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PubMed1995

Transforming growth factors beta: conformational stability and features of the denaturation of recombinant human transforming growth factors beta 2 and beta 3.

Transforming growth factors beta (TGF-beta) are cytokines with multiple biological activities. Their development as biopharmaceutical drugs targets the control of complex physiological processes such as osteogenesis and epithelial cell differentiation. We report here the first characterization of the recombinant human (rh) TGF-beta 2 and rhTGF-beta 3 isoforms in terms of their conformational stability and structural transitions induced by a chaotrope or temperature. The transitions detected by CD spectroscopy suggested that thermal denaturation of both TGF-beta isoforms apparently fitted a simple two-state (N<==>D) model. However, the ratios of calorimetric to van't Hoff enthalpies, significantly different from unity, indicated that these molecules most probably consist of independently denaturing subdomains. The complex transitions induced by guanidine hydrochloride, at pH 1.8 or 8.0, also suggested intermediately denatured structures. Thermodynamic stabilities under pH conditions useful for bioprocessing were derived from spectroscopic and calorimetric measurements. Treatment of thermal denaturation data by van't Hoff analysis yielded, for the beta 2 and beta 3 isoforms respectively, apparent delta G(25 degrees C, pH 1.8) of 20.4/17.2 kJ/mol and 17.5/18.6 kJ/mol (near-UV CD/far-UV CD data) in 20 mM hydrochloric acid, and apparent delta G (25 degrees C, pH 3.0) of 35.1 and 33.5 kJ/mol in 0.25 M acetic acid (calorimetric data). Neither low-pH-induced denatured states nor soluble aggregates were detected in both acidic solvents. The spectroscopic and thermodynamic data should be useful for assessing the homogeneity and proper folding of these recombinant molecules.

Calorimetry, Differential Scanning↗

PubMed1994

Bioadhesion technologies for the delivery of peptide and protein drugs to the gastrointestinal tract.

For the efficient delivery of peptides, proteins, and other biopharmaceuticals by nonparenteral routes, in particular via the gastrointestinal, or GI, tract, novel concepts are needed to overcome significant enzymatic and diffusional barriers. In this context, bioadhesion technologies offer some new perspectives. The original idea of oral bioadhesive drug delivery systems was to prolong and/or to intensify the contact between controlled-release dosage forms and the stomach or gut mucosa. However, the results obtained during the past decade using existing pharmaceutical polymers for such purposes were rather disappointing. The encountered difficulties were mainly related to the physiological peculiarities of GI mucus. Nevertheless, research in this area has also shed new light on the potential of mucoadhesive polymers. First, one important class of mucoadhesive polymers, poly(acrylic acid), could be identified as a potent inhibitor of proteolytic enzymes. Second, there is increasing evidence that the interaction between various types of bio(muco)adhesive polymers and epithelial cells has direct influence on the permeability of mucosal epithelia. Rather than being just adhesives, mucoadhesive polymers may therefore be considered as a novel class of multifunctional macromolecules with a number of desirable properties for their use as biologically active drug delivery adjuvants. To overcome the problems related to GI mucus and to allow longer lasting fixation within the GI lumen, bioadhesion probably may be better achieved using specific bioadhesive molecules. Ideally, these bind to surface structures of the epithelial cells themselves rather than to mucus by receptor-ligand-like interactions. Such compounds possibly can be found in the future among plant lectins, novel synthetic polymers, and bacterial or viral adhesion/invasion factors. Apart from the plain fixation of drug carriers within the GI lumen, direct bioadhesive contact to the apical cell membrane possibly can be used to induce active transport processes by membrane-derived vesicles (endo- and transcytosis). The nonspecific interaction between epithelia and some mucoadhesive polymers induces a temporary loosening of the tight intercellular junctions, which is suitable for the rapid absorption of smaller peptide drugs along the paracellular pathway. In contrast, specific endo- and transcytosis may ultimately allow the selectively enhanced transport of very large bioactive molecules (polypeptides, polysaccharides, or polynucleotides) or drug carriers across tight clusters of polarized epi- or endothelial cells, whereas the formidable barrier function of such tissues against all other solutes remains intact.

Adhesiveness↗

PubMed1995

Step-up multiple testing of parameters with unequally correlated estimates.

We consider the problem of simultaneously testing k > or = to 2 hypotheses on parameters theta(1), ..., theta(k) using test statistics t(1), ..., t(k) such that a specified familywise error rate alpha is achieved. Dunnett and Tamhane (1992a) proposed a step-up multiple test procedure, in which testing starts with the hypothesis corresponding to the least significant test statistic and proceeds towards the most significant, stopping the first time a significant test result is obtained (and rejecting the hypotheses corresponding to that and any remaining test statistics). The parameter estimates used in the t statistics were assumed to be normally distributed with a common variance, which was a known multiple of an unknown sigma(2), and known correlations which were equal. In the present article, we show how the procedure can be extended to include unequally correlated parameter estimates. Unequal correlations occur, for example, in experiments involving comparisons among treatment groups with unequal sample sizes. We also compare the step-up and step-down multiple testing approaches and discuss applications to some biopharmaceutical testing problems.

