bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of Tissue Spaces of the Isolated Hindlimb of the Rat Using Netilmicin as an Extracellular Space Indicator
Authors: Casquero-Dorado Ana Cristina , Sánchez-Navarro AMPARO 
Published: October 2002

Abstract
The kinetic behaviour of drugs in extracellular space is of interest as it influences the drug's access to, and permanence in, those areas of the body upon which drugs exert pharmacological or toxicological actions. A series of experiments was carried out to characterize the vascular, interstitial and cellular spaces of the isolated hindlimb of the rat. Certain specific experimental conditions were met: body weight was under 230 g to avoid fat tissue in the preparations; a perfusion flow rate of 3 mL min−1; and 3% of bovine albumin in the perfusate supplied at 25°C to the tissues.
The isolation of the hindlimb followed the method described by Ruderman with some modifications to restrict the perfusion to the right hindlimb. Tritiated water, netilmicin and methylene blue were injected separately and efferent fluid samples were collected for 15 min after solute injection. Analysis of the efferent curves was performed to calculate the statistical moments (AUC, area under concentration-time curve; MTT, mean transit time; VTT, variance of mean transit times) and solute distribution volumes, which were subsequently used to estimate the tissue spaces of the isolated hindlimb.
The results revealed that methyl blue and netilmicin can be respectively used as alternatives to radiolabeled indicators of the vascular and extracellular spaces of tissues included in the rat isolated hindlimb.
Protective Effects of Pseudoginsenoside-F11 on Scopolamine-induced Memory Impairment in Mice and Rats
Authors: Li Z , Guo Y Y , Wu C F , Li X , Wang J H 
Published: October 2002

Abstract
This study assessed the effects of pseudoginsenoside-F11, a component of Panax quinquefolium L., on scopolamine-impaired memory performance in mice and rats.
In the one-trial step-down and step-through passive avoidance tests, although pseudoginsenoside-F11 used alone did not affect passive avoidance behaviour in naive mice, the latency of avoidance shortened by intraperitoneal scopolamine (2 mg kg−1) was prolonged after intragastric administration of pseudoginsenoside-F11 (2 or 4 mg kg−1 for five days) in both test systems in mice. In the water-maze test, in mice, the time taken to locate the platform after administration of pseudoginsenoside-F11 was shorter than that after administration of scopolamine (1 mg kg−1 i.p.). In the two-way active avoidance response test, the latency of avoidance was significantly shorter for the pseudoginsenoside-F11-(1 · 2or 2 · 4 mg kg−1 i.g. for five days) and scopolamine-treated group than for the group of rats given scopolamine only (2 mg kg−1, i.p.). The percentage avoidance was also reduced after intraperitoneal injection of scopolamine, but was reversed by administration of pseudo-ginsenoside-F11.
These results suggest that pseudoginsenoside-F11 antagonized the memory dysfunction induced by scopolamine. However, the mechanism of the memory facilitative action of pseudoginsenoside-F11 merits further elucidation.
Effect of Saiboku-to, an Oriental Herbal Medicine, on Gastric Lesion Induced by Restraint Water-immersion Stress or by Ethanol Treatment
Authors: Yuzurihara Mitsutoshi , Ikarashi Yasushi , Kase Yoshio , Torimaru Yasutaka , Ishige Atsushi , Maruyama Yuji 
Published: October 2002

