bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Pharmacological Study of Ropinirole (SKF-101468) and its Metabolites in Rats
Authors: Reavill C , Boyfield I , Coldwell M , Nelson P 
Published: July 2003

Abstract
The dopamine receptor agonist ropinirole (SKF-101468) is used to treat Parkinson's disease. Ropinirole is metabolized by two routes to a series of different metabolites although the predominant pathway is species-dependent. It is unknown whether any of the metabolites contribute to its antiparkinsonian activity and whether D3 or D2 receptor agonist activity plays a preferential role. Therefore ropinirole and its primary metabolites, SKF-104557, SKF-97930 and SKF-96990, and the rat metabolite, SKF-89124 were tested in the 6-hydroxydopamine lesion model of Parkinson's disease. SKF-89124 and SKF-96990 were also assayed in radioligand binding and microphysiometer functional assays at cloned human dopamine D2 and D3.
Ropinirole and SKF-89124 were equipotent in-vivo, and produced dose-related increases in circling at 0.05-0.8 mg kg−1, s.c. (ropinirole) and 0.05-0.75 mg kg−1, s.c. (SKF-89124). Neither SKF-96990 or SKF-97930, at doses up to 15 mg kg−1, increased the circling rate. Some circling was observed with 15 mg kg−1 SKF-104557 but the response was less than half that produced by ropinirole (0.8 mg kg−1). SKF-104557 was 150-fold less potent than ropinirole. SKF-89124 possessed-30-fold higher affinity for D3 over D2 receptors in radioligand binding studies, but was not selective in the functional microphysiometer assay. SKF-96990 was 10-fold selective for D3 over D2 receptors in the radioligand binding assay. Ropinirole and SKF-104557 are 20-fold selective for D3 over D2 receptors in radioligand binding assays whereas in microphysiometry, selectivity is 10-fold. SKF-97930 is inactive in radioligand binding and microphysiometer assays.
Primary metabolites of ropinirole did not contribute significantly to its activity in this model of Parkinson's disease. The lack of dopamine D3/D2 receptor selectivity for ropinirole rules out the possibility of attributing the degree of either D2 or D3 receptor activity to the behavioural efficacy of ropinirole.
Antitussive Efficacy of Dextromethorphan in Cough Associated with Acute Upper Respiratory Tract Infection
Authors: Lee P C L , Jawad M S M , Eccles R 
Published: July 2003

Abstract
Dextromethorphan is one of the most widely used antitussives for the treatment of cough associated with acute upper respiratory tract infection. However, there is very little data to support the efficacy of dextromethorphan in this disease state. This aim of this study was to obtain more information about the efficacy of a single dose of 30 mg dextromethorphan in the treatment of cough associated with acute upper respiratory tract infection.
The study was a double-blind, stratified, randomized and parallel group design. Both objective and subjective measurements of cough were recorded over 10-min recording periods in a quiet room before (baseline) and at 90, 135 and 180 min after treatment. Forty-three patients (30 females and 13 males), mean age 22.9 years (range 18–46 years), with acute dry or slightly productive cough and otherwise healthy were included in the study. Patients were randomized to placebo treatment (n = 22) and dextromethorphan treatment (n = 21). The results showed similar trends in both treatment groups with statistically significant reductions (P &lt; 0.05) in cough sound pressure level (CSPL), cough frequency (CF) and subjective scores for cough severity within treatment groups but little difference between the treatment groups during the study period. The only statistically significant difference between treatment groups was for the mean CSPL changes from baseline to 90 min (P = 0.019). There was a significant positive correlation between CSPL and CF (r = 0.752, P = 0.000) for changes in cough measurements from baseline to 90 min after treatment and this indicates that CSPL may be a useful measure of cough severity.
This study provides very little if any support for clinically significant antitussive activity of a single 30 mg dose of dextromethorphan in patients with cough associated with acute upper respiratory tract infection.
Comparative Cerebrospinal Fluid Diffusion of Imipenem and Meropenem in Rats
Authors: Dupuis Antoine , Caillaud Aurelien , Pariat Claudine , Courtois Phillipe , Couet William , Bouquet Serge 
Published: July 2003

