bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetic Evidence for Facilitated Peritoneal Transport of Benzoic acid in Rats
Authors: Nakashima Emi , Matsushita Ryo , Kanada Naomi , Ichimura Fujio
Published: April 2011

To evaluate the dose dependency in apparent peritoneal permeability (Pd) of benzoic acid as a model compound for a monocarboxylic acid transport system, a kinetic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied.

We compared the Pd value of benzoic acid to that of phenobarbital which is a more lipophilic drug than benzoic acid. The concentration-time courses of phenobarbital in both peritoneal cavity and serum after the intraperitoneal administration with various doses were parallel according to dose, whereas those of benzoic acid varied in a dose-dependent manner. Using the values of unbound fraction (fu), the value of Pd for unbound drugs was estimated. The Pd values of benzoic acid at 20 μg mL−1 was three times the value determined at 1000 μg mL−1.

We suggest that certain facilitated transport systems constitute the mechanism of enhanced peritoneal membrane permeability of benzoic acid.
Permeation Characteristics of 8-Methoxypsoralen Through Human Skin; Relevance to Clinical Treatment
Authors: Anigbogu A N C , Williams A C , Barry B W
Published: April 2011

The permeation characteristics through human skin of 8-methoxypsoralen (8-MOP) and its physical attributes were investigated.

The log octanol/water partition coefficient and saturated aqueous solubility of 8-MOP at