Abstract
The effect of saiboku-to on gastric lesions induced by restraint water-immersion stress and ethanol has been examined in rats.
Thirty minutes after oral administration of saiboku-to, the rats were placed in restraint cages and immersed in water at 23°C for 7 h, or orally administered 99.5% ethanol (1 mL) and placed in normal cages for 1 h. The stress for 7 h or the ethanol treatment for 1 h induced erosion in the glandular area of the stomach. Histology showed that the surface epithelial cells were desquamated and part of the lamina propria mucosae was injured. The evaluation of lesion index, the cumulative length of the gastric lesion, on the gross appearance of the stomach, revealed that saiboku-to dose-dependently inhibited both the water-immersion stress-induced gastric erosion and ethanol-induced gastric erosion. To determine whether the anti-erosion effect of saiboku-to was because of a mild irritant effect, saiboku-to or 20% ethanol, which is known as a typical mild irritant, were given orally. After 30 min a strong irritant, 99.5% ethanol, was given orally. Histological examination was performed 30 min after administration of saiboku-to or the mild irritant, and 1 h after administration of the strong irritant. The mild irritant induced a reduction in surface epithelial cells 30 min after administration. Furthermore, the mild irritant protected the stomach against mucosal erosion produced by the strong irritant. Saiboku-to protected the strong irritant-induced erosion without producing mild irritation as observed in stomach treated with 20% ethanol. Pretreatment with saiboku-to also inhibited the decrease in the levels of hexosamine, gastric mucus glycoprotein, induced by the strong irritant. In pylorus-ligated rats, saiboku-to dose-dependently inhibited gastric acid secretion, a gastric aggressive factor.
These results suggest that the anti-erosion effect of saiboku-to which is not a mild irritant, involves both inhibition of aggressive factors, such as gastric acid secretion, and augmentation of defensive factors, such as gastric mucus cells.
Preparation, Characterization and Biological Evaluation of Copper(II) and Zinc(II) Complexes with Cephalexin
Authors: Iqbal Mohammad S , Ahmad Abid R , Sabir Mohammad , Asad Syed M 
Published: October 2002

Abstract
Copper(II) and zinc(II) complexes of cephalexin have been prepared and characterized by microanalysis and by thermogravimetric, magnetic and spectroscopic analysis.
The complexes were found to be five-coordinate, monohydrate, and ML2 type. The electron paramagnetic resonance spectral lines revealed rhombic distortion from axial symmetry, with g∥ &gt; g⊥ &gt; ge, in the elongated-tetragonal copper(II) complex. The geometry of the zinc(II) complex seems to be square-pyramidal. On complexation with copper and zinc the antimicrobial activity of cephalexin improved significantly. The copper complex was found to be active against kaolin paw oedema whereas the parent drug was inactive.
These results suggest that the metallic elements should be seriously considered during drug design, and that complexes already reported should be subjected to clinical evaluation. Their use could provide an easy way of improving the activity and reducing the toxicity of drug substances.
Single- and Repeated-dose Local Toxicity in the Nasal Cavity of Rabbits after Intranasal Administration of Different Glycols for Formulations Containing Benzodiazepines
Authors: Hjortkjær Rolf K , Bechgaard Erik , Gizurarson Sveinbjörn , Suzdak Carol , Mcdonald P , Greenough R J 
Published: October 2002

Abstract
To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 μL, the maximum volume that can be applied as a single administration in one nostril in man. The objectives of these studies were to examine the local toxicity of formulations containing benzodiazepines and to document the effects to support clinical trials in man.
After stability, pharmacological and pharmacokinetic studies of several benzodiazepine formulations, we studied nasal toxicity after single and repeated administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene glycol), glycofurolum and mixtures of these vehicles both with and without benzodiazepines. Single-dose studies with examinations 5 or 10 min after application were undertaken with poly(ethylene glycol), tetra(ethylene glycol), glycofurolum and tetra(ethylene glycol)-glycofurolum in the ratio 95:5; the reactions were similar to that after physiological saline. A 14-day repeated-dose study was conducted with diazepam, lorazepam and flunitrazepam formulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene glycol)-glycofurolum in the ratio 70:30; the two vehicles without any benzodiazepine were also examined. Microscopic study revealed mild changes only in the treated groups. A final four-week study was conducted with repeated administration of clonazepam formulated in tetra(ethylene glycol)-glycofurolum in the ratio 95:5; microscopy revealed mild changes after three 150-μL doses daily, but no abnormalities after one or three 100-μL doses daily.
It was concluded that these three solvents individually or as mixtures resulted in only mild local toxicity and might be acceptable as vehicles in nasal preparations of benzodiazepines and other non-irritating drugs for short-term use in man.
Pharmacokinetics of Ticlopidine in the Rabbit
Authors: Onyeji Cyprian O , Tessier Pamela R , Nightingale Charles H , Vallee Francois , Nicolau David P 
Published: October 2002