Abstract
The main objective of this study was to compare the cerebrospinal fluid (CSF) diffusion of imipenem and meropenem at steady state, following intravenous infusions at various rates in rats. A preliminary experiment was conducted to estimate the elimination half-lives of these two carbapenem antibiotics, and then to evaluate the infusion duration necessary to reach steady state.
CSF diffusion of imipenem was essentially linear over the wide range of infusion rates (66–1320 μg min−1) and corresponding steady-state plasma concentrations (11.7–443.0 μg mL−1). Conversely the CSF diffusion of meropenem was saturable, with a predicted maximum CSF concentration equal to 1.3 μg mL−1.
Extrapolation of these data to the clinical situation may not be possible since the rats had normal blood-brain and blood-CSF barriers whereas patients with diseases such as meningitis may not. However, it is suggested that the observed differences in the diffusion characteristics of imipenem and meropenem may be partly responsible for their differences in toxicity and efficacy at the central level.
A Post-ischaemic Single Administration of Galanthamine, a Cholinesterase Inhibitor, Improves Learning Ability in Rats
Authors: Iliev A I , Traykov V B , Mantchev G T , Stoykov I , Prodanov D , Yakimova K S , Krushkov I M 
Published: July 2003

Abstract
Transient forebrain ischaemia is widely observed in clinical practice. We have examined the effect of a single administration of the Cholinesterase inhibitor galanthamine (2 mgkg−1, i.p.) 25 min after reperfusion in male Sprague-Dawley rats (180 ± 20 g) after a 20-min common carotid artery occlusion.
Twenty-four-hours post-ischaemia there was no difference in motor co-ordination or muscle tonus of the rats treated with or without galanthamine as assessed by the rota-rod test. Learning ability was examined using the shuttle-box test, evaluating the latency time and the number of errors for six days in succession. The performance of the ischaemic saline-injected rats was significantly impaired on days 4, 5, 6 (latency time) compared with the non-ischaemic rats and with the ischaemic animals administered galanthamine (P&lt; 0.05). Similar results were obtained when counting the number of errors (failure to cross the cage during conditioned or unconditioned stimulus). The monitoring of body temperature during the first 12-h post-ischaemia did not show any significant difference between the groups.
The data showed a beneficial effect of galanthamine on the recovery of learning ability when administered once only post-ischaemia. This suggests a direct effect on the early pathologic mechanisms of CNS damage. Cholinesterase inhibitors may prove useful in the early clinical treatment of ischaemic conditions.
The Anti-ulcerogenic Effect of an Alkaloidal Fraction from Mikania cordata on Diclofenac Sodium-induced Gastrointestinal Lesions in Rats
Authors: Mosaddik M Ashik , Alam Khandker M Faisal 
Published: July 2003

Abstract
A decoction of Mikania cordata (Compositae) is commonly used for the treatment of gastric ulcer in the Rajbari district of Bangladesh. We have evaluated the anti-ulcerogenic effect of the alkaloidal fraction from the whole plant of M. cordata on diclofenac sodium-induced gastrointestinal lesion in rats.
Long Evan's rats were divided into five groups. The control group was kept undisturbed. The vehicle group received vehicle after a 48-h fast. The diclofenac group received diclofenac sodium suspension (80mgkg−1) after a 48-h fast. The diclofenac-ranitidine group (anti-ulcer drug used as a standard) received 35 mgkg−1 ranitidine hydrochloride suspension 1 h after diclofenac sodium administration, after a 48-h fast. The diclofenac-extract group received alkaloidal fraction (50 mgkg−1) 1 h after diclofenac administration, after a 48-h fast. The biochemical, morphological and histological changes were studied.
The data showed that the pH values of the stomach and duodenum were increased significantly (P &lt; 0.001) in the alkaloidal-administered group compared with the control group (3.09 ± 0.0429 vs 2.07 ± 0.0339 and 6.79 ± 0.1162 vs 6.19 ± 0.1273, respectively). There were significant changes (P &lt; 0.001) detected in the morphological study. The ulcer index of the stomach (0.268 ± 0.0346) and of the duodenum (0.050 ± 0.0129) in the alkaloidal-administered group were significantly lower than the diclofenac-only administered group (0.691 ± 0.0184 and 0.093 ± 0.0138, respectively). According to the grading of tissue damage in the histological study, there were less or no lesions on the gastrointestinal mucosa of the alkaloidal-administered group compared with the diclofenac-only group (0 vs 5, respectively). When the results of the alkaloid extract group where compared with the ranitidine hydrochloride group a similar or more potent effect was observed with the alkaloidal extract group.
The results of this study revealed that the bioactive principles of M. cordata have anti-ulcerogenic effects. The results validate the traditional use of this plant for the treatment of gastric ulcer in Bangladesh.
Antioxidant Lignans from Machilus thunbergii Protect CCl4-injured Primary Cultures of Rat Hepatocytes
Authors: Yu Young Uck , Kang So Young , Park Hae Young , Sung Sang Hyun , Lee Eun Ju , Kim Sun Yeou , Kim Young Choong 
Published: July 2003

