bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uptake and Dispersion of Metformin in the Isolated Perfused Rat Liver
Authors: Chou Chen-Hsi 
Published: July 2003

Abstract
Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in-situ rat liver preparation. The liver was perfused in single-pass mode with protein-free Krebs bicarbonate medium at a flow rate of 20mLmin−1.
During constant infusion with 1 mgL−1 metformin hydrochloride the hepatic uptake of metformin approached equilibrium within 10 min. The steady-state availability, F, determined from the ratio of outflow concentration to input concentration, was 0.99±0.02 (mean±s.d., n=4). The outflow profile of metformin resulting from a bolus injection of 25 μg into the portal vein, had a sharp peak then a slower declining terminal phase. The mean transit time (MTT; 49.5±14.5, n = 6) and normalized variance (CV2; 4.13±0.05) of the hepatic transit times of metformin were estimated by numerical integration from the statistical moments of the outflow data. The volume of distribution of metformin in the liver (1.58±0.28 mL (g liver)−1) was estimated from its MTT. The volume of distribution is greater than the water space of liver, indicating that metformin enters the hepatic aqueous space and becomes distributed among cellular components. The magnitude of CV2 for metformin is greater than for the vascular marker sucrose, suggesting that distribution of metformin into hepatic tissue is not instantaneous.
In conclusion, hepatic uptake of metformin is rate-limited by a permeability barrier. Although metformin is accumulated in the liver, the organ does not extract it.
Does Dihydrohonokiol, a Potent Anxiolytic Compound, Result in the Development of Benzodiazepine-like Side Effects?
Authors: Kuribara Hisashi , Kishi Eiko , Maruyama Yuji 
Published: July 2003

Abstract
The aims of this study were to assess whether dihydrohonokiol, 3′-(2-propenyl)-5-propyl-(1,1′-biphenyl)-2,4′-diol (DHH-B), a potent anxiolytic compound, developed benzodiazepine-like side effects.
A 1 mgkg−1 dose of diazepam, almost equivalent to the minimum dose for the anxiolytic effect, disrupted the traction performance, potentiated hexobarbital-induced sleeping and impaired learning and memory performance. DHH-B, even at a dose of 1 mg kg−1 (i.e. five times higher than the minimum dose for significant anxiolytic effect) neither developed diazepam-like side effects nor enhanced the side effects of diazepam. Rather, the potentiation by diazepam of hexobarbital-induced sleeping was reduced by 1 mg kg−1 DHH-B. Furthermore, mice treated with 10 daily administrations of 1 and 5 mg kg−1 diazepam, but not 0.2–5 mg kg−1 DHH-B, showed precipitated withdrawal symptoms characterized by hyper-reactivity, tremor and tail-flick reaction when they were challenged with flumazenil (10 mg kg−1 i.p.).
These results suggest that, unlike the benzodiazepine anxiolytic diazepam, DHH-B is less likely to induce motor dysfunction, central depression, amnesia or physical dependence at the effective dose required for the anxiolytic effect.
Interaction of Drugs and Chinese Herbs: Pharmacokinetic Changes of Tolbutamide and Diazepam Caused by Extract of Angelica dahurica
Authors: Ishihara Kazuhisa , Kushida Hirotaka , Yuzurihara Mitsutoshi , Wakui Yoko , Yanagisawa Toshihiko , Kamei Hideo , Ohmori Shigeru , Kitada Mitsukazu 
Published: July 2003

Abstract
The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied.
The 2α- and 16α-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28.5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg−1 dose. 6β-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1.
The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg−1 dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg−1. Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg−1), but not low dose (0.3 g kg−1), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg−1.
It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs.
Radish Extract Stimulates Motility of the Intestine via the Muscarinic Receptors
Authors: Jung Kyu Yong , Choo Young Kug , Kim Hyung Min , Choi Bong Kyu 
Published: July 2003

