bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term Clomipramine Treatment Upregulates Forebrain Acetylcholine Muscarinic Receptors, and Reduces Behavioural Sensitivity to Scopolamine in Mice
Authors: Tsukagoshi Hiroshi , Morita Toshihiro , Hitomi Shinichiro , Saito Shigeru , Kadoi Yuji , Uchihashi Yoshitaka , Kuribara Hisashi , Goto Fumio 
Published: July 2003

Abstract
We have investigated the effects of long-term treatment with clomipramine, a tricyclic antidepressant, on central muscarinic acetylcholine receptors (mAChR) in mice.
Repeated clomipramine administration resulted in an increase in the forebrain receptor density value (Bmax) for [3H]quinuclidinyl benzilate, a muscarinic ligand (P &lt; 0.05), that was dependent on dose per administration (saline or 5, 10, or 20 mg kg−1 once a day for 7 days) and number of days treated (20 mg kg−1 for 1, 3, 5, or 7 days). No change in apparent affinity (defined as the reciprocal of the dissociation constant) (KD) occurred. Seven daily treatments with clomipramine (saline or 5, 10, or 20 mg kg−1) reduced hyperlocomotion induced by scopolamine (0.5 mg kg−1, s.c.) dose-dependently, and the effect of 20 mg kg−1 clomipramine was significant (P &lt; 0.05).
These results suggest that an upregulation of mAChR is produced by repeated clomipramine administration, and such a change is responsible for the decreased sensitivity to the muscarinic antagonist scopolamine.
Time Dependent Effects of Glucocorticoids on Adrenocorticotropin Secretion of Rat Pituitaries Ex-vivo
Authors: Bruns R , Rohdewald P 
Published: July 2003

Abstract
Different glucocorticoids have been compared with respect to the inhibition of corticotropin-releasing factor (CRF)-mediated adrenocorticotropin (ACTH) secretion from pituitary fragments of the rat. The influence of time of exposure to glucocorticoids and glucocorticoid concentration has been investigated.
CRF-stimulated ACTH secretion of perifused rat pituitary fragments was measured by a chemiluminescence immunoassay. ACTH secretion was monitored over three days. Inhibition of CRF-stimulated ACTH secretion by glucocorticoids was quantified by the area under the curve of CRF-stimulated ACTH secretion over baseline. Concentrations needed to inhibit ACTH secretion decreased with the receptor affinities of the glucocorticoids as follows: fluticasone propionate; receptor affinity 1800, concentration 10−8 M; budesonide, 935 and 3–2.5 times 10−8 M; flunisolide, 478 and 5 times 10−7 M; prednisolone, 10 and 10−6 M. CRF-stimulated secretion was inhibited by glucocorticoids after incubation for 1 min at concentrations between 10−8 and 10−6 M. The same absolute quantity of the glucocorticoids produced no inhibition when incubation was prolonged to 50 min or when a lower concentration was used. Immediately after the perifusion stimulation of ACTH secretion was observed.
The results suggest the possibility of minimizing the side effects of glucocorticoids by prolonging drug release.
Influence of Extracellular K+ Concentrations on Quinidine-induced K+ Current Inhibition in Rat Ventricular Myocytes
Authors: Hirota Michiko , Ohtani Hisakazu , Hanada Erika , Sato Hitoshi , Kotaki Hajime , Uemura Hiroko , Nakaya Haruaki , Iga Tatsuji 
Published: July 2003

