bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Interferons on Cortisol Production in Bovine Adrenal Fasciculata Cells Stimulated by Adrenocorticotropin
Authors: Tachikawa Eiichi , Itho Koji , Kudo Kenzo , Harada Kazuho , Kashimoto Takeshi , Hirota Yoshikazu 
Published: October 2002

Abstract
The effects of interferons (IFNs) IFN-α, IFN-β and IFN-γ on the production of cortisol in bovine adrenal fasciculata cells have been investigated.
Pretreatment of the fasciculata cells with recombinant interferon-α-2b from man (over 300 units mL−1), but not with fibroblast IFN-β or recombinant IFN-γ from man, reduced the production of cortisol in cells stimulated with adrenocorticotropin (ACTH) (1 nM). IFN-α-2b inhibited ACTH-induced cortisol production in a concentration- (300-15 000 units mL−1) and time- (2–24 h) dependent manner. The inhibitory effect of IFN-α-2b on the production was abolished when the cells were simultaneously treated with anti-IFN-α antibody, and it was reversible. IFN-α-2b also inhibited dibutyryl cyclic AMP-induced production of cortisol but not pregnenolone-induced production. The effect of IFN-α-2b was not influenced by increases in external ACTH and Ca2+ concentrations and IFN-α-2b did not affect the ACTH-induced increase in cyclic AMP level in the cells.
These results strongly suggest that IFN-α-2b reduces ACTH-induced production of cortisol in bovine adrenal fasciculata cells by affecting the early process of cortisol synthesis. The results also indicate that IFNs might not directly affect steroidogenesis in the adrenal cortex in-vivo, because of the requirement of high concentrations of IFN-α-2b for inhibition, and because of the ineffectiveness of IFN-β and IFN-γ.
Effect of Plasma-calcium-level-responsive Oestradiol Release from Apatitic Bone Cement on Bone Mineral Density in Ovariectomized Rats
Authors: Otsuka Makoto , Yoneoka Kazuki , Matsuda Yoshihisa , Fox Jeffrey L , Higuchi William I 
Published: October 2002

Abstract
The effects of plasma calcium levels on oestradiol release from apatite bone cement and on the bone mineral density of ovariectomized rats have been investigated.
Apatite cement was prepared from an equimolar mixture of tetracalcium phosphate, dicalcium phosphate dihydrate and 0.5% β-oestradiol bulk powder. After subcutaneous implantation of the cement, oestradiol release in diseased rats (ovariectomized rats on a low-calcium diet) was significantly higher than in normal rats. The drug levels of recovery-model rats (ovariectomized, but on a high-calcium diet) were significantly lower than those of the diseased rats. Calcium levels in diseased rats remained low during drug release but the plasma calcium levels of the recovery-model rats increased. The areas under the plasma calcium concentration-time curves (Ca-AUCs) for the recovery-model rats were higher than those for the diseased-model rats. The plasma oestradiol concentration AUCs and the Ca-AUCs were linearly related. The body weight of the recovery-model rats increased after five days, but that of the diseased-model rats did not. The bone mass of the recovery-model rats was greater after the experiment than before.
The relationship between the bone mineral density and Ca-AUC of the diseased rats suggested that bone mineral density increased with increasing Ca-AUC. The results suggest that the severity of osteoporosis in this animal model is reduced by implantation of the oestradiol-loaded apatite cement.
Stability Study of Human Serum Albumin Pharmaceutical Preparations
Authors: Oliva Alexis , Santoveña Ana , Llabres Matias , Fariña Jose B 
Published: October 2002