Abstract
The effects of radish (Brassica oleraceae, Cruciferae) on gastrointestinal motility were examined using rat intestinal segments with myenteric plexus in-vitro and measuring the intestinal transit of charcoal in-vivo. Radish extract (10 μg mL−1 to 2 mg mL−1) caused a dose-dependent increase in contractions of the duodenum, jejunum and ileum, and 1 mg mL−1 was the maximum effective dose. The largest contraction by the extract was found in ileal segments. The extract-induced (0.5 mg ML−1) ileal contraction was remarkably inhibited by pretreatment of segments with atropine (10−7 M) for 10 min, but not by hexamethonium (0.5 mM). Moreover, antagonists of the muscarinic receptor reduced the radish-induced ileal contraction by a different ratio. The rank order of inhibitory effects was 4-diphenylacetoxy-N-methyl-(2-chloroethyl)-piperidine methiodide (90.5% of control) &gt; tropicamide (67.4%) &gt; pirenzepine (42.8%) &gt; methoctramine (16.7%). Oral administration of radish extract (300–500 mg kg−1 body weight) to mice remarkably improved the intestinal transit of charcoal, and this was significantly attenuated by co-administration of atropine (50 mg kg−1). Taken together, these results suggest that radish extract stimulates gastrointestinal motility through activation of muscarinic pathways.
Induction of Apoptosis in Human Leukaemic Cell Lines K562, HL60 and U937 by Diethylhexylphthalate Isolated from Aloe vera Linne
Authors: Lee Keyong Ho , Hong Hee Sun , Lee Chi Ho , Kim Chang Han 
Published: July 2003

Abstract
We investigated the effect of diethylhexylphthalate (DEHP) from Aloe vera Linne on the apoptosis of human leukaemic cell lines K562, HL60 and U937 to examine its pharmacological activity.
At a level of 10 μ mL−1 DEHP a significant anti-leukaemic effect was observed for all three cell lines, as measured by clonogenic assay. After treatment with 10 μg mL−1 DEHP for 4 h, agarose gel electrophoresis and flow cytometric analysis confirmed the occurrence of apoptosis.
These results indicate that DEHP isolated from Aloe vera Linne has a potent anti-leukaemic effect, and thus represents a new type of pharmacological activity with respect to human leukaemic cells.
Chronopharmaceutical Drug Delivery from a Pulsatile Capsule Device based on Programmable Erosion
Authors: Ross Alistair C , Macrae Ross J , Walther Mathias , Stevens Howard N E 
Published: July 2003

Abstract
We report the development of a chronopharmaceutical capsule drug delivery system capable of releasing drug after pre-determined time delays.
The drug formulation is sealed inside the insoluble capsule body by an erodible tablet (ET). The release time is determined by ET erosion rate and increases as the content of an insoluble excipient (dibasic calcium phosphate) and of gel-forming excipient (hydroxypropylmethylcellulose; HPMC) increases. The time-delayed release of a model drug (propranolol HCl) was investigated by dissolution testing (USP XXIII paddle method). Both composition and weight of ET influence the time of drug release. Moreover it was found that drug release was controlled by the quantity of HPMC, irrespective of lactose content within the tablet weight range 80–160 mg, when above a threshold concentration of 20% HPMC.
Programmable pulsatile release has been achieved from a capsule device over a 2–12-h period, consistent with the demands of chronotherapeutic drug delivery. The time of drug release can be controlled by manipulation of tablet formulation.
Improvement of Subcutaneous Bioavailability of Insulin by Sulphobutyl Ether β-Cyclodextrin in Rats
Authors: Tokihiro Keiichi , Arima Hidetoshi , Tajiri Shinichirou , Irie Tetsumi , Hirayama Fumitoshi , Uekama Kaneto 
Published: July 2003

Abstract
The objective of this study was to examine and compare how hydrophilic β-cyclodextrin derivatives (β-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats.
When insulin solutions in the absence of β-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-β-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-β-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-β-cyclodextrin with a degree of substitution of the sulphobutyl group of 3–9 (SBE4-β-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8h. The bioavailability of the insulin/SBE4-β-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-β-CyD may be in part due to the inhibitory effects of SBE4-β-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability.
These results suggest that SBE4-β-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.
Ion-pair Formation as a Strategy to Enhance Topical Delivery of Salicylic Acid
Authors: Megwa Stella A , Cross Sheree E , Benson Heather A E , Roberts Michael S 
Published: July 2003