Abstract
Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (IK), the transient outward current (Ito), and the inward rectifier potassium current (IK1), as measured in isolated rat ventricular cells using patch-clamp techniques.
Concentration-dependent effects of quinidine on IK, Ito, and IK1 were evaluated under both normal ([K+]o = 5.4 mM) and hypokalaemic ([K+]o = 3.5 mM) conditions. In contrast to both IK and Ito, which were barely influenced by changes in [K+]o, IK1 was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both IK and Ito in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+]o. The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 μM (IK), and 17.6 and 17.3 μM (Ito). Although higher concentrations of quinidine were required to inhibit IK1, the inhibitory potency of quinidine was also found to be insensitive to changes in [K+]o. Thus, in rats, the inhibitory potency of quinidine for the K+ current-types IK, Ito and IK1 is barely influenced by changes in [K+]o.
These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalaemia does not affect IK or Ito, it can inhibit IK1 and can result in QT prolongation in-vivo.
Comparison of Analgesic Effects of Khat (Catha edulis Forsk) Extract, D-Amphetamine and Ibuprofen in Mice
Authors: Connor John , Makonnen Eyasu , Rostom Amr 
Published: July 2003

Abstract
We have compared the analgesic properties of khat (Catha edulis Forsk) extract, amphetamine and ibuprofen in mice. After intragastric administration of the drugs analgesia was measured relative to water-injected controls using the hot-plate, the tail-flick, and abdominal-constriction tests.
At the highest doses examined (amphetamine 1.8 mg kg−1, ibuprofen 90 mg kg−1, khat extract 1800 mg kg−1), all three substances produced analgesia, but the order of efficacy varied with the test. Khat and ibuprofen were significantly different from the control in the hot-plate assay at three or more time points post-injection. In the tail-flick test, khat and amphetamine were efficacious; ibuprofen means were somewhat lower but still significantly different from control. Higher doses of the drugs decreased the number of responses in the acetic acid-induced abdominal-constriction assay.
We conclude that khat, like amphetamine and ibuprofen, can relieve pain. Differences in assay results may reflect differences in modes and sites of action, as well as in the type of pain generated by the chemical and thermal stimuli for nociception.
Effect of Sho-saiko-to Extract on HGF and TGF-β Levels of Intraorgans in Liver-injured Rats after Partial Hepatectomy
Authors: Ono Masahide , Miyamura Mitsuhiko , Kyotani Shojiro , Saibara Toshiji , Ohnishi Saburo , Nishioka Yutaka 
Published: July 2003

Abstract
To examine the effects of Sho-saiko-to extract on liver regeneration, Sho-saiko-to extract (0.75%, 1.5% or 3.) was administered to 70% partial hepatectomized rats with dimethyl-nitrosamine-induced liver-injury.
S phase cell number, liver retinoid levels, hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-β) levels in each intraorgan were measured as indicators of liver regeneration. Three to seven days after hepatectomy, HGF and TGF-β levels of the liver and spleen of the Sho-saiko-to extract groups were significantly different from the levels of the ordinary food group (P &lt; 0.05–0.1). HGF levels in the Sho-saiko-to extract groups were approximately 1.3–1.8 times higher in the liver and approximately 1.8–2.1 times higher in the spleen compared with the levels found in the ordinary food group. TGF-β levels in the Sho-saiko-to extract groups were approximately 0.38–0.47 times the level in the liver and 0.58–0.77 times the level in the spleen of the ordinary food group. There was no difference in HGF and TGF-β levels of the kidney and lung between the Sho-saiko-to extract group and the ordinary food group. There was a significant and positive correlation between HGF level and S phase cell number in the liver (r = 0.826, P &lt; 0.01). There was a significant and negative correlation between TGF-β level and the retinoid level in the liver (r = −0.696, P &lt; 0.01). In addition, the levels of the active constituents of Sho-saiko-to extract (glycyrrhetic acid, baicalin and baicalein) showed high values in the liver and spleen of partial hepatectomized rats, and increased from the third day after partial hepatectomy.
These results show that Sho-saiko-to extract induces liver regeneration by increasing the production of HGF and suppressing the production of TGF-β in the liver and spleen of partial hepatectomized rats. It was considered that the increase in the Sho-saiko-to extract active constituent levels in the liver and spleen greatly influences this action.
Inhibitory Effect of Euphol, a Triterpene Alcohol from the Roots of Euphorbia kansui, on Tumour Promotion by 12-O-Tetradecanoylphorbol-13-acetate in Two-stage Carcinogenesis in Mouse Skin
Authors: Yasukawa Ken , Akihisa Toshihiro , Yoshida Zen-Ya , Takido Michio 
Published: July 2003

