bluuebunny/crossref_metadata_2025 huggingface dataset:
In-vitro In-vivo Correlation Models for Glibenclamide after Administration of Metformin/Glibenclamide Tablets to Healthy Human Volunteers
Authors: Balan Guhan , Timmins Peter , Greene Douglas S , Marathe Punit H
Published: July 2003

In this study, level C and A in-vitro in-vivo correlation (IVIVC) models were developed for glibenclamide. In-vitro dissolution data were collected for the glibenclamide component of three metformin/glibenclamide tablets using a USP Type II apparatus. In-vivo plasma concentration data were obtained after administration of the prototype formulations to 24 healthy volunteers and subject to deconvolution analysis to obtain percentage in-vivo absorbed profiles. Multiple linear level C models were developed for CMAX and AUC(0–48) using percentage in-vitro dissolved data at 10, 45 and 120 min. Initially, the level A model was constructed for the first 2 h only, based on availability of in-vitro data. Another level A model was attempted using a time-scaled approach, with percentage in-vivo absorbed at time t and percentage in-vitro dissolved at time t/I as the correlating data. Internal predictability was evaluated for the level C and time-scaled level A models.

For all level C approaches, linear regression models with r2 > 0.99 were determined. The prediction errors (% PE) for Cmax and AUC(0–48) were less than 1% for all formulations at all three chosen time points. The deconvolution analysis indicated biphasic absorption for glibenclamide, with one phase occurring at 2–3 h and another at 6–12 h after dose administration. The level A model using 2-h data was not unique for all formulations and was therefore not developed. The time-scaling factor I correlated highly (r2 = 0.99) with in-vitro mean dissolution time (MDT). A linear regression time scaled model (r2 = 0.97) was successfully developed using in-vitro and in-vivo data from all 3 formulations. However, the internal predictability of the time-scaled model was poor, with % PE values for Cmax and AUC(0–48) being as much as 30.5% and 18.7%, respectively.

The results indicate that level C models have good internal predictability. Though a time-scaled level A IVIVC model was successfully developed, the model was found to have poor internal predictability.
Tiospirone and the Reinforcing Effects of Cocaine in the Conditioned Place Preference Paradigm in Rats
Authors: Arolfo Maria Pia , McMillen Brian A
Published: July 2003

Tiospirone (TSP) is an atypical antipsychotic drug. It has 5HT-2 antagonistic properties as well as affinity for D2, 5HT-1a, 5HT-6 and sigma receptors.

Behavioural studies in our laboratory, which used a 24 h free access to food and fluids paradigm, showed a decreased alcohol and increased food intake after twice-daily administration of TSP; the maximal effect was obtained at a dose of 0.48 mg kg−1. This study used the conditioned place preference paradigm to determine the effect of TSP on the reinforcing properties of cocaine. Intraperitoneal administration of 5.0 mg kg−1 cocaine, but not saline, increased the time rats spent in the drug-paired compartment of a three-compartment shuttle box by 104.9%. Two doses of TSP, 0.143 and 0.48 mg kg−1, were tested subcutaneously 60 min before saline or cocaine administration during the conditioning phase only. A dose-response effect was observed with a significant reduction in the time rats spent in the cocaine-paired compartment on the drug-free test day produced by the dose of 0.48 mg kg−1 (an increase of only 38.1% when post-conditioned times were compared with preconditioned times).

These findings suggest that TSP reduces the reinforcing properties of cocaine exhibited in the conditioned place preference paradigm.
The Effects of Potassium Channel Blockers on Progesterone-Induced Suppression of Rat Portal Vein Contractility
Authors: Mukerji Mark S , Leathard Helen L , Huddart Henry
Published: July 2003

The suppression of contractility of rat portal vein caused by progesterone appears to be due to the potassium (K+) channel opening effect of this hormone. The identity of the specific K+ channels involved has been investigated using a variety of K+ channel blockers.

Incubation with 100 nM iberiotoxin antagonised the progesterone-induced inhibition of spontaneous and 20 mM K+-induced phasic activity of the portal vein such that the contractions resembled those of the non-progesterone, non-iberiotoxin control tissues treated with the corresponding solvent vehicles. Incubation with barium chloride (20 and 100 μm), 4-aminopyridine (1 mM), tetraethylammonium chloride (1 mM), glibenclamide (1 μm) or apamin (1 mM) did not, however, have the same antagonistic effect.

These results suggest that progesterone's selective suppression of rat portal vein contractility is mediated by the opening of BKCa channels.
Effect of Aegle marmelos on Biotransformation Enzyme Systems and Protection Against Free-radical-mediated Damage in Mice
Authors: Singh R P , Banerjee S , Rao A Ramesha
Published: July 2003

The effect of hydroalcoholic (80% ethanol, 20% water) extract of leaves of Aegle marmelos was examined on carcinogen-metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation, using two doses of dried extract (50 and 100 mg kg−1 daily for 14 days), in the liver of mice. The modulatory effect of the extract was also examined on extrahepatic organs (lung, kidney and fore-stomach) for effects on the activity of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase.

Extract treatment significantly increased the basal levels of acid-soluble sulphydryl (–SH) content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase, DT-diaphorase, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in the liver. Aegle acted as a bifunctional inducer since it induced both phase-I and phase-II enzyme systems. Both doses significantly decreased the activity of lactate dehydrogenase and formation of malondialdehyde in liver, suggesting a role in cytoprotection as well as protection against pro-oxidant-induced membrane damage. Butylated hydroxyanisole (positive control) induced almost all the antioxidative parameters measured in this study. The extract was effective in inducing glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase in lung, glutathione S-transferase, DT-diaphorase and superoxide dismutase in fore-stomach, and DT-diaphorase and superoxide dismutase in lung.

These significant changes in the levels of drug-metabolizing enzymes and antioxidative profiles are strongly indicative of the chemopreventive potential of this plant, especially against chemical carcinogenesis.
The Effect of Acute Ethanol Exposure on the Chronotropic and Inotropic Function of the Rat Right Atrium
Authors: Campbell Patrick H , Barker Louis A , McDonough Kathleen H
Published: July 2003

Consumption of ethanol (CH2CH3OH), both acutely and chronically, is known to affect cardiac function and may alter the autonomic control of the heart. This study investigated the effects of two modes of acute exposure to ethanol on the chronotropy and inotropy of the rat right atrium with emphasis on alterations in the adrenergic responses.

Atria from rats infused with an anesthetizing level of ethanol for 21 h showed a tendency for a greater increase of the unstimulated beating rate with isoproterenol (ISO), while both unstimulated inotropy and the inotropic response to ISO were significantly decreased compared with the control. Right atria in the presence of ethanol in-vitro demonstrated decreased basal active tension development and decreased inotropic responses to ISO. No alteration of the chronotropic response to ISO was evident with any concentration of ethanol.

These results demonstrate both an immediate as well as a persistent effect of ethanol on right atrial chronotropy and inotropy. Alterations in the G-stimulatory subunit of the adenylate cyclase system and alterations in myofilament binding of Ca2+ are consistent with these observed ethanol effects.
Uptake and Dispersion of Metformin in the Isolated Perfused Rat Liver
Authors: Chou Chen-Hsi
Published: July 2003

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

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

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

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) > tropicamide (67.4%) > pirenzepine (42.8%) > 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

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

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

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

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

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

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

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

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

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

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

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

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

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 < 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

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

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< 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

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 < 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 < 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

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

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

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 < 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 < 0.01), in M cells (+366%, P < 0.001), in enterocytes adjacent to M cells (+70%, P < 0.05) and in lymph vessels (+59%, P < 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

Drug-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.