Animals↗

PubMed1994

[The basis and goals of the pharmacy profession--pharmacobotany and its contribution to the development of drugs].

Pharmacy is one of very comprehensive and complex fields of human activity; the interrelationships of its individual principal disciplines did not always develop synergically in the course of time. At present, when the field commemorates important anniversaries and develops in the period of new social changes, it is necessary to contemplate the development of the individual fields and their balances in the principal entity for the pharmacist--the medicament. The historiography of the field unambiguously points at the cardinal position of classic pharmacognosy in this process, showing its development, separation of pharmacology, the relationship of pharmacognosy to pharmaceutical chemistry, the differences between the two disciplines and the origin of galenical pharmacy, or the not very fortunate concept of biopharmaceutics. This process takes place in the picture of the dialectical unity of the principal pharmaceutical categories: the drug--the pharmaceutical preparation--the medicament. The development of pharmacobotany as a practical complex discipline originated from pharmacognosy shows in a graphic way the development of the discipline "an sich" into the entity "für sich" and suggests the approach of the pharmacist to the phenomenon of the medicament from the historiographical viewpoint.

Chemistry, Pharmaceutical↗

PubMedDate not supplied

[Absolute and relative bioavailability of germanium in the rabbit].

The debated consumption of germanium suggested the authors to compare biopharmaceutical parameters of germanium oxide and germanium sesquioxide. A first evaluation, in rabbit, has been based on Germanium blood levels determined by atomic absorption spectrometry, after cross administration of both products by the I.V. and oral routes. When given orally, the apparent oxide bioavailability is very low (about 10%) but better than that of the sesquioxide. That difference could result from differences of disposition parameters of both products, which have to be studied late.

Animals↗

PubMed1995

Controversy still simmers over plan to build plasma-fractionation plant in Nova Scotia.

Controversy still simmers over a plan by the Canadian Red Cross Society and a US biopharmaceutical manufacturer to build a plasma-fractionation plant near Halifax. The unilateral decision to go ahead with the plant was taken as the Krever inquiry into Canada's blood-supply system was holding public hearings across the country. A panel created to evaluate the proposal has supported the fractionation plant, but made additional recommendations concerning product pricing, research and development, plasmapheresis centres and membership of the Board of Directors.

Chemical Fractionation↗

PubMed1994

Biological accessibility of calcitonin and osteocalcin marked 125J for rats.

Biological accessibility of calcitonin and osteocalcin marked 125J for rast. In this study we estimated the biological accessibility and the degree of biological accessibility of calcitonin in relation to highly specific marker-osteocalcin after a single intraperitoneal administration. We showed mean values of biopharmaceutical parameters for the analysed hormones.

Animals↗

PubMed1994

Bioavailability of hydrocortisone acetate from ophthalmic ointments.

The biopharmaceutical studies of 1% hydrocortisone acetate ophthalmic ointments were carried out with isolated pig's eyes and demonstrated that the drug concentration in intraocular fluids depended on: a) ointment base used - the best bioavailability was obtained using white petrolatum with addition of 10% anhydrous lanolin, b) eye fluid examined - concentration of hydrocortisone acetate in aqueous humor was several times higher than in vitreous humor, c) presence of corneal epithelium - in all studied cases abrasion of corneal epithelium was accompanied by well-marked increase of drug concentration in intraocular fluids.

Administration, Topical↗

PubMed1994

A new method for the determination of the bioavailability of thyroid hormone preparations.

Levothyroxine and levotriiodothyronine are vital hormones that are produced and stored in the thyroid gland. Due to endogenic hormone production and regulation, it is impossible to determine the bioavailability of exogenic hormone using conventional trial designs since exogenic hormone cannot be distinguished from endogenic hormone in serum unless radiolabelled. Bioavailability, however, is an essential quality attribute of thyroid hormone preparations. A new trial design was developed that allows the bioavailability of thyroid hormone preparations to be determined without the use of radiolabelled substances. The trial subjects were volunteers (athyreotic patients) who, after thyroidectomy and postoperative radioiodine therapy, do not produce endogenic thyroid hormone and have to be supplied with exogenic levothyroxine on a permanent basis (replacement therapy). An oral solution of levothyroxine was used as a reference. Such a solution can be prepared with the same biopharmaceutical quality on a reproducible basis and is suitable for comparing preparations with one another that are used in different trials with the same design. The orally given reference solution is well tolerated and can therefore be administered over the required periods of time (e.g., 3 x 4 weeks). In a randomized, 3-way Latin-square design, the volunteers were given either L-Thyroxin Henning, another tablet preparation, or the reference solution, each for 28 days running during each period. On days 26, 27 and 28 of each period, the serum concentrations of levothyroxine and levotriiodothyroine were determined in order to verify the steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Bioavailability of selenium from selenium preparations in rats.