Abstract
An in-vitro study was carried out to determine the possibility of improving the efficiency of transdermal delivery of salicylate through human epidermis by ion-pair formers (alkylamines and quaternary ammonium ions). Further, the relationship between the physico-chemical properties of the counter-ions and salicylate flux was examined.
It was found that flux can be related to the conductivity associated with the penetrant solution, molecular size of the counter-ion and lipophilicity expressed as either octanol/water partition coefficient of the ion pairs or the carbon chain-length of the counter-ions.
Equations have been developed to predict salicylate flux from these physicochemical parameters.
Effect of Ion Pairing with Alkylamines on the In-vitro Dermal Penetration and Local Tissue Disposition of Salicylates
Authors: Megwa Stella A , Cross Sheree E , Whitehouse Michael W , Benson Heather A E , Roberts Michael S 
Published: July 2003

Abstract
Hydrophilic ionic drugs can be rendered lipophilic by ion-pair formation with hydrophobic counter-ions. This study examines the value of forming ion pairs between anionic salicylate and a series of amines as model cationic counter-ions to facilitate topical delivery and skin penetration. The in-vitro translocation of salicylate ions from a non-aqueous vehicle through human epidermis was estimated in the presence or absence of amines. The distribution into, and accumulation of the salicylate ion in various tissues following topical application to anaesthetised rats were also investigated.
Although the epidermal permeation constants of the salicylate-amine ion pairs were lower than that of salicylate itself (enhancement ratios: 0–74–0.87), salicylate retention and localisation in the underlying rat tissues increased in the presence of some of the counter-ions studied. Salicylate concentrations (μg (g tissue)−1) in the dermis were 877.2 ± 78.6 for salicylate alone and 1098 ± 121.9–2586 ± 332.5 for salicylate-amine ion pairs. The levels of salicylate in tissues up to the top muscle layer were 1.2–3.7-fold higher in the presence of the counter-ions.
It is concluded that, although amine counter-ions have the ability to influence the penetration of salicylate, in-vitro permeability studies do not reflect the in-vivo increases in tissue concentrations resulting from probable changes in systemic clearance.
An Investigation Into the Low Temperature Thermal Behaviour of Vitamin E Preparation USP Using Differential Scanning Calorimetry and Low Frequency Dielectric Analysis
Authors: Barker Susan A , Yuen Kah Hay , Craig Duncan Q M 
Published: July 2003

Abstract
The thermal and dielectric responses of Vitamin E Preparation USP have been examined to further understand the melting and solidification of this material. A TA Instruments 2920 Differential Scanning Calorimeter was used to examine the thermal response of the sample at a range of scanning speeds. Isothermal dielectric studies were performed using a Novocontrol Dielectric Spectrometer over a range of temperatures down to − 70°C and a frequency range of 106−10−2 Hz.
The differential scanning calorimetry (DSC) studies showed an anomalous response whereby at slow heating rates (2°C min−1) a small exotherm followed immediately by an endotherm was observed. This response was considerably diminished in magnitude at higher rates (5°C min−1) and was not observed at the fastest heating rate of 10°C min−1. No thermal events were seen on cooling the sample to −60°C. It was suggested that the material formed a glass on cooling, with a predicted transition temperature of approximately −100°C. Further studies using a liquid nitrogen cooling system indicated that the system did indeed exhibit a glass transition, albeit at a higher temperature than predicted (ca −63°C). Low frequency dielectric analysis showed a clear relaxation peak in the loss component, from which the relaxation time could be calculated using the Havriliak-Negami model. The relationship between the relaxation time and the temperature was studied and was found to follow the Vogel-Tammann-Fulcher (VTF) modification of the Arrhenius equation.
It is therefore concluded that Vitamin E Preparation USP is a glass-forming material that exhibits kinetically-hindered recrystallisation and melting behaviour. The study has also indicated that DSC and low frequency dielectric analysis may be powerful complementary tools in the study of the low temperature behaviour of pharmaceuticals.
Solid Dispersion of Hydroxypropyl β-Cyclodextrin and Ketorolac: Enhancement of In-vitro Dissolution Rates, Improvement in Anti-inflammatory Activity and Reduction in Ulcerogenicity in Rats
Authors: Nagarsenker Mangal S , Meshram Rupali N , Ramprakash G 
Published: July 2003

