bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Fenfluramine on the Pulmonary Disposition of 5-Hydroxytryptamine in the Isolated Perfused Rat Lung: a Comparison with Chlorphentermine
Authors: Valodia P , Syce J A 
Published: July 2003

Abstract
A possible mechanism for fenfluramine-induced pulmonary hypertension has been investigated. Fenfluramine, like chlorphentermine, may inhibit the pulmonary uptake and/or metabolism of 5-hydroxytryptamine (5-HT). This allows more 5-HT to remain in the pulmonary circulation, where it may exert a greater vasoconstrictor action resulting in pulmonary hypertension. Chlorphentermine has been shown to inhibit the uptake and metabolism of 5-HT.
The effect of fenfluramine on the pulmonary disposition of [14C]5-HT has been investigated, in comparison with chlorphentermine, using a recirculating isolated perfused rat lung system. The pulmonary disposition of [14C]5-HT was assessed by measuring the change in [14C]5-HT concentration in the perfusion medium during the experiment and at the end, and the concentration in the lung at the end of the experiment. The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, was measured in perfusate and lung samples. Mean pulmonary clearance of 5-HT for the control lung and lungs challenged with either fenfluramine (2.5 μM) or chlorphentermine (2.5 μM) was 4.514, 1.316 and 1.007 mL min−1, respectively (n = 5). The concentration of 5-HT found in the lungs at the end of the experiment for the control and the lungs preloaded with fenfluramine or chlorphentermine was 695.05 ± 9.69, 638.65 ± 10.27 and 617.3 ± 14.38 ng g−1, respectively.
Fenfluramine, like chlorphentermine, inhibited the pulmonary disposition of 5-HT resulting in an elevated perfusate level of 5-HT. This is a possible contributing mechanism for fenfluramine-induced pulmonary hypertension. The effect of fenfluramine was less pronounced than chlorphentermine.
Glutamate and Kynurenate in the Rat Central Nervous System Following Treatments with Tail Ischaemia or Diclofenac
Authors: Edwards Stephen R , Mather Laurence E , Lin Yiguang , Power Ian , Cousins Michael J 
Published: July 2003

Abstract
Kynurenate is an endogenous antagonist at the allosteric glycine site on the N-methyl-D-aspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of non-steroidal anti-inflammatory drugs (NSAIDs) are mediated peripherally and possibly centrally through inhibition of prostaglandin synthesis, there is also evidence for centrally mediated prostaglandin-independent antinociceptive effects that may result from increased central nervous system (CNS) concentrations of kynurenate. We have investigated the effects of the NSAID diclofenac, (40 mg kg−1, s.c.; administered to rats 1 h before killing) or the exposure of rats to noxious stimulation (tail ischaemia for 20 min before killing), on the concentrations of glutamate and kynurenate in discrete CNS regions.
Regional CNS tissue concentrations of diclofenac were between 3.0–3.8 nmol g−1. The corresponding regional glutamate concentrations ranged between 4.8–10.6 μmol g−1, and were significantly lower in the ischaemia group when compared with both control (15%, P &lt; 0.05) and diclofenac-treated (19%, P &lt; 0.002) groups. Kynurenate concentrations in these CNS regions ranged between 3.3–45.8 pmol g−1. Pairwise comparisons between the control and diclofenac-treated groups found significant increases in kynurenate concentrations in the diencephalon and lumbo-sacral regions of the CNS (P = 0.05).
Noxious stimulation from tail ischaemia appeared to be associated with increased release of glutamate. Additionally, NSAIDs appeared to increase kynurenate concentrations in the spinal cord and diencephalon. Antagonism by kynurenate of glutamate effects at NMDA receptors may contribute to the antinociceptive effects of NSAIDs.
Fluvastatin, a New Inhibitor of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, Resists Hydroxyl Radical Generation in the Rat Myocardium
Authors: Obata Toshio , Ebihara Akio , Yamanaka Yasumitsu 
Published: July 2003