Abstract
The anti-inflammatory activity of euphol, twelve other triterpene alcohols and sitosterol-β-D-glucopyranoside, isolated from the dichloromethane extract of the roots of Euphorbia kansui, has been evaluated in mice with inflammation induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA).
TPA (1.7 nmol; 1.0 μg/ear) was dissolved in acetone and 10 μL delivered to the inner and outer surfaces of the right ear of ICR mice. A triterpene alcohol, sterol glucoside or vehicle (20 μL; chloroform—methanol 1: 1), was applied topically approximately 30 min before each TPA treatment. The ear thickness was measured before treatment and then oedema was measured 6 h after TPA treatment.
For the two-stage carcinogenesis experiment, initiation was accomplished by administration of a single topical application of 7,12-dimethylbenz[a]anthracene (DMBA; 195 nmol; 50 μg/mouse) to the shaved backs of mice. Promotion was with 1.7 nmol (1.0 μg) TPA, applied twice weekly to the same shaved area, begun one week after the initiation. Euphol (2.0 μmol; 853 μg), or its vehicle (acetone-dimethylsulphoxide, 9:1; 100 μL), was applied topically 30 min before each TPA treatment. The number and diameter of skin tumours were measured every other week for 20 weeks.
All the compounds were found to possess marked inhibitory activity and their 50% inhibitory dose for TPA-induced inflammation was 0.2–1.0 mg/ear. Topical application of euphol (2.0 μmol; 853 μg/mouse) markedly suppressed the tumour-promoting effect of TPA (1.7 nmol; 1.0 μg/mouse) in mouse skin initiated with DMBA.
Analysis of the Stability and Degradation Products of Triptolide
Authors: Mao Yan Ping , Tao Xue Lian , Lipsky Peter E 
Published: July 2003

Abstract
Triptolide is the major active ingredient of the Chinese herbal remedy Tripterygium wilfordii Hook F. (TwHF). As triptolide content is used to estimate the potency of preparations of TwHF, assessment of its stability is warranted.
The accelerated stability of triptolide was investigated in 5% ethanol solution in a light-protected environment at pH 6.9, within a temperature range of 60–90°C. The observed degradation rate followed first-order kinetics. The degradation rate constant (K25°C) obtained by trending line analysis of Arrhenius plots of triptolide was 1.4125 times 10−4 h−1. The times to degrade 10% (t1/10) and 50% (t1/2) at 25°C were 31 and 204 days, respectively. Stability tests of triptolide in different solvents and different pH conditions (pH 4–10) in a light-protected environment at room temperature demonstrated that basic medium and a hydrophilic solvent were the major factors that accelerated the degradation of triptolide. Triptolide exhibited the fastest degradation rate at pH 10 and the slowest rate at pH 6. In a solvent comparison, triptolide was found to be very stable in chloroform. The stability of triptolide in organic polar solvents tested at both 100% and 90% concentration was greater in ethanol than in methanol than in dimethylsulphoxide. Stability was also greater in a mixture of solvent: pH 6 buffer (9:1) than in 100% solvent alone. An exception was ethyl acetate, which is less polar than the other solvents tested, but permitted more rapid degradation of triptolide. Two of the degradation products of triptolide were isolated and identified by HPLC and mass spectroscopy as triptriolide and triptonide. This suggested that the decomposition of triptolide occurred at the C12 and C13 epoxy group and the C14 hydroxyl. The opening of the C12 and C13 epoxy is an irreversible reaction, but the reaction occurring on the C14 hydroxyl is reversible.
These results show that the major degradation pathway of triptolide involves decomposition of the C12 and C13 epoxy group. Since this reaction is very slow at 4°C at pH 6, stability is enhanced under these conditions.
Triboelectrification of Spray-dried Lactose Prepared from Different Feedstock Concentrations
Authors: Cassidy Orla E , Carter Paul A , Rowley Geoff , Merrifield David R 
Published: July 2003