Abstract
Ketorolac, is a non-steroidal anti-inflammatory drug, with strong analgesic activity. It is practically insoluble in water and has been implicated in causing gastrointestinal ulceration. This study describes the formulation of solid dispersions of ketorolac using hydroxypropyl β-cyclodextrin (HPβ-CyD) and β-cyclodextin (β-CyD) as carriers, to improve the aqueous solubility of the drug, thus enhancing its bioavailability. Also, reduction in ulcerogenicity was anticipated.
Differential scanning calorimetry and X-ray diffraction studies indicated loss of crystalline nature of the drug, in the dispersions prepared with HPβ-CyD. NMR studies revealed a strong interaction between drug and HPβ-CyD. Solid dispersions of drug with β-CyD retained the crystalline nature of the drug. All the solid dispersions showed a remarkable improvement in the rate and extent of dissolution of ketorolac. The kneaded dispersion with HPβ-CyD prepared using a 1: 1 alcohol—water mixture showed promise in reducing the ulcer-inducing effect of ketorolac in rats. Oral administration of this dispersion was found to inhibit carrageenan-induced paw oedema in rats to a significantly greater extent compared with ketorolac or its trometamol salt. Though β-CyD as a carrier for ketorolac gave faster release of the poorly soluble drug, HPβ-CyD proved to be superior to β-CyD, as a carrier in the kneaded dispersion prepared using 1: 1 alcohol—water mixture.
These results suggest that solid dispersions of ketorolac with HPβ-CyD aid in faster dissolution and better bioavailability of the drug. The higher solubility of the drug in the presence of HPβ-CyD also reduces local gastrointestinal side-effects of the drug.
Simultaneous Determination of Unbound Cefoperazone in Rat Blood and Brain Using Microdialysis
Authors: Chang Y L , Chou M H , Lin M F , Chen Y F , Chen C F , Cheng F C , Tsai T H 
Published: July 2003

Abstract
A sensitive microbore HPLC method was developed for the simultaneous determination of unbound cefoperazone in rat blood and brain using microdialysis.
Two microdialysis probes were inserted into the jugular vein/right atrium and brain striatum of Sprague—Dawley rats. Cefoperazone (50 mg kg−1, i.v.) was then administered via the femoral vein. Blood and brain dialysates were collected and eluted with a mobile phase containing methanol-100 mM monosodium phosphoric acid (30:70, v/v, pH 5.5). The wavelength of the UV detector was set at 254 nm. The detection limit of cefoperazone was 20 ng mL−1. Isocratic separation of cefoperazone was achieved within 10 min. The intra- and inter-assay accuracy and precision of the analyses were ≤ 10% in the range of 0.05–10 μg mL−1.
The ratio of the area under the concentration curve of cefoperazone in rat brain and blood was estimated to be about 7.8%. It is concluded that cefoperazone is capable of penetrating the blood—brain barrier.
Ventricular Function and Cardiac Hypertrophy after Coronary Thrombolysis with Tissue-type Plasminogen Activator (t-PA) in Dogs with Coronary Artery Thrombi
Authors: Suzuki Masanori , Asano Hironobu , Kimoto Aishi , Tanaka Hideyuki , Usuda Shinji 
Published: July 2003