Abstract
Eleven lignans (1–11) were isolated from the CH2Cl2 fraction of the bark of Machilus thunbergii Sieb, et Zucc. (Lauraceae). These were identified as (-)-acuminatin (1), (-)-isoguaiacin (2), meso-dihydroguaiaretic acid (3), (+)-galbacin (4), (-)-sesamin (5), (+)-galbelgin (6), machilin A (7), machilin G (8), licarin A (9), and nectandrin A (10) and B (11).
Primary cultures of rat hepatocytes were co-incubated for 90 min with the hepatotoxin CCl4 and each of the 11 lignans (50 μM). Hepatoprotective activity was determined by measuring the level of glutamic pyruvic transaminase released into the medium from the primary cultures of rat hepatocytes. (-)-Acuminatin, (-)-isoguaiacin and meso-dihy-droguaiaretic acid all significantly reduced the level of glutamic pyruvic transaminase released. Further investigation revealed that these three compounds significantly preserved the levels and the activities of glutathione, superoxide dismutase, glutathione peroxidase and catalase. (-)-Acuminatin, (-)-isoguaiacin and meso-dihydroguaiaretic acid also ameliorated lipid peroxidation as demonstrated by a reduction of malondialdehyde production.
These results suggest that (-)-acuminatin, (-)-isoguaiacin and meso-dihydroguaiaretic acid exert diverse hepatoprotective activities, perhaps by serving as potent antioxidants.
Influence of Nanoparticles on the Brain-to-serum Distribution and the Metabolism of Valproic Acid in Mice
Authors: Darius Joerg , Meyer Frank P , Sabel Bernhard A , Schroeder Ulrike 
Published: July 2003

Abstract
The suitability of nanoparticles as a drug-carrier system for the antiepileptic valproic acid has been studied in mice. The aim of the study was to increase the brain-to-serum ratio of the drug to reduce dose-related side effects in the periphery. The influence of nanoparticles on the metabolism of valproic acid was also investigated.
The serum kinetics and the brain tissue levels of valproic acid were not altered by administration with nanoparticles. However, the nanoparticles did inhibit the metabolic degradation of valproic acid via mitochondrial β-oxidation but did not influence any other metabolic pathway.
It can be concluded that nanoparticles loaded with valproic acid may help to reduce the toxic side effects of valproate therapy, not by reducing the therapeutically necessary dosage but by inhibition of formation of toxic metabolites. Using their ability to selectively block a pathway nanoparticles may serve as a tool to investigate the metabolic origin of metabolites and their contribution to therapeutic efficacy and side effects.
Ileal Uptake of Polyalkylcyanoacrylate Nanocapsules in the Rat
Authors: Damgé Christiane , Aprahamian Marc , Humbert Willy , Pinget Michel 
Published: July 2003