Abstract
The aim of this study was to determine whether fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist Cu (II)-induced hydroxyl radical generation (.OH) in the extracellular fluid of rat myocardium.
Rats were anaesthetized and sodium salicylate in Ringer's solution (O.5 nmol μL−1 min−1) was infused through a microdialysis probe to detect the generation of .OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) in the myocardium. When Cu (II) (0, 10, 25 or 50 μm) was administered to 1 mm tyramine-pretreated rats, a marked elevation in the levels of 2,3-DHBA was found, indicating a positive linear correlation between Cu (II) and the increase in .OH formation trapped as 2,3-DHBA in the dialysate (r2 = 0.977). In the presence of fluvastatin (100 μm), a marked decrease in the levels of 2,3-DHBA was found. Corresponding experiments performed with iron (II) (0, 10, 25 or 50 μm), showed a marked elevation in the levels of 2,3-DHBA, indicating a positive linear correlation between iron (II) and the increase in .OH formation trapped as 2,3-DHBA in the dialysate (r2 = 0.986). However, in the presence of fluvastatin (100 μm) a small decrease in the level of 2,3-DHBA was found.
The results show that iron (II) against LDL oxidation may be insensitive compared with Cu (II). Cu (II)-induced .OH formation may be reduced by inhibiting LDL with fluvastatin.
The Role of Nitric Oxide and Prostaglandin E2 on the Hyperalgesia Induced by Excitatory Amino Acids in Rats
Authors: Park Yang Hae , Shin Chang Yell , Lee Tai Sang , Huh In Hoi , Sohn Uy Dong 
Published: July 2003

Abstract
The present study was designed to investigate the role of nitric oxide (NO), N-methyl-D-aspartate (NMDA) receptor and prostaglandins on hyperalgesia induced in rats by excitatory amino acids and the possibility that prostaglandins may act as the retrograde messenger in the spinal cord like NO.
Nω-nitro-L-arginine methyl ester (L-NAME; 500 μg/paw, intraplantarly (i.pl.)), MK-801 (10 μg/paw, i.pl.) or indomethacin (300 μg/paw, i.pl.) reduced the duration of phase 2 of the biting/licking and scratching (B/L + S) response induced by formalin injection from 255.6±16.7 s to 155.6 ± 16.9, 172.2 ± 33.3 or 205.6 ± 16.7 s, respectively. L-NAME (0–3 mg, i.th.), MK-801 (8 μg, i.th.) or indomethacin (20 μg, i.th) reduced the duration of phase 2 of the B/L + S response induced by saline injection from 288.5 ± 7.7 s to 207.7 ± 19.2, 184.6 ± 7.7 or 192.3 ± 38.5 s, respectively.
L-NAME or indomethacin injected into the spinal cord of the rat significantly reduced the hyperalgesia induced by NMDA (1 μg, i.th.) from 43.8 ± 4.6% to 12.3 ± 3.1 and 19.2 ± 2.3%, respectively. It is assumed that NO produced by excitatory amino acids may increase prostaglandin production by cyclooxygenase activation. L-NAME, MK-801 or indomethacin injected into the rat spinal cord significantly reduced the hyperalgesia induced by prostaglandin E2 (PGE2, 25 ng, i.th.) in the tail-flick test from 40.6 ± 3.5% to 18.2 ± 3.2, 18.8 ± 1.8 or 17.6 ± 4.1%, respectively, but had little effect on hyperalgesia in the paw pressure test (except for indomethacin).
In conclusion, NO and PGE2 affect the hyperalgesia induced by excitatory amino acids. It is suggested that PGE2, like NO, may act as a retrograde messenger in the spinal cord.
Protective Effect of Curcumin in Rat Liver Injury Induced by Carbon Tetrachloride
Authors: Park Eun-Jeon , Jeon Chul Hyun , Ko Geonil , Kim Jaebaek , Sohn Dong Hwan 
Published: July 2003