Abstract
The influence of temperature on the stability of human serum albumin (HSA) pharmaceutical preparations has been studied by size-exclusion high-performance liquid chromatography with multi-angle laser-light-scattering detection and by particle-size analysis.
The behaviour of HSA in two pharmaceutical preparations stored at different temperatures (40, 55 and 70°C) followed the same pattern—an increase in the relative percentage of dimer (MW 132 000 Da) and aggregate (MW &gt; 200 000 Da), and then a decrease in the concentration of all species and, finally, sudden protein coagulation. These results suggest a time- and temperature-dependent process. At 70°C, monomer only was detected for both preparations; the amount remaining was 83 and 72% for formulations A and B, respectively. Analysis of size-distribution curves also seems to confirm these results. Initially, three distributions were observed with length-volume mean diameters (dl,v)of 1.67, 10.6 and 57 μm. After 80 days at 55°C, only two distributions were observed, with dl,v of 3.07 and 76 μm. An additional study using pure HSA at different concentrations (0.3, 2.5, 5 and 10% w/v) and storage at 75°C was performed to determine the influence of the concentration of auxiliary substances and of the HSA. Only when the HSA concentration was 0.3% w/v did the remaining fraction of HSA fit a Prout-Thompkins nucleation model. Initially three distributions with mean sizes of 2, 20 and 40 μm were observed whereas at the end of the assay only one distribution, mean size 129 μm, was seen. The methodology used enabled us to separate the HSA degradation products and to determine the absolute molecular weight of albumin monomer and dimer.
It is possible to conclude that the degradation mechanism for the formulations studied is complex, and that it is possible to fit the degradation data to Prout-Thompkins kinetics only when the concentration of HSA is low enough (0.3% w/v).
Halofantrine Metabolism in Microsomes in Man: Major Role of CYP 3A4 and CYP 3A5
Authors: Baune B , Flinois J P , Furlan V , Gimenez F , Taburet A M , Becquemont L , Farinotti R 
Published: October 2002

Abstract
We have clarified the contribution of the different enzymes involved in the N-debutylation of halofantrine in liver microsomes in man. The effect of ketoconazole and cytochrome P450 (CYP) 3A substrates on halofantrine metabolism has also been studied.
The antimalarial drug halofantrine is metabolized into one major metabolite, N-debutylhalofantrine. In microsomes from nine livers from man, N-debutylation of halofantrine was highly variable with apparent Michaelis-Menten constant Vmax and Km values of 215 ± 172 pmol min−1 mg−1 and 48 ± 26/μmol L−1, respectively, (mean ± standard deviation). Formation of N-debutylhalofantrine was cytochrome P450 (CYP)-mediated. Studies using selective inhibitors of individual CYPs revealed the role of CYP 3As in the formation of N-debutylhalofantrine. α-Naphthoflavone, a CYP 3A activator, increased metabolite formation. In microsomes from 12 livers from man the rate of N-debutylation of halofantrine correlated strongly with CYP 3A4 relative levels (P = 0.002) and less strongly, but significantly, with CYP 2C8 levels (P = 0.025). To characterize CYP-mediated metabolism of halofantrine further, incubations were performed with yeast microsomes expressing specific CYP 3A4, CYP 3A5, CYP 2D6, CYP 2C8 and CYP 2C19 from man. The rate of formation of N-debutylhalofantrine was six- and twelvefold with CYP 3A4 than with CYP 3A5 and CYP 2C8, respectively. CYP 2D6 and CYP 2C19 did not mediate the N-debutylation of halofantrine, but, because in-vivo CYP 2C8 is present at lower concentrations than CYP 3A in the liver in man, the involvement of CYP 3As would be predominant. Diltiazem, erythromycin, nifedipine and cyclosporin (CYP 3A substrates) inhibited halofantrine metabolism. Similarly, ketoconazole inhibited, non-competitively, formation of N-debutylhalofantrine with an inhibition constant, Ki, of 0–05 μM. The theoretical percentage inhibition of halofantrine metabolism in-vivo by ketoconazole was estimated to be 99%.
These results indicate that both CYP 3A4 and CYP 3A5 metabolize halofantrine, with major involvement of CYP 3A4. In-vivo, the other CYPs have a minor role only. Moreover, strong inhibition, and consequently increased halofantrine cardiotoxicity, might occur with the association of ketoconazole or other CYP 3A4 substrates.
The Effect of Immunosuppressive Agents (FK-506, Rapamycin) on Renal P450 Systems in Rat Models
Authors: Yoshimura Rikio , Yoshimura Norio , Ohyama Akira , Ohmachi Tetsuji , Yamamoto Keisuke , Kishimoto Taketoshi , Wada Seiji 
Published: October 2002