Abstract
There is no information about the pharmacokinetics of ticlopidine in rabbits. Such information is valuable in designing appropriate dosing regimens for experimental studies of the drug with ultimate applications in man. The disposition kinetics of ticlopidine at three dose levels were evaluated in three groups of six rabbits which received 10, 50 or 100 mg kg−1 drug once daily via the oral-gastric route. Blood samples were collected at predetermined times after the third dose. Plasma concentrations of the unchanged drug were determined by a validated liquid chromatography-mass spectrometry method with a limit of detection of 5 μg L−1.
There was a disproportionate increase in the mean maximum plasma concentration (Cmax) and the area under the plasma drug-concentration-time curve (AUC) for the 10 and 50 mg kg−1 doses. The apparent terminal half-life (t 1/2β), apparent volume of distribution (Vdβ/F), and total plasma clearance (CLp/F) of the drug were all dose-dependent. For example, t1/2β for the 10, 50 and 100 mg kg−1 doses were 1.04 ± 0.10, 4.24 ± 1.92 and 12.80 ± 6.35 h, respectively, whereas the Vdβ/F values for the corresponding doses were 214 ± 31, 475 ± 221 and 998 ± 420 L kg−1, respectively.
These results show that the 100-mg kg−1 dose produces plasma ticlopidine concentrations similar to those found in man after administration of 250 mg of the drug. It is suggested that 100 mg kg−1 might be the appropriate dose of ticlopidine for use in rabbit experimental studies with ultimate application to man.
Influence of Glycerol-induced Acute Renal Failure on the Pharmacokinetics of Cyclosporin in Rats
Authors: Shibata Nobuhito , Ohmae Takahiro , Hoshino Nobuo , Minouchi Tokuzo , Yamaji Akira 
Published: October 2002

Abstract
Although it is widely believed that renal dysfunction has no effect on the pharmacokinetics of cyclosporin, many clinical reports suggest that renal dysfunction after renal transplantation is closely related to the pharmacokinetics of cyclosporin. To clarify the relationship between renal dysfunction and the pharmacokinetics of cyclosporin, we examined the influence of acute renal failure (ARF) on its pharmacokinetics in glycerol-induced ARF rats.
The values of indicators of renal function (serum creatinine, blood urea nitrogen), but not those of indicators of hepatic function, were significantly increased in ARF rats that received glycerol compared with values for control rats. The area under the blood cyclosporin concentration-time curve after oral administration (AUCpo) were 4.976 ± 0.847 mg hL−1 for ARF rats and 9.684 ± 1.100 mg hL−1 for control rats; AUCpo in ARF was significantly reduced in a manner dependent on renal function. The oral clearance of cyclosporin in ARF and control rats was 1.172 ± 0.207 and 0.544 ± 0.062 Lh−1 kg−1, respectively, whereas total body clearance in ARF and control rats was 0.151 ± 0.008 and 0.183 ± 0.010 Lh−1 kg−1, respectively. The relative bioavailability of cyclosporin in ARF and control rats was 0.118 and 0.336, respectively. In an in-vitro study using everted sac and liver-slice methods, the apparent first-order rate constants for cyclosporin uptake (kuptake) and metabolism (kmetab) in gut tissues were reduced, whereas kuptake and kmetab in liver were increased. Gastric emptying, measured by use of paracetamol, was significantly reduced in ARF rats.
These results suggest that glycerol-induced ARF results in several changes in the pharmacokinetics of cyclosporin in rats. From these results, we conclude that reduction of the absorbed fraction of cyclosporin strongly contributes to the decrease in AUCpo in the presence of ARF.
Aldehyde Oxidase-catalysed Oxidation of Methotrexate in the Liver of Guinea-pig, Rabbit and Man
Authors: Jordan C Geraldine M , Rashidi Mohammed R , Laljee Hussain , Clarke Stephen E , Brown John E , Beedham Christine 
Published: October 2002