AbstractThis study was carried out to investigate the protective effects of curcumin on acute or subacute carbon tetrachloride-induced liver damage in rats.Acute hepatotoxicity was induced by intraperitoneal injection of carbon tetrachloride after 4 consecutive days of curcumin treatment. Subacute hepatotoxicity was induced by oral administration of carbon tetrachloride twice a week during 4 weeks of curcumin treatment. In rats with acute liver injury, curcumin (100 and 200 mg kg−1) lowered the activity of serum alanine aminotransferase to 52–53% (P &lt; 0.05) and aspartate aminotransferase to about 62% (P &lt; 0.05) those of control rats. In rats with subacute liver injury, curcumin (100 mg kg−1) lowered the activity of serum alanine aminotransferase to 34% (P &lt; 0.01) and alkaline phosphatase to 53% (P &lt; 0.05) of control rats. The liver hydroxyproline content in the curcumin (100 mg kg−1)-treated group was reduced to 48% of the carbon tetrachloride control group (P &lt; 0.01). Malondialdehyde levels in curcumin (100 mg kg−1) treated rat liver was decreased to 67% of the control rat liver (P &lt; 0.01) in subacute injury.It was concluded that curcumin improved both acute and subacute liver injury induced by carbon tetrachloride in rats.
SM-20220, a Potent Na+/H+ Exchange Inhibitor, Improves Consciousness Recovery and Neurological Outcome Following Transient Cerebral Ischaemia in Gerbils
Authors: Kuribayashi Yoshikazu , Itoh Natsuko , Horikawa Naotsugu , Ohashi Naohito 
Published: July 2003

Abstract
We studied the cerebroprotective effect of SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulphonate), a newly synthesized Na+/H+ exchanger (NHE) inhibitor, in Mongolian gerbil global ischaemia.
Transient cerebral ischaemia was induced by clipping both common carotid arteries for 30 min followed by 24 h reperfusion. Intravenous administration of SM-20220 (0.3 or 1.O mg kg−1) immediately after reperfusion significantly shortened the consciousness recovery time (P &lt; 0.01). SM-20220 also improved the neurological outcome (McGraw's scale) after reperfusion. At the dose of 1.0 mg kg−1, the mortality rate was significantly reduced at 24 h after reperfusion (P &lt; 0.01).
This study shows that NHE is involved in the aggravation of cerebral function, represented by consciousness recovery, and neurological outcome following transient forebrain ischaemia, and that its inhibitor may exert protective effects on post-ischaemic brain damage.
Estimation of Individual Sennosides in Plant Materials and Marketed Formulations by an HPTLC Method
Authors: Shah Shailesh A , Ravishankara M N , Nirmal Anjoo , Shishoo Chamanlal J , Rathod Ishwarsinh S , Suhagia Bhanubhai N 
Published: July 2003

Abstract
Senna is a well-known drug, used in the Ayurvedic and Allopathic systems of medicine, and is a treatment for constipation. The purgative action of senna and its formulations is due to the presence of sennosides A and B. An HPTLC method has been developed for the determination of individual sennosides (A, B, C, D) without any derivatization in marketed formulations (three tablet formulations, two granule formulations and one liquid formulation) and plant materials (senna leaf and pod).
The methanolic solution of a sample was applied on a pre-coated silica gel G60 F254 TLC plate (E. Merck.) and was developed using n-propanol: ethyl acetate: water: glacial acetic acid (3:3:2:0.1 v/v) as the mobile phase. The relative band speeds (Rf values) obtained were 0.35, 0.25, 0.61, 0.46 for sennosides A, B, C and D, respectively. The densitometric response was monitored at 366 nm. Calibration curves were found to be linear in the concentration ranges 193–1356, 402–2817, 71–497 and 132–927 ng per spot for sennosides A, B, C, and D, respectively. The correlation coefficients were found to be 0.9978, 0.9987, 0.9939 and 0.9983 respectively for sennosides A, B, C and D. The result obtained with the HPTLC method for total sennoside content was compared with the results using the pharmacopoeial methods (spectrophotometric (British Pharmacopoeia) and spectrofluorimetric (United States Pharmacopeia) using the ‘F’ test). The results revealed no significant difference in the three different methods for estimation of total sennoside.
The proposed HPTLC method was found to be simple, specific, precise, accurate and rapid. It can be used for routine quality control of sennosides or senna-containing formulations for individual sennosides.
Identification of Kaempferol as a Monoamine Oxidase Inhibitor and Potential Neuroprotectant in Extracts of Ginkgo Biloba Leaves
Authors: Sloley B D , Urichuk L J , Morley P , Durkin J , Shan J J , Pang P K T , Coutts R T 
Published: July 2003