Abstract
It is well known that cyclosporin, rapamycin and FK-506 (tacrolimus) are metabolized by the liver microsomal cytochrome P450 enzyme system. Although there have been reports of interaction between these drugs and the renal P450 enzyme system, differences among these immunosuppressants has not been comprehensively demonstrated. We have studied the individual capacities of these immunosuppressants to induce renal microsomal P450 enzymes similar to CYP2B4 and CYP4A2 by examining renal function in treated rats, and have correlated the results by means of biochemical, immunological and immunohistochemical assays of renal P450 enzymes.
Cyclosporin caused impairment of renal function with an increase in renal-specific P450 content, but FK-506 and rapamycin did not. Laurate ω- and (ω-1)-hydroxylase activity increased in rats treated with rapamycin but decreased in those treated with FK-506. Prostaglandin A1 (PGA1) ω-hydroxylase activity increased in rats treated with FK-506 but was reduced by treatment with cyclosporin. Aminopyrine N-demethylase activity increased in rats treated with cyclosporin or FK-506, but not in those treated with rapamycin. Western-blot analysis revealed significant induction of P450, (similar to CYP2B4 of the rabbit P450 isozyme) in kidneys from rats treated with cyclosporin but not in those from rats receiving FK-506 or rapamycin. Histochemical studies clearly demonstrated a form of P450 such as CYP4A2 in the proximal tubules of rats treated with cyclosporin, but not in those of rats treated with FK-506 or rapamycin.
These results show that although cyclosporin has a strong effect on renal P450 systems and induces such a system in kidney cortex (microsomal P450), FK-506 and rapamycin have no substantial effect on the induction of renal P450. These findings might clarify the nephrotoxicity induced by these immunosuppressive drugs.
Overlap in the Pharmacology of L-type Ca2+-channel Blockers and 5-HT2 Receptor Antagonists in Rat Aorta
Authors: Okoro E O 
Published: October 2002

Abstract
We have previously shown that elimination of buffer Ca2+ markedly reduced maximum 5-HT-induced contractions. We have now investigated the effect of L-type Ca2+-channel blockers and 5-HT2 receptor antagonists on 5-HT- and K+-induced contractions in rat aorta to explore the possibility of a relationship between blockade of L-type Ca2+ channels and 5-HT2 receptor antagonism.
Sodium nitroprusside, felodipine, nifedipine, diltiazem, cinnarizine, verapamil, ritanserin, cyproheptadine, ketanserin and mianserin inhibited 5-HT-induced contractions of rat aorta with mean IC50 values (concentration (M) resulting in 50% inhibition) of 2.2 × 10−11, 6.6 × 10−11, 1.5 × 10−9,1.7 × 10−9, 3.2 × 10−7, 5.4 × 10−7, 9.7 × 10−10, 1.9 × 10−8, 5.0 × 10−7 and 6.4 × 10−7, respectively. The same compounds antagonized K+-induced rat aortic contractions with the rank order of potency (mean IC50, M): felodipine (7.0 × 10−11) &gt; nifedipine (4.8 × 10−9) &gt; sodium nitroprusside (4.1 × 10−8) &gt; verapamil (5.5 × 10−8) &gt; cyproheptadine (6.2 × 10-8) &gt; diltiazem (4.1 × 10−7) &gt; cinnarizine (1.3 × 10−6) &gt; ritansarin(1.8 × 10−6) &gt; ketanserin (9.0 × 10−6) &gt; mianserin (2.0 × 10−5).
These data are indicative of a highly significant correlation (r = 0.81, P = 0.03) between potency against 5-HT-induced contraction and that against contractile response to K+ depolarization, and suggest overlap of the pharmacology of L-type Ca2+-channel blockers and 5-HT2 receptor antagonists in rat aorta.
Evidence for a Neuroprotective Effect of Pyrid-3-yl-sulphonylurea in Photochemically Induced Focal Ischaemia in Rats: Magnetic Resonance Imaging Evaluation
Authors: Baudelet Christine , Demeure Roger , Frois Ana , Masereel Bernard , Goudemant Jean-François , Ritter Christian , Gallez Bernard 
Published: October 2002

