolescent↗

PubMed2005

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.

AIMS: It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS: Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. RESULTS: The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. CONCLUSION: With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

Administration, Sublingual↗

PubMed1994

A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse.

The biopharmaceutical properties of four fixed trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 +/- 0.48 h for a commercial paste (1), and at 1.84 +/- 0.66 h and 1.95 +/- 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (+/- SD) were 1.72 +/- 0.36 micrograms/ml, 1.42 +/- 0.37 micrograms/ml and 1.31 +/- 0.36 micrograms/ml, and mean peak plasma SDZ concentrations 12.11 +/- 4.55 micrograms/ml, 12.72 +/- 3.47 micrograms/ml and 15.45 +/- 4.74 micrograms/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 +/- 20.3%, 57.7 +/- 21.6% and 60.9 +/- 18.9% and of SDZ 57.6 +/- 14.8%, 59.3 +/- 19.5% and 65.9 +/- 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (+/- 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2006

Mucosal permeability of water-soluble drugs in the equine jejunum: a preliminary investigation.

Ussing chambers have been used to study the mucosal permeability of drugs in humans, rats and other species. This data can then be used to develop in vitro/in vivo correlations (IVIVC) for drugs based on the Biopharmaceutics Classification System (BCS). Due to the poor oral bioavailability of many drugs in the horse, this method may be useful for screening drugs before development to determine if they warrant further study. Cephalexin (CPX), marbofloxacin (MAR), metronidazole (MTZ) and fluconazole (FCZ) were chosen for this study based on the wide range of physicochemical properties and bioavailability in the horse. Permeability was ranked as follows: MTZ > FCZ > MAR > CPX. This correlated with the bioavailability (R(2) = 0.633447), the Log P (R(2) = 0.648517), as well as the molecular weight (R(2) = 0.851208) of the drugs. Metronidazole induced a decrease in the tissue transepithelial resistance, suggestive of the possibility of tissue toxicity, which may have falsely increased its permeability. The low permeability of cephalexin across the tissue may indicate a lack of active transporters that are found in other species. From this study, we can conclude that the Ussing chamber is a promising method for determining mucosal permeability in the horse.

Animals↗

PubMed2006

Biosimilars: how similar or dissimilar are they?

The imminent expiry of patents on biological medicinal products, such as epoetin alfa in 2006, has significant implications for nephrology in Australia. The purpose of this review is to examine the differences between biosimilars (similar biological medicinal products) and generic low molecular weight (chemical) drugs. The approach that regulatory agencies, including the European Medicines Agency (EMEA) and the Therapeutic Goods Administration (TGA), are taking towards biosimilars is also discussed. Biosimilars differ from generic chemical drugs in many important ways, including the size and complexity of the active substance, the nature of the starting materials (cell banks, tissues and other biological products), and the complexity of the manufacturing processes. Therefore, it has been acknowledged by the EMEA that established legal and regulatory principles of 'essential similarity' that are applied to standard chemical generics cannot be readily applied to biosimilars. One of the key areas of concern with the introduction of biosimilars into the field of nephrology will be guaranteeing the safety and efficacy of biosimilars. New manufacturers will need to ensure that their biopharmaceutical has a similar efficacy and safety profile to the innovator product through more extensive clinical trials than the limited testing done for generic versions of low molecular weight chemical medicines.

Biological Products↗