Abstract
The effects of Ginkgo biloba leaf extract on rat brain or livermonoamine oxidase (MAO)-A and -B activity, biogenic amine concentration in nervous tissue, N-methyl-d-aspartate (NMDA)- and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced neurotoxicity and antioxidant activity was investigated to determine the effects of the extract on monoamine catabolism and neuroprotection.
Ginkgo biloba leaf extract was shown to produce in-vitro inhibition of rat brain MAO-A and -B. The Ginkgo biloba extract was chromatographed on a reverse-phase HPLC system and two of the components isolated were shown to be MAO inhibitors (MAOIs). These MAOIs were identified by high-resolution mass spectrometry as kaempferol and isorhamnetin. Pure kaempferol and a number of related flavonoids were examined as MAOIs in-vitro. Kaempferol, apigenin and chrysin proved to be potent MAOIs, but produced more pronounced inhibition of MAO-A than MAO-B. IC50 (50% inhibition concentration) values for the ability of these three flavones to inhibit MAO-A were 7 times 10−7, 1 times 10−6 and 2 times 10−6 m, respectively. Ginkgo biloba leaf extract and kaempferol were found to have no effect ex-vivo on rat or mouse brain MAO or on concentrations of dopamine, noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Kaempferol was shown to protect against NMDA-induced neuronal toxicity in-vitro in rat cortical cultures, but did not prevent DSP-4-induced noradrenergic neurotoxicity in an in-vivo model. Both Ginkgo biloba extract and kaempferol were demonstrated to be antioxidants in a lipid-peroxidation assay.
This data indicates that the MAO-inhibiting activity of Ginkgo biloba extract is primarily due to the presence of kaempferol. Ginkgo biloba extract has properties indicative of potential neuroprotective ability.
Protection by Osbeckia aspera Against Carbon Tetrachloride-mediated Alterations in Microsomal Drug Metabolizing Enzyme Activity
Authors: Jayatilaka K A P W , Thabrew M I 
Published: July 2003

Abstract
Previous investigations have confirmed the protective effect of Osbeckia aspera leaf extract on carbon tetrachloride-mediated liver injury in rat models. It is well known that the earliest alterations in liver cell structure and function following carbon tetrachloride poisoning involve the endoplasmic reticulum and its drug metabolizing enzymes. Therefore, we investigated whether an aqueous leaf extract of O. aspera could offer protection against carbon tetrachloride-induced changes in the microsomal drug metabolizing enzymes aniline hydroxylase and p-aminopyrine N-demethylase. This enzyme activity was compared with phenobarbital-induced righting reflex and lipid peroxidation.
Treatment of rats with the aqueous leaf extract of O. aspera (before or after the administration of carbon tetrachloride) resulted in a marked decrease in carbon tetrachloride-mediated alterations in aniline hydroxylase and p-aminopyrine N-demethylase activity, phenobarbital-induced loss of righting reflex and malondialdehyde formation due to lipid peroxidation. The Km value of these enzymes in control and Osbeckia-treated rats were the same.
These results show that the plant extract can markedly decrease the carbon tetrachloride-mediated reduction in aniline hydroxylase and p-aminopyrine N-demethylase activity and inhibit peroxidative damage to the cell membrane. Phenobarbital-induced sleeping time in rats and kinetic enzyme studies suggested that the effects of the plant extract was neither due to an induction of the drug-metabolizing enzymes under investigation, nor due to an alteration in the Km values of these enzymes.
Skin Permeation of Testosterone and its Ester Derivatives in Rats
Authors: Kim Mi-Kyeong , Lee Chi-Ho , Kim Dae-Duk 
Published: July 2003