Abstract
Subacute prognosis of cardiac function after thrombolysis with a modified tissue-type plasminogen activator (t-PA) YM866 was determined in dogs with coronary artery thromboses induced by injection of a thrombin, fibrinogen and autogenous blood mixture.
The left ventricular ejection fraction (LVEF) decreased 30 min after occlusion and had not improved 1 week later. Examination after sacrifice revealed myocardial infarction as well as increases in both the left ventricular myocardial area and heart mass. Occluded coronary arteries reperfused by YM866 (0.1 mg kg−1 i.v.) treatment 30 min after occlusion, by contrast, had improved LVEF and inhibited myocardial infarction development. In addition, the left ventricular myocardial area and heart mass were significantly reduced compared with the vehicle control group 1 week after administration. Although occluded coronary arteries reperfused by YM866 (0.1 mg kg−1 i.v.) treatment 3 h after occlusion did not show an improvement in the LVEF or inhibition of myocardial infarction development, the left ventricular myocardial area and heart mass decreased significantly compared with the vehicle control group 1 week after administration.
In conclusion, early reperfusion by t-PA treatment 30 min after occlusion improved the ventricular function and cardiac hypertrophy, whereas late reperfusion by t-PA treatment 3 h after occlusion did not improve the ventricular function but did inhibit hypertrophy in dogs with coronary artery thrombi.
In-vitro Hydrolysis, Permeability, and Ocular Uptake of Prodrugs of N-[4-(Benzoylamino)phenylsulfonyl]glycine, a Novel Aldose Reductase Inhibitor
Authors: Sunkara Gangadhar , DeRuiter Jack , Clark C Randall , Kompella Uday B 
Published: July 2003

Abstract
To enhance the ocular uptake of N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), two ester (methyl and isopropyl) prodrugs were synthesized and evaluated for their stability in various buffers (pH 1–9), hydrolysis in rabbit ocular tissues (cornea, conjunctiva, iris-ciliary body, lens, aqueous humor, and vitreous humor), transport across cornea and conjunctiva, and in-vivo uptake following topical administration.
Lipophilic ester prodrugs of BAPSG showed good aqueous solution stability in tissue homogenates. However, these prodrugs lacking the free carboxylate anion exhibited reduced in-vitro permeability and in-vivo uptake, suggesting the importance of free carboxylate anion in the delivery of BAPSG.
Over the pH range of 1–9, the rate constants for degradation ranged from 5.67 to 218.9 times 10−3 h−1 for the methyl ester and from 3.14 to 4.45 times 10−3 h−1 for the isopropyl ester. At all pH conditions, the isopropyl ester was more stable when compared with the methyl ester. A change in buffer concentration at pH 7.4 did not influence the stability of the prodrugs. The prodrugs were rapidly hydrolysed in the tissue homogenates, with the rate constants for hydrolysis ranging from 1.98 to 7.2 times 10−3 min−1 for the methyl ester and 3.32 to 6.53 times 10−3 min−1 for the isopropyl ester. The in-vitro permeability of the methyl ester was less than the parent drug across cornea and conjunctiva. Isopropyl ester levels were not detectable in the receiver chamber even at the end of the 4-h transport study. Following topical administration of BAPSG and the two prodrugs at a dose of 60 μg/eye, the lowest levels were seen in vitreous humor for parent compound and its methyl ester. In general, the tissue uptake of methyl ester was less than BAPSG. Isopropyl ester levels were below detection limits in all the ocular tissues.
Structure–Activity Relationships for the Inhibition of Lipid Peroxidation and the Scavenging of Free Radicals by Synthetic Symmetrical Curcumin Analogues
Authors: Venkatesan P , Rao M N A 
Published: July 2003

Abstract
A number of ring substituted analogues of curcumin were synthesized. Their antioxidant properties were studied using three models, inhibition of lipid peroxidation, scavenging of 1,1′-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azinobis(3-ethyl-benzthiazoline-6-sulphonate radical (ABTS+).
In all the models, the phenolic analogues were more active than the non-phenolic analogues, some of which were inactive. The highest antioxidant activity was obtained when the phenolic group was sterically hindered by the introduction of two methyl groups at the ortho position. This and several other compounds were more active than the standard antioxidants α-tocopherol and trolox.
This study has demonstrated that the phenolic group is important for the antioxidant activity of curcumin and that the structural features that enhance the antioxidant properties of phenols are optimized in curcumin to a significant extent.