Abstract
Powder systems may acquire electrostatic charge during various pharmaceutical processing operations and may give rise to difficulties in handling and powder flow, mainly due to adhesion/cohesion effects. We have investigated the electrostatic charging of spray-dried lactose prepared from different feedstock concentrations using a laboratory spray-dryer.
Triboelectrification of the spray-dried lactose samples was effected through contact with the stainless steel surface of either a mixing vessel or a cyclone separator. Results from both techniques showed differences in charge accumulation and particle-steel adhesion between the spray-dried lactose samples. As the feedstock concentration used to produce the spray-dried lactose was increased in the range 10–50% w/v, the mean charge on the lactose decreased from −20.8 to −1.3 nC g−1 and −54.9 to −4.1 nC g−1 for the mixing vessel and cyclone separator, respectively, with a corresponding decrease in adhesion. In addition, as the feedstock concentration was increased from 10 to 50% w/v, decreases were obtained in surface area values (1.06 to 0.56 m2 g−1), pore diameter (198.7 to 83.5 μm) and pore volume (1.09 to 0.75 cm3 g−1), and together with differences in crystal form correlated with the charge and adhesion results.
The results suggested that the feedstock concentration could have a considerable influence on the charging and adhesional properties of spray-dried lactose. This may have relevance during pharmaceutical processing and manufacturing operations.
Development of a Lyophilization Formulation that Preserves the Biological Activity of the Platelet-inducing Cytokine Interleukin-11 at Low Concentrations
Authors: Page Christopher , Dawson Peter , Woollacott David , Thorpe Robin , Mire-Sluis Anthony 
Published: July 2003

Abstract
Recombinant human interleukin-11 (rhIL-11) is a licensed biological therapeutic product in at least one country and is used to combat thrombocytopenia during chemotherapeutic regimens, as well as undergoing clinical trials for a range of other disorders. Following attempts to lyophilize IL-11 at low concentrations, it was clear that a significant loss of recoverable biological activity occurred.
Investigation of a variety of factors, including the type of container in which the rhIL-11 was lyophilized, revealed that surface adsorption to glass was a major factor resulting in loss of activity of rhIL-11 in solution (&gt; 40% reduction after 3 h at room temperature), in addition to losses of activity post-lyophilization. To overcome this problem, different formulations containing combinations of human serum albumin (HSA), trehalose and Tween-20 have been investigated.
Two formulations were successful in entirely preserving the biological activity of rhIL-11 through lyophilization and subsequent reconstitution (potency estimates of formulated relative to original material being ≥0.97). Accelerated degradation studies, performed at intervals over a six-month period, demonstrated the stability of freeze-dried rhIL-11 using these formulations (predicted annual reduction in potency after storage at −20°C ≤1.4%).
In conclusion, we have developed a working combination of excipients (0.5% HSA, 0.1% trehalose and 0.02% Tween-20 in potassium phosphate buffer (pH 7.4)) to formulate a stable rhIL-11 freeze-dried product in glass containers, with no loss in potency. These findings should facilitate development of low dose rhIL-11 products and be an indicator of caution to those using this and other material with similar physical properties, without taking appropriate precautions to avoid losses through adsorption.
Tissue Distribution and Pharmacological Potential of SM-16896, a Novel Oestrogen-bisphosphonate Hybrid Compound
Authors: Tsushima Naomi , Yabuki Masashi , Harada Hideyuki , Katsumata Takashi , Kanamaru Hiroshi , Nakatsuka Iwao , Yamamoto Michihiro , Nakatsuka Masashi 
Published: July 2003