Abstract
To establish the optimum conditions for improving the transdermal delivery of testosterone, we studied the relationship between the lipophilicity of testosterone ester derivatives and the rat skin permeation rate of testosterone. We performed a rat skin permeation study of testosterone and its commercially available ester derivatives, testosterone hemisuccinate, testosterone propionate and testosterone-17β-cypionate, using an ethanol/water co-solvent system.
The aqueous solubility and rat skin permeation rate of each drug, saturated in various compositions of an ethanol/water system, was determined at 37°C. The aqueous solubility of testosterone and its ester derivatives increased exponentially as the volume fraction of ethanol increased up to 100% (v/v). The stability of testosterone propionate in both the skin homogenate and the extract was investigated to observe the enzymatic degradation during the skin permeation process. Testosterone propionate was found to be stable in the isotonic buffer solution and in the epidermis-side extract for 10 h at 37°C. However, in the skin homogenate and the dermis-side extract testosterone propionate rapidly degraded producing testosterone, implying that testosterone propionate rapidly degraded to testosterone during the skin permeation process. The steady-state permeation rates of testosterone in the ethanol/water systems increased exponentially as the volume fraction of ethanol increased, reaching the maximum value (2.69 ± 0.69 μg cm−2 h−1) at 70% (v/v) ethanol in water, and then decreasing with further increases in the ethanol volume fraction. However, in the skin permeation study with testosterone esters saturated in 70% (v/v) ethanol in water system, testosterone esters were hardly detected in the receptor solution, probably due to the rapid degradation to testosterone during the skin permeation process. Moreover, a parabolic relationship was observed between the permeation rate of testosterone and the log P values of ester derivatives. Maximum flux was achieved at a log P value of around 3 which corresponded to that of testosterone (log P = 3.4).
The results showed that the skin permeation rate of testosterone and its ester derivatives was maximized when these compounds were saturated in a 70% ethanolic solution. It was also found that a log P value of around 3 is suitable for the skin permeation of testosterone related compounds.
The Encapsulation of Bleomycin Within Chitosan Based Polymeric Vesicles Does Not Alter its Biodistribution
Authors: Sludden J , Uchegbu I F , Schätzlein A G 
Published: July 2003

Abstract
Polymeric vesicles have recently been developed from an amphiphilic chitosan derivative—palmitoyl glycol chitosan. Their potential as a drug delivery system was evaluated using the anti-cancer compound bleomycin as a model drug.
Palmitoyl glycol chitosan (GCP41) was synthesised by conjugation of palmitoyl groups to glycol chitosan. Bleomycin-containing vesicles (669 nm diameter) were prepared from a mixture of GCP41 and cholesterol by remote loading. The vesicles were imaged by freeze-fracture electron microscopy and their in-vitro stability tested. Incubation of the larger vesicles with plasma in-vitro led to a reduction of mean size by 49%, a reaction not seen with control sorbitan monostearate niosomes (215 nm in size). They also showed a higher initial drug release (1 h), but GCP41 and sorbitan monostearate vesicles retained 62% and 63% of the encapsulated drug after 24 h, respectively. The biodistribution of smaller vesicles (290 nm) prepared by extrusion through a 200-nm filter was also studied in male Balb/c mice. Encapsulation of bleomycin into polymeric vesicles did not significantly alter the pharmacokinetics of biodistribution of bleomycin in male Balb/c mice although plasma and kidney levels were slightly increased.
It is concluded that the extruded GCP41 vesicles break down in plasma in-vivo and hence are unlikely to offer any therapeutic advantage over the free drug.
Enhancement of Ursodeoxycholic Acid Bioavailability by Cross-linked Sodium Carboxymethyl Cellulose
Authors: Scalia Santo , Giunchedi Paolo , Pazzi Paolo , Conte Ubaldo 
Published: July 2003