Abstract
The ileal uptake of polyalkylcyanoacrylate nanocapsules (less than 300 nm in diameter) has been investigated in the rat. Iodised oil (Lipiodol) was used as the tracer for X-ray microprobe analysis in scanning electron microscopy.
Lipiodol nanocapsules, or an emulsion of Lipiodol, were administered in the lumen of an isolated ileal loop of rat. Lipiodol nanocapsules improved the absorption of the tracer as indicated by increased concentrations of iodine in the mesenteric blood (+27%, P &lt; 0.01, compared with Lipiodol emulsion). Intestinal biopsies were taken at different time points and the samples underwent cryofixation and freeze-drying. The nanocapsules were characterized by their strong iodine emission, and electron microscopy of the biopsy samples revealed nanocapsules in the intraluminal mucus of the non-follicular epithelium, then in the intercellular spaces between enterocytes, and finally the nanocapsules were found within intravillus capillaries. However, nanocapsules were most abundant in the Peyer's patches, where the intestinal epithelium had been crossed by way of the specialized epithelial cells, designated membranous cells, or M cells, and their adjacent absorptive cells. These observations were confirmed quantitatively by measuring iodine concentrations in the various tissue compartments. Ten minutes after the intraluminal administration of Lipiodol nanocapsules, the emission of iodine peaked in the mucus (+77%, P &lt; 0.01), in M cells (+366%, P &lt; 0.001), in enterocytes adjacent to M cells (+70%, P &lt; 0.05) and in lymph vessels (+59%, P &lt; 0.05).
Polyalkylcyanoacrylate nanocapsules were able to pass through the ileal mucosa of the rat via a paracellular pathway in the non-follicular epithelium, and most predominantly, via M cells and adjacent enterocytes in Peyer's patches.
Biodistribution of Stealth and Non-stealth Solid Lipid Nanospheres after Intravenous Administration to Rats
Authors: Podio Valerio , Zara Gian Paolo , Carazzone Marilena , Cavalli Roberta , Gasco Maria Rosa 
Published: July 2003

AbstractDrug-free stealth and non-stealth solid lipid nanospheres (SLNs) were administered intravenously to rats to evaluate their tissue distribution and their transport across the blood-brain barrier.Two types of experiments were performed using unlabelled and labelled SLNs. Rats were administered labelled non-stealth or stealth nanospheres (NSSLNs and SSLNs) and their tissue distribution was monitored for 60 min. In another experiment, rats were injected with unlabelled NSSLNs or SSLNs and the cerebrospinal fluid (CSF) was analysed using transmission electron microscopy (TEM) to confirm the presence of the SLNs.Some differences were found in the biodistribution between labelled NSSLNs and SSLNs. In particular, the radioactivity in the liver and the lung was much lower for SSLNs than for NSSLNs, confirming a difference in their uptake. Both types of SLNs were detected in the brain. TEM analysis showed both types of SLNs in rat CSF.
Clearance of Fentanyl, Alfentanil, Methohexitone, Thiopentone and Ketamine in Relation to Estimated Hepatic Blood Flow in Several Animal Species: Application to Prediction of Clearance in Man
Authors: Björkman Sven , Redke Finn 
Published: July 2003

Abstract
We have used estimated hepatic blood flow (Qhep) as an aid to evaluate clearance (CL) values in animals and to predict clearance in man of five anaesthetic agents: fentanyl, alfentanil, methohexitone, thiopentone and ketamine.
The disposition of methohexitone was determined in rats and that of ketamine in rats, rabbits and pigs. Further data were compiled from the literature and supplemented experimentally as needed. Allometric interspecies scaling, according to three different methods, was used to estimate blood clearance and unbound clearance (CLu) in man. The results of scaling according to the three different methods were evaluated in relation to estimated hepatic extraction ratio (CL/Qhep) of the drugs.
In most animals the clearance of the drugs were comparable with or lower than estimated Qhep. However, ketamine showed extensive extrahepatic clearance in rabbits. Prediction of clearance in man was successful by at least one method for all five drugs, while prediction of CLu generally failed. Estimates of CL/Qhep gave no indication as to the choice of the best method. Volume of distribution at steady state could be predicted for alfentanil, thiopentone and ketamine.
Comparison of clearance with Qhep should be used to evaluate clearance data in animals, however estimation of hepatic extraction ratios appears to be of little use for allometric scaling. The use of ketamine as an anaesthetic agent in rabbits is questionable, while the use of fentanyl in pigs, methohexitone in rats and ketamine in rats and pigs is well supported by the pharmacokinetic data.
Comparative Pharmacodynamics and Pharmacokinetics of Candesartan and Losartan in Man
Authors: Fuchs Bettina , Breithaupt-Grögler Kerstin , Belz Gustav G , Roll Susanna , Malerczyk Claudius , Herrmann Volker , Spahn-Langguth Hildegard , Mutschler Ernst 
Published: July 2003