Abstract
Postmenopausal osteoporosis is caused mainly by a deficiency of oestrogen with rapid bone loss. To target oestrogen to the bone effectively, we have synthesized and evaluated the effects of a novel hybrid compound of oestrogen and bisphosphonate, SM-16896. The tissue distribution pattern and pharmacological potential are reported.
Although the affinity for calf uterine oestrogen receptor was very low (IC50: 73.3 μM; 1/25000 of that of 17β-oestradiol (2.84 nM)), SM-16896 showed oestrogenic activity. SM-16896 (1 μM) induced a 4.5-fold transcriptional activity in rat osteosarcoma UMR-106 cells compared with vehicle-treated control, when we used the expression vector for human oestrogen receptor and a CAT reporter plasmid containing an oestrogen-responsive element. The distribution of SM-16896 after a subcutaneous administration to 7-week-old female rats was examined by radioluminography using 3H-labelled SM-16896. At 30 min after the administration, significant radioactivity was detected in the bone. At 24 h after administration, a high level of radioactivity was detected in the bone, but in the uterus it was only at a background level. Daily subcutaneous administration of 0.5 mg kg−1 SM-16896 for 12 weeks (five times per week) to 13-week-old ovariectomized rats suppressed the ovariectomized-induced reduction in bone mineral density. A bone mineral density ratio of 120% was maintained compared with sham-operated rats, whereas a relatively low suppression of uterine weight was observed (about 50% loss compared with sham-operated rats). In the same experiment, the implantation of a 17β-oestradiol time-release pellet (0.25 mg/pellet/90 days) almost completely suppressed the reduction of both the bone mineral density and uterine tissue weight. It is likely that the effect of SM-16896 on bone was due to its oestrogenic activity, since 1.0 mg kg−1 SM-18108, the bisphosphonate moiety of this compound, had no effect on bone in 7-week-old ovariectomized rats.
The results suggest that SM-16896, a bisphosphonate-conjugated oestrogen, showed a preference profile in the uterus and bone due to its characteristic distribution pattern compared with the natural oestrogen analogue 17β-oestradiol. Thus, bisphosphonate-conjugated oestrogens have the potential to improve patient compliance in oestrogen therapy by minimizing adverse effects and reducing the frequency of medication.
The Effect of Divalent Cations on the Membrane Properties and Pharmacokinetics in Rat of the Lipid A Analogue E5531
Authors: Asai Yasuyuki , Sano Yoshihisa , Kikuchi Kiyomi , Iwamoto Kiyoshi , Watanabe Sumio 
Published: July 2003

Abstract
To obtain information on the effects of Ca2+ on the membrane properties of the lipid A analogue E5531, we have determined the aggregate size, zeta potential, membrane fluidity, micropolarity and permeability of the E5531 membrane as a function of Ca2+ levels.
Within the molar ratios of [Ca2+]/[E5531] = 1 and 3, Ca2+ increased the zeta potential of the E5531 membrane but had no effect on aggregate size (approximately 20 nm). Within the above ratios, Ca2+ decreased the membrane fluidity, as measured by micropolarity of E5531 and increased the phase transition temperature.
The pharmacokinetics in rats for these samples with different membrane fluidity, prepared by changing the pre-dose formulation concentration of Ca2+, was determined and a correlation between membrane fluidity and pharmacokinetics was clearly observed.
It thus appears that Ca2+ effects the membrane fluidity of E5531 as well as its pharmacokinetics in rats.
Oral, Intraperitoneal and Intravenous Pharmacokinetics of Deramciclane and its N-desmethyl Metabolite in the Rat
Authors: Nemes Katalin Balogh , Abermann Miklós , Bojti Erzsébet , Grézal Gyula , Al-Behaisi Samar , Klebovich Imre 
Published: July 2003

Abstract
The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mg kg−1 deramciclane fumarate was administered orally, intraperitoneally or intravenously.
A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite.
After oral administration the absorption of the parent compound was very fast (tmax 0.5 h). The maximum plasma concentration (Cmax) was detected at 44.9, ≥177.8 and ≥2643.0 ng mL−1 after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, ≥25.4 and 51.0 ng mL−1. The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tβ1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90–5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-∞ of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-∞ ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration.
The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.