In the study the relative bioavailability as well as the extent of bioavailability of selenium after a single intragastric administration of selenium yeast and sodium selenite have been determined. Also, the mean values of biopharmaceutical parameters of the tested selenium preparations have been presented.

Animals↗

PubMed1994

Influence of the emulsion sign in phenytoin bioavailability.

To study the influence of the emulsion sign in phenytoin bioavailability, two emulsions (w/o and o/w) were prepared. Bioavailability studies were carried out with both emulsions in Wistar male rats. The study was of a randomized two-way cross over design. A radiotracer technique was chosen as analytical procedure, due to the small blood sample collected. 14C-phenytoin was synthesized with a high yield and suitable radiochemical purity. It is concluded, from a biopharmaceutic point of view, that the emulsion sign does not seem to affect the amount of phenytoin absorbed, as it is shown through the comparison of the areas under curve up to 24 h. An emulsion with oil as an external phase is responsible of a longer absorption, taking into account the apparent elimination constant rates.

Animals↗

PubMed1993

[Principles of the pharmacokinetics and pharmacodynamics of calcium antagonists].

Today calcium antagonists (Ca-antagonists) are widely used agents in the management of various diseases of the circulatory system. More than 20 years ago the Ca-antagonists of the so-called 1st generation (Verapamil, Diltiazem, Nifedipine) were introduced for treatment of angina pectoris and later of essential hypertension. In the last decade an increasing number of agents structurally related to dihydropyridines were developed for the treatment of hypertension and/or coronary heart disease or cerebral disorders; the main target was to reduce side effects and to guarantee once or at least twice daily administration. Therefore the Ca-antagonists of the so-called 2nd generation (e.g. Amlodipine, Felodipine, Isradipine, Nitrendipine, Nicardipine, Nimodipine, Nisoldipine) tend to longer elimination-half-lives; Amlodipin is an exception with an elimination-half-life of 30 hours on the average. Apart from elimination rates, however, the biopharmaceutical and pharmacokinetic characteristics of all Ca-antagonists are similar: they are highly cleared drugs and are relatively highly protein bound. As they are subject to significant hepatic first-pass-metabolism old age and hepatic disease will increase their plasma-concentrations. Renal impairment affects little their pharmacokinetics since the fraction eliminated unchanged by the kidneys is small. For most agents, plasma-concentration-response relationships have been described. With exception of nicardipine a linear pharmacokinetic in all Ca-antagonists was demonstrated. Drugs and food affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. With regard to the acute pharmacodynamic effects the Ca-antagonists show similar qualitative effects, though there are quantitative differences. Orally administered dihydropyridine-derivatives induce acute hypotensive effects, whereas the other compounds show clinically relevant hypotensive effects only when administered chronically per os or less pronounced when given as intravenous infusion.

Biological Availability↗

PubMed1993

[Pharmaceutical aspects of drug side effects].

The drug delivery systems which contain not only the active principle but also many auxiliary substances are often underestimated with respect to their desired and undesired effects. Due to their composition, their purity, their physical, chemical or biopharmaceutical properties, the pharmaceutical system may be taken into consideration at each pharmacodynamic and clinical evaluation. The importance of some pharmaceutical properties on nondesired effects are shown with the examples of insufficient degradation and drug release, too quick drug alteration, inhomogeneous distribution and the role of badly selected excipients as well as the negative influence of food on drug plasma levels.

Chemistry, Pharmaceutical↗

PubMedDate not supplied

[Efforts toward the formulation of the therapeutic stereoisomer of ibuprofen].

In an on going effort to optimize ibuprofen antiinflammatory therapy, development studies on the active stereoisomer of ibuprofen have been conducted. The effects of pharmaceutical processing on the racemate (RAC-ibuprofen) and the enantiomer (S(+)-ibuprofen) were investigated. The formulation of the new stereospecific system, was impossible using wet granulation. The pharmaceutical development of S(+)-ibuprofen using direct compression appeared as a practical solution to this problem. The biopharmaceutical properties of the resulting tablets were well within pharmacopeia requirements. Nevertheless, mixing S(+)-ibuprofen with the excipients induced a drop in the enthalpy of fusion and after compaction, a low temperature eutectic appeared on the differential scanning calorimetry endotherms. Aging studies indicated that the raw material and pharmaceutical mixtures of S(+)-ibuprofen should be stored under strictly controlled conditions or processed immediately.

Ibuprofen↗

PubMed1995

Biologic interventions in rheumatoid arthritis.

An increasing understanding of the immunopathogenesis of rheumatoid arthritis and advances in biotechnology have lead to the therapeutic application of immune-specific interventions. The complexity of this disorder has generated numerous investigations using a wide range of biologic interventions. This article presents the current and potential targets for such biopharmaceutical agents and discusses their utility in rheumatoid arthritis.

Adjuvants, Immunologic↗

PubMed1996

Development and pharmacology of fluvastatin.

Fluvastatin is the first synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor to be approved for clinical use, and has been studied extensively in humans since 1986. It is structurally distinct from the other currently available HMGCoA reductase inhibitors (lovastatin, simvastatin, and pravastatin), leading to unique biopharmaceutical properties relative to the other agents of this class. Absorption of fluvastatin is virtually complete across all species, including man, and is not affected by the presence of food. Systemic exposure is limited, as fluvastatin is subject to first-pass metabolism, and the plasma half-life of the drug is approximately 30 minutes. Some 95% of a single dosage of fluvastatin is excreted via the biliary route, with less than 2% of this being the parent compound. Additionally, there is no evidence of circulating active metabolites or accumulation during chronic dosing. Studies of the effect of food on the pharmacokinetics of fluvastatin have demonstrated marked reductions in the rate of bioavailability--from 40% to 60%; however, a comparison of fluvastatin administration with the evening meal or at bedtime has revealed no significant differences in the extent of bioavailability (area under the curve) of these two regimens. Furthermore, no significant difference in pharmacodynamic effect (reduction in low-density lipoprotein cholesterol levels) could be ascertained between mealtime dosing and bedtime dosing. The pharmacokinetics of fluvastatin have also been assessed in various demographic groups. Relative to the general population, plasma concentrations of fluvastatin do not vary as a function of either age or gender. In addition, administration to a patient population with hepatic insufficiency resulted in a 2.5-fold increase in both the rate and extent of bioavailability relative to controls. Also, although minimal alterations of fluvastatin clearance in patients with renal insufficiency are anticipated due to limited renal excretion (5%), a study in this patient group is currently underway to examine this further. Interaction studies have been performed with fluvastatin and several drugs with which it might be coadministered. Cholestyramine, an anionic-binding resin, has a considerable effect in lowering the rate and extent of fluvastatin bioavailability. Although this effect was noted even when cholestyramine was given 4 hours prior to fluvastatin, this regimen did not result in diminished efficacy. Further, no effects on either warfarin levels or prothrombin times were observed in a study involving concomitant administration of warfarin and fluvastatin. Moreover, additional interaction studies with niacin and propranolol have not demonstrated any effect on fluvastatin plasma levels, and administration to a patient population chronically receiving digoxin resulted in no difference in the extent of bioavailability of digoxin relative to control data. The results generated to date in clinical pharmacokinetic studies with fluvastatin thus support its use in a broad population of hypercholesterolaemic patients.

Adult↗

PubMed1996

Investigation of the therapeutic equivalence of different galenical preparations of O-(beta-hydroxyethyl)-rutosides following multiple dose peroral administration.

Oxerutins (O-(beta-hydroxyethyl)-rutosides, HR, Venoruton) are available in different releasing galenical formulations for the treatment of chronic venous insufficiency (CVI). In order to investigate the biopharmaceutical relevance of the releasing properties of the galenical forms the therapeutic efficacy between the commercially available forms was investigated (500 mg sustained release film tablets, 300 mg sustained release film tablets, 300 mg normally releasing capsules) in comparison to an aqueous solution and placebo. In total 100 female patients with CVI grade II participated. The study was carried out following a randomized, placebo controlled design with parallel treatment groups. Following a two-week run-in phase patients were treated for 12 weeks with different posologies of HR (2 x 1/d 500 mg, 3 x 1/d 300 mg, 1 x 1000 mg/d as aqueous solution). Main criterion was the reduction of leg volume following 12 weeks treatment. Subjective criteria were descriptively evaluated. All four HR treatments were significantly superior to placebo (p < 0.0008). The different posologies had no influence on the efficacy. The therapeutic efficacy is independent of the in vitro rate of release. The available forms are regarded as bioequivalent.

Aged↗

PubMed1996

Pharmacokinetics and drug interactions--relevant factors for the choice of a drug.

Pharmacokinetics serve as a useful tool in drug development by identifying the drug's disposition and elimination characteristics, the absorption characteristics of the biopharmaceutical formulation, and the therapeutic dose regimen in various patient populations. Where two or more drugs of a class have a similar efficacy, the choice of the drug may depend upon the reproducibility of the pharmacokinetics and the minimal risk of drug interaction. Pantoprazole, a selective proton pump inhibitor, appears to meet the above criteria. As opposed to other members of the class, pantoprazole exhibits linear, predictable pharmacokinetics and lack of drug interactions.

2-Pyridinylmethylsulfinylbenzimidazoles↗