Abstract
The angiotensin II antagonistic effects of candesartan and losartan were compared in-vivo after single and repeated doses. Effects were related to antagonistic activity in plasma.
In this double-blind, crossover study, 12 healthy male volunteers received, in random order, daily oral doses of 8 mg candesartan cilexetil or 50 mg losartan for seven days. On day 1 and day 8, dynamics and kinetics were assessed up to 48 h after dosing. Antagonistic effect was determined from the antagonist-induced rightward shifts of the diastolic blood pressure response curves to exogenously administered angiotensin II measured as the dose ratio (DR). The antagonistic activity in plasma was measured using an ex-vivo/in-vitro radioreceptor assay. Specific high-performance liquid chromatography assays determined plasma concentrations of candesartan, losartan and its active metabolite EXP-3174.
The pharmacokinetic properties of candesartan and losartan were comparable and antagonistic activity in plasma almost identical (ratio candesartan: losartan = 0.97 and 1.2 after single and multiple doses, respectively). However, the antagonistic effects of candesartan and losartan in-vivo were quite different. Twenty-four hours after single dosing with candesartan a clinically relevant rightward shift in the angiotensin II dose-response curve (DR = 3.2) occurred that was more pronounced than that following losartan administration (DR = 2.1, ratio candesartan: losartan = 1.65). Twenty-four hours after multiple doses of candesartan or losartan, the values of the DR were 4.8 and 2.3, respectively (ratio candesartan: losartan = 1.94). The values of DR for candesartan were significantly higher compared with losartan between 6 and 36 h after a single dose and between 3 and 24 h post-dose following multiple dose administration. A counter-clockwise hysteresis was apparent between antagonistic activity in plasma and antagonistic effect.
Despite equivalent angiotensin II antagonistic activity in plasma, the pharmacodynamic effect of candesartan cilexetil was greater than that of losartan. Candesartan appeared to have a slower off-rate from the angiotensin AT1-receptor compared with losartan, nevertheless differences in distributional phenomena or the extent of insurmountable antagonistic activity cannot be ruled out.
Chronopharmacokinetics of Sumatriptan in Healthy Human Subjects
Authors: Poondru Srinivasu , Devaraj Rambhau , Boinpally Ramesh R , Yamasani Madhusudan R 
Published: July 2003

Abstract
Rhythms in the onset and symptoms of several diseases are well established. Migraine is a disorder that exhibits periodicity in its symptoms and so chronotherapy may be beneficial in treating the problem. Designing a chronotherapeutic schedule requires chronopharmacokinetic and chronopharmacodynamic data of the drugs prescribed. We have studied the chronopharmacokinetics of sumatriptan, a drug of choice in migraine treatment.
Twelve healthy male volunteers were treated with 100 mg sumatriptan orally at 0700, 13 00, 19 00 and 01 00 h in a randomized 4 times 4 Latin square crossover design, with a washout period of one week. Serum samples were analysed by high performance liquid chromatography with an electrochemical detector. Pharmacokinetic parameters were calculated using noncompartmental methods. The pharmacokinetic parameters were analysed using analysis of variance and a two-tailed paired t-test at the probability of 95%.
The mean peak serum concentration following the 07 00 h administration (Cmax; 59.09 ± 10.53 ng mL−1) was significantly (P &lt; 0.05; n = 12) higher than after the 19 00 h administration (Cmax 41.88 ± 12.21 ng mL−1). The mean area under the serum concentration-time curve from time zero to the last time-point (AUC0-t), the area under the serum concentration-time curve from zero to infinity (AUC0-∞), and the area under the first moment curve (AUMC) were significantly (P &lt; 0.05; n = 12) higher following the 07 00 and 01 00 h administrations than after the 19 00 h administration. Following administration at 07 00 h, the mean oral clearance (CLs/f; 781 ± 186 mL h−1 kg−1) and the apparent volume of distribution (Vd/f; 2379 ± 684) were significantly lower (P &lt; 0.05; n = 12) than after the 19 00 h administration (CLs/f 1208 ± 458 mL h−1 kg−1, Vd/f 4655 ± 2096 mL kg−1). The mean Vd/f value was again lower after the 1300h administration than after the 19 00 h administration (2763 ± 1417 vs 4655 ± 2096 mL kg−1; P &lt; 0.05; n = 12).
The variations may be due to the time dependent changes in the extent of absorption and/or circadian variations in hepatic blood flow.