Abstract
The bioavailability of ursodeoxycholic acid from a new formulation based on drug-loaded cross-linked sodium carboxymethyl cellulose was studied in man. The plasma levels of ursodeoxycholic acid were determined by gas chromatography-mass spectrometry after derivatization and sample purification by solid-phase extraction. Capsules containing the drug/polymer system were prepared and compared with conventional commercial ursodeoxycholic acid capsules after single oral administration using a randomized crossover experimental design.
Although the drug/polymer system improved the in-vitro dissolution rate of ursodeoxycholic acid in simulated intestinal fluid, statistical evaluation of the area under the plasma concentration curves indicated no significant difference in the extent of bioavailability between the two formulations (14.93 ± 4.43 vs 14.95 ± 5.79 μm h; P &gt; 0.2). However, following the administration of the ursodeoxycholic acid/cross-linked sodium carboxymethyl cellulose system with an enteric-coated capsule, the mean area under the plasma concentration curve (27.60 ± 10.11 μm h) was significantly higher than that obtained after treatment with the commercially available ursodeoxycholic acid capsule (16.24 ± 8.38 μm h; P &lt; 0.05).
We concluded that improved intestinal absorption of the drug was obtained with enteric-coated capsules filled with the ursodeoxycholic acid/polymer system. Moreover, the simplicity of the preparation and the non-toxicity of the polymer used as the carrier represented additional advantages of this dosage form.
Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics
Authors: Mets B , Soo E , Diaz J , Pantuck C , Singh G , Blair I A 
Published: July 2003

Abstract
The aim of this study was to determine the effect of chronic cocaine infusion on urine cocaine, ecgonine methylester and benzoylecgonine concentrations to establish if they varied with dose and duration of cocaine administration.
Male rats were continuously infused with cocaine at either 6 or 18 mg kg−1 daily for 13 days. Three urine samples taken over the course of the infusion period showed that cocaine, ecgonine methylester and benzoylecgonine concentrations varied with the dose administered and the duration of administration. Cocaine, ecgonine methylester and benzoylecgonine concentrations were 2–3 times greater in the high-dose group than the low-dose group at each sampling time point. These decreased, respectively, from 7.0 ± 1.1, 26.7 ± 4.5 and 29.5 ± 5.4 μg mL−1 to 2.5 ± 0.5, 10.5 ± 1.8 and 11.8 ± 1.5 μg mL−1 in the high-dose group and from 1.0 ± 0.2, 7.8 ± 1.5 and 6.3 ± 0.1 μg mL−1 to 0.5 ± 0.1, 4.0 ± 0.6 and 3.1 ± 0.4 μg mL−1 in the low-dose group (P &lt; 0.05) over the infusion period. We also studied the pharmacokinetic and metabolic profile of an intravenous bolus dose of 2.5 mg kg−1 cocaine hydrochloride after a similar cocaine infusion in rats. Cocaine pharmacokinetics and the profile of ecgonine methylester, benzoylecgonine and norcocaine were no different from rats chronically infused with saline for the same period. Altered cocaine metabolism could not explain the effect of the duration of cocaine infusion on altered metabolite concentrations in urine. Ecgonine methylester/benzoylecgonine urine concentration ratios did not alter with duration of infusion (1.2 ± 0.2 and 1.1 ± 0.2 in the high-dose group at the first and last time point) and were not affected by the dose of cocaine (1.3 ± 0.6 and 1.2 ± 0.1 at corresponding times in the low-dose group (P &gt; 0.05)).
We conclude that chronic cocaine infusion does not alter cocaine metabolism. This was not reflected by absolute cocaine metabolite urine concentrations, which varied with time, but was represented by urine ecgonine methyl ester/benzoylecgonine concentration ratios.