Abstract
A neuroprotective effect can be obtained with N-[(4-cycloheptylaminopyrid-3-yl)sulphonyl]N′-cycloheptyl urea (BM27), a pyrid-3-yl-sulphonylurea structurally related to torasemide, a loop diuretic. We have investigated the neuroprotective effect of BM27 by magnetic resonance imaging and use of the photothrombotic model of cerebral infarction in the rat. This method enables non-invasive quantification of the extent of the cerebral oedema from T2-weighted spin-echo images.
This article reports the evolution of the extent of oedema with time (0.5, 1, 2, 4, 6, 24 and 48 h, 7 and 15 days and 1 month after induction of the lesion) in rats pretreated with 5mg kg−1 BM27 or an appropriate control. At all times, the rats treated with BM27 had, on average, smaller lesions than control rats (30% decrease between 2 h and 6 h).
These results strongly suggest a significant (P &lt; 0.01) but modest neuroprotective effect of BM27 in ischaemic cerebral stroke. Further investigations should be performed to determine if BM27 or its analogues are of clinical interest.
Some Misconceptions in the Kinetic Analyses of Pharmaceutical Systems
Authors: Galwey Andrew K 
Published: October 2002

Abstract
Some problems encountered during the formulation of reaction mechanisms, by the interpretation of kinetic and other experimental observations, in studies of reactions that occur on heating reactants that are initially solid, are critically reviewed. The representative chemical changes selected for inclusion here appear to be relatively simple. It has been found, however, that the provision of acceptable representational models is less straightforward than might have been anticipated. Accordingly, it is concluded that, when interpreting kinetic data, it is essential to consider most carefully the significance of all experimental measurements in the context of the overall change.
Interpretational difficulties, recognised in the literature, that identify inconsistencies that may complicate kinetic analysis are illustrated through consideration of the following systems (and other examples): characterisation of the changes in reaction stoichiometry that result from the presence of a gaseous atmosphere during NiSO4.6H2O dehydration; the sensitivity of kinetic behaviour to reaction conditions during the dehydration of NiC2O4.2H2O and in the dissociation of CaCO3; the formation of intermediates and the possibility of melting during the decompositions of KMnO4 and of copper(II) malonate.
It is concluded that the formulation of reaction models through the interpretation of kinetic (with other) data for solid-state decomposition is more difficult than is sometimes acknowledged. It is not known how widely problems of the types described in this short review apply. These are mentioned here as types of behaviour that require more general consideration in kinetic and mechanistic studies of the changes that occur on heating reactants that are originally solid.
Prediction of Clearance, Volume of Distribution and Half-life by Allometric Scaling and by use of Plasma Concentrations Predicted from Pharmacokinetic Constants: a Comparative Study
Authors: Mahmood Iftekhar 
Published: October 2002

Abstract
Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t½β) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, α and β, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and α and β are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively.
The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, α and β obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t½β. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t½β predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdCand t½β predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide).
The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.
Microdialysis Study of Biliary Excretion of Chloramphenicol and its Glucuronide in the Rat
Authors: Tsai T H , Hung L C , Chen C F 
Published: October 2002

Abstract
The biliary excretion of chloramphenicol and its glucuronide has been evaluated by use of a microdialysis probe linked to automatic on-line microbore high-performance liquid chromatography.
The microdialysis probe was inserted into the bile duct between the liver and the duodenum; to avoid obstruction of the bile duct or bile salt waste, a shunt linear probe was used. After intravenous administration of chloramphenicol succinate (100 mg kg−1) the amounts of unbound chloramphenicol and its glucuronide in the bile microdialysate were recorded. According to the pharmacokinetic results disposition of chloramphenicol seems to fit a two-compartment model whereas that of chloramphenicol glucuronide fits a one-compartment model in rat bile. The area under the concentration-time curve for chloramphenicol glucuronide was twice that for chloramphenicol in rat bile duct.
Clearance of chloramphenicol glucuronide was significantly higher than that of chloramphenicol in biliary excretion, indicating that chloramphenicol and its glucuronide are actively excreted into the bile.
Inhibitory Effects of the Antihistamines Epinastine, Terfenadine, and Ebastine on Potassium Currents in Rat Ventricular Myocytes
Authors: Ohtani Hisakazu , Hanada Erika , Hirota Michiko , Sato Hitoshi , Kotaki Hajime , Sawada Yasufumi , Uemura Hiroko , Nakaya Haruaki , Iga Tatsuji 
Published: October 2002

Abstract
We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (IK) and transient outward potassium current (Ito) of rat isolated ventricular myocytes, using a patch clamp technique.
Terfenadine, ebastine and epinastine were found to inhibit IK with IC50 values of 5.96, 15.3 and 145 μM, respectively. Ito was suppressed by epinastine with an IC50 value of 69.5 μM. The order of arrhythmogenicity, assessed by the inhibition of IK, was ranked as terfenadine &gt; ebastine &gt; epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.
Relationships Between the Modulus of Elasticity and Tensile Strength for Pharmaceutical Drugs and Excipients
Authors: Roberts R J , Rowe R C 
Published: October 2002

Abstract
The relationship between the modulus of elasticity and tensile strength for a variety of pharmaceutical drugs and excipients has been explored as a means of generating algorithms for use in computer simulations and expert systems.
From literature data two equations have been developed to enable the formulator, from knowledge of one property, to predict the other with a reasonable degree of accuracy.
Such relationships are invaluable for use in computer simulation programs or formulation expert systems, enabling formulators to screen potential formulations quickly without the need for extensive experimental work.
A Dissolution Test for a Pressure-controlled Colon Delivery Capsule: Rotating Beads Method
Authors: Yukako Yoshikawa , Hu Zhaopeng , Kimura GO , Murakami Masahiro , Yoshikawa Hiroshi , Takada Kanji 
Published: October 2002

Abstract
The rotating beads method is a new in-vitro dissolution test proposed for drugs formulated as pressure-controlled colon delivery capsules (PCDCs).
The apparatus consisted of a glass vessel (500 mL) containing 4-mm (i.d.) glass beads (5000, 10000 or 15000) and dissolution medium (0.067 M phosphate buffer, pH 7; 25, 50 or 100 mL) containing polyvinyl alcohol (PVA; 5, 10 or 20 w/v%) to simulate the viscosity of the colon. The vessel was rotated at 5, 10 or 25 rev min−1 and the temperature was maintained at 37°C. Fluorescein was used as a model drug to explore the optimized conditions under which differences in the drug dissolution rate are detected between colon delivery systems. Fluorescein was formulated in four types of colon delivery systems. One was a tablet coated with an enteric polymer, Eudragit S-100, and the other three were PCDCs prepared with different thicknesses of ethylcellulose coating membrane (type I, II, III).
The dissolution behaviour of fluorescein from the PCDC formulation was significantly different from that of the Eudragit S-100-coated tablets, when the dissolution conditions were as follows: rotation speed, 10 rev min−1; bead number, 10000; dissolution medium, 50 mL with 10% PVA. This dissolution method was applied to acetaminophen sustained-release tablets and two other drugs having low solubility in the colon, tegafur and 5-aminosalicylic acid. Similarly, significant differences in the dissolution rates of drugs from the PCDC formulation and the enteric tablet were detected. There was good correlation between the in-vitro dissolution rates and in-vivo absorption rates using T50 (the time for half of the amount of drug to be released from the preparation) and Cmax/Tmax (enteric tablet) or Cmax/(Tmax-Ti) (PCDC), where Ti is the first appearance time in the systemic circulation.
The rotating beads method is a valuable technique for evaluating the dissolution rate of drugs formulated in PCDC.
Studies on the Co-encapsulation, Release and Integrity of Two Subunit Antigens: rV and rF1 from Yersinia pestis
Authors: Spiers Ian D , Alpar H Oya , Eyles Jim E , Bozkir Asuman , Miller Julie , Williamson E Diane 
Published: October 2002

Abstract
In the development of combination or multiple sub-unit vaccines, determination of the encapsulation, release and integrity of two or more proteins co-encapsulated within microspheres is an important issue. A new extraction method, which exhibits excellent protein recovery, has been developed which enables samples to be used for sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and subsequent measurement of individual antigens encapsulated within microspheres. Using the new method, the protein loading of poly-(L-lactide) microspheres co-encapsulating two plague sub-unit antigens was found to be 1.22% (w/w) for recombinant V antigen (rV) and 1.24% (w/w) for recombinant F1 (rF1) by SDS-PAGE. The total protein loading was 2.49% (w/w) by bicinchoninic acid assay. The individual release of the two subunit antigens from the co-encapsulated microspheres was determined by SDS-PAGE analysis and rF1 was found to have a higher burst release than rV. The integrity and immunological activity of both rF1 and rV antigens was shown to be unaffected by the microencapsulation process.
This study shows that encapsulation of more than one antigen within poly-(L-lactide) microspheres is a viable method for the delivery of intact proteins.