Abstract
Although 7-hydroxymethotrexate is a major metabolite of methotrexate during high-dose therapy, negligible methotrexate-oxidizing activity has been found in-vitro in the liver in man. The goals of this study were to determine the role of aldehyde oxidase in the metabolism of methotrexate to 7-hydroxymethotrexate in the liver and to study the effects of inhibitors and other substrates on the metabolism of methotrexate. Methotrexate, (±)-methotrexate and (-)-methotrexate were incubated with partially purified aldehyde oxidase from the liver of rabbit, guinea-pig and man and the products analysed by HPLC. Rabbit liver aldehyde oxidase was used for purposes of comparison.
In-vitro aldehyde oxidase from the liver of man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, but the turnover is low. However, formation of 7-hydroxy-methotrexate from all forms of methotrexate by the liver in guinea-pig and man was significantly inhibited in the presence of 100 μM menadione and chlorpromazine, potent inhibitors of aldehyde oxidase. Allopurinol (100 μM) had a negligible inhibitory effect on liver aldehyde oxidase from guinea-pig and man. Allopurinol is a xanthine oxidase inhibitor. The production of 7-hydroxymethotrexate was enhanced in the presence of allopurinol. Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate.
By employing potent selective inhibitors of aldehyde oxidase, menadione and chlorpromazine, we have demonstrated for the first time that liver aldehyde oxidase from man is minimally involved in methotrexate oxidation.
Mucolytic and Antitussive Effects of Erdosteine
Authors: Hosoe Hisashi , Raise Toshihiko , Ohmori Kenji , Isohama Youichirou , Kai Hirofumi , Takahama Kazuo , Miyata Takeshi 
Published: October 2002

AbstractTo investigate the influence of erdosteine, a new homocysteine-derived expectorant, on airway clearance we studied the effects of the drug on the viscosity of mucin, on the mucociliary transport rate in quails, on airway secretion in rats and on the cough reflex in guinea-pigs.The active metabolite of erdosteine, M1 (10 μM to 1 mM), significantly reduced the viscosity of porcine stomach mucin. Erdosteine by itself did not reduce viscosity. Erdosteine significantly promoted mucociliary transport in quails and increased airway secretion in rats. The effect was still apparent 24 h after administration. Erdosteine significantly suppressed citric acid-induced cough reflexes in guinea-pigs but did not suppress mechanical stimuli-induced cough reflexes. Erdosteine suppressed the reduction of the recovery volume of bronchoalveolar lavage fluid and albumin leakage into the fluid in citric acid-exposed guinea-pigs.These results indicate that erdosteine removes sputum by reducing its viscosity, and by promoting mucociliary transport and sustained enhancement of airway secretion. It also suppressed the chemical stimulation-induced cough reflex and plasma leakage into the airway. These results suggest that erdosteine is an excellent expectorant with several modes of action.
Chronopharmacokinetics: Implications for Drug Treatment
Authors: Lemmer Björn 
Published: October 2002

Abstract
Nearly all functions of the human body are organized across the 24 hours of the day. This is also true for functions involved in the regulation of pharmacokinetics such as gastric absorption and emptying, gastro-intestinal perfusion, and liver and kidney functions. Several clinical studies, performed in a cross-over design, have provided evidence that the pharmacokinetics of mainly lipophilic drugs can be circadian phase-dependent. These studies show that after oral dosing, peak drug concentration (Cmax) is, in general, higher or time-to-peak (tmax) shorter after morning, compared with evening application. A few studies performed with both immediate-release and sustained-release preparations (iso-sorbide-5-mononitrate, nifedipine) gave evidence that only the immediate-release formulation displayed circadian time-dependent pharmacokinetics, but not the sustained-release form. Most importantly, pharmacodynamic studies performed in parallel revealed that the effects, as well as the dose-response relationship, can be circadian phase-dependent, an observation which has an impact on pharmacokinetic/pharmacodynamic modelling. Moreover, this can be of relevance because the onset of certain diseases (e.g., bronchial asthma, coronary infarction, angina pectoris, rheumatic complaints) is not randomly distributed across the 24-h scale. In conclusion, there is now convincing evidence that the time-of-day has to be taken into account both in clinical pharmacokinetic and pharmacodynamic studies.
Cancer Chronotherapy
Authors: Lévi Francis 
Published: October 2002

Abstract
The cytotoxicity of more than thirty anticancer drugs varies by more than 50% as a function of dosing time along the 24-h time-scale in laboratory animals. Mechanisms involve circadian changes in cellular metabolism and proliferation processes, as well as drug pharmacokinetics. Moreover, the administration of chemotherapy at the least toxic time usually achieves best antitumour efficacy in experimental tumour models. Here we review experiences in utilising these phenomena in the optimization of cancer chemotherapy in the clinic.
Chronotherapy has been administered to 1500 patients with metastatic colorectal cancer using 5-fluorouracil and leucovorin with or without oxaliplatin. Sinusoidal chronomodulated delivery of 2- or 3-drug chemotherapy was performed in the patient's home or during usual activities, with a computer-programmed multi-reservoir pump. Courses lasted 4–5 days and were repeated every 14–21 days. Three-drug chronotherapy proved largely superior to flat infusion with respect to both tolerability and antitumour efficacy. The better tolerability of chronotherapy further allowed an increment of both 5-fluorouracil and oxaliplatin doses, which in turn further improved objective tumour response rate to 66%. This enabled surgical removal of previously inoperable metastases and the achievement of &gt; 20% survival at three years.
Second generation programmable-in-time pumps have simplified chronotherapy administration and decreased its costs. A broad use of fully ambulatory chronotherapy requires thorough definitions of drug stability, and compatibility with pump reservoirs and other medications.
Breaking out of the Ivory Tower: from Academia to Clinic
Authors: Woolfson A D 
Published: October 2002

Abstract
This paper considers the relationship between academic research and industry in terms of the commercial exploitation of product or process driven programmes originating in academic institutions. The commercial exploitation of pharmaceutical research is the only practical means of achieving the desired end-point of all research programmes in the pharmaceutical sciences—achieving patient benefits. The requirements for generating intellectual property rights (IPR), types of IPR likely to be encountered, time scales, costs, potential partnerships and commercial routes for exploitation are discussed. The ability to link up with industry to exploit new pharmaceutical products or processes is exemplified through two models. Model 1 involves out-licensing of IPR generated wholly within an academic setting and is illustrated by reference to the development of Ametop Gel, a novel percutaneous anaesthetic preparation. Model 2 involves a partnership with industry in a risk-sharing format, with both partners contributing expertise to the project. This latter model is illustrated by reference to a new controlled and sustained release intravaginal ring delivery system for oestrogen replacement therapy.
The Influence of Plasma Binding on Absorption/Exsorption in the Caco-2 Model of Human Intestinal Absorption
Authors: Walgren Richard A , Walle Thomas 
Published: October 2002

Abstract
The Caco-2 cell monolayer has become an increasingly useful in-vitro model of human intestinal absorption. In this study we have determined the effect of plasma on the basolateral side on the absorption as well as exsorption of several drugs that are highly bound to plasma proteins. The drugs used included propranolol and quercetin, which both use the transcellular route of absorption, and taxol and oestradiol 17 β-D-glucuronide, which are thought to undergo efflux by P-glycoprotein and the multidrug resistance protein MRP, respectively. All experiments were carried out under sink conditions to mimic normal absorption. It was necessary to use heparin anticoagulation for generation of the plasma, as EDTA was found to make the monolayers very leaky.
The apparent permeability (Papp) values for absorption were 1.54×10−6 cms−1 for oestradiol 17 β-D-glucuronide, 3.33×10−6 cms−1 for taxol, 20.8×10−6 cms−1 for quercetin, and 35.3×10−6 cms−1 for propranolol. For these four compounds, plasma on the basolateral side had no influence on absorption. However, plasma on the basolateral side significantly reduced the efflux of oestradiol 17 β-D-glucuronide by 66%, taxol by 75%, propranolol by 82%, and quercetin by 94%.
Failure to consider the effect of plasma binding can result in an overestimate of basolateral to apical efflux and result in misleading net flux calculations.
Antisecretory and Relaxatory Effects of Tachykinin Antagonists in the Guinea-pig Intestinal Tract
Authors: Goldhill Jon , Porquet Marie-France , Selve Norma 
Published: October 2002

Abstract
Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by β-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion. Using these models the potency of therapeutically useful compounds was determined.
NK1 and NK2 activation directly contracted smooth muscle, while NK1-mediated secretion was nerve-mediated. NK3 stimulation of contraction and secretion was neurally mediated, involving cholinergic nerves and 5-HT release. NK1-mediated contraction and secretion were antagonized by SR140333 (pD′2 = 9.29 and pKb = 8.53); NK2-mediated contraction was antagonised by SR48968 (pD′2 = 8.35) and NK3-mediated contraction and secretion were antagonized by SB223412 (pKb = 8.97 and 8.79). The mixed antagonist MDL103392 blocked NK1- and NK2-mediated contraction with pKb values of 7.92 and 6.71 respectively and NK1-mediated secretion with a pKb value of 6.57.
This data characterizes existing tachykinin antagonists, and should orientate the development of improved compounds as therapies for intestinal disease.