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  • 1
    ISSN: 1573-904X
    Keywords: antiplatelet drug ; association and dissociation constant ; efficiency factor ; G4120 ; gpIIb/IIIa ; residence time
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-904X
    Keywords: relaxin ; pharmacokinetics ; absorption ; intravenous ; intracervical ; intravaginal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., ≥20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-904X
    Keywords: hydrochlorothiazide ; triamterene ; Dyazide ; Maxzide ; amiloride ; Moduretic ; food–drug interactions ; food-formulation interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-904X
    Keywords: allometric equation ; interspecies scaling ; therapeutic proteins ; pharmacokinetics ; clearance ; volume of distribution ; soluble rCD4 ; CD4-IgG ; growth hormone ; tissue-plasminogen activator ; relaxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immuno-globulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the pre-clinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-904X
    Keywords: recombinant human transforming growth factor beta1 ; wound-healing ; pharmacokinetics ; plasma-based enzyme-linked immunosorbent assay (ELISA) ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Recombinant human transforming growth factor beta (rhTGF-β1) enhances the healing process after topical application to various animal wound models. A detailed pharmacokinetic and tissue distribution study was performed to support the clinical development of rhTGF-β1 for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-β1 as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-β1 were estimated from TCA-precipitable radioactivity or were measured by ELISA. Following iv administration, the initial half-life was rapid (〈11 min), regardless of whether radi-olabeled or unlabeled rhTGF-β1 was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and relatively short (≤61 min) when given at high doses and assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE revealed a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabolites. The majority of the radioactivity was associated with highly perfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high dose (0.8 mg/kg), no immunoreactive TGF-β1 was detectable in plasma samples taken over a 48-hr period. However, trace amounts (≤0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [125I]rhTGF-β1 (1 µg/kg, 126 µCi/kg). A significant portion (35%) of the [125I]rhTGF-β1 persisted intact (25 kDa) at the wound site 24 hr after application. In conclusion, rhTGF-β1 was rapidly cleared after iv bolus administration and distributed primarily to the liver, lungs, kidney, and spleen. Little systemic exposure was observed after applying a single topical dose of rhTGF-β1 to a wound, and the intact molecule persisted at the wound site.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-904X
    Keywords: gp120 ; AIDS-HIV-1 vaccine ; alum adjuvant ; aluminum hydroxide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The characterization of recombinant MN gp120/alum vaccine requires the study of the gp120-alum interaction for the successful formulation of an alum-based HIV-1 vaccine. Methods. Several observations suggest that the gpl20-alum interaction is weak, wherein buffer counterions such as phosphate, sulfate, bicarbonate may cause the desorption of gp120 from alum. Comparison of gp120 with other proteins using particle mobility measurements shows that the weak binding of gp120 to alum is not an anomaly. Serum and plasma also cause desorption of gp120 from alum with a half-life of only a few minutes, wherein this half-life may be faster than the in-vivo recruitment of antigen presenting cells to the site of immunization. Results. Immunization of guinea pigs, rabbits and baboons with gp120 formulated in alum or saline demonstrated that alum provides adjuvant activity for gp120, particularly after early immunizations, but the adjuvant effect is attenuated after several boosts. Conclusions. These observations indicate that both the antigen and the adjuvant require optimization together.
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  • 7
    ISSN: 1573-904X
    Keywords: bioequivalence ; biotechnology products ; recombinant proteins ; pharmacokinetics ; pharmacodynamics ; efficacy ; immunogenicity ; safety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The determination of biological equivalence requires that studies are conducted to establish that two molecules, two formulations, or two dosing regimens, for example, are indistinguishable with respect to safety and efficacy profiles that have been previously established. The criteria that are used to establish biological equivalence will depend on the nature of the change (e.g., molecular, process, formulation), the stage of the development program, the duration of treatment, and the intended clinical indications. Key components of an equivalence program include chemical characterization, in vitro and in vivo bioactivity against reference material, pharmacokinetics, and safety. Special considerations for patient populations, endogenous concentrations, environmental factors, immunogenicity, assay methodology, biochemical identity, pharmacodynamic equivalence, and statistical methodology are discussed. In addition, the role of preclinical in vivo assessments is addressed. Specific case studies provide insight into the varied nature of approaches that are currently employed.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-904X
    Keywords: allometric scaling ; compartmental and noncompartmental pharmacokinetics ; dilution factor ; exit time ; permanence time ; protein therapeutics ; recombinant human CD4 immunoglobulin G (rCD4-IgG) ; steady-state volume ; tracers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract General solutions for exit time, permanence time, dilution factor, and volume of distribution at steady state are derived for compartmental and noncompartmental systems. These derivations require that the systems are linear and state-determined. Unique values for these parameters cannot be determined when the site of elimination is not known; in this case the parameters can be defined by a range. Interpretation of this range and its significance and use in clinical situations are illustrated with two examples.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Two chimpanzees were pretreated with CD4-IgG (5 mg kg"1 given intravenously (i.v.)) at 8 h and 1 h before challenge, then inoculated with 120 tissue culture infectious doses (TCID50s) of HIV-1 IIIB (30 chimp infectious doses). After challenge, the animals received further CD4-IgG treatment for 9 ...
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  • 10
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Type of Medium: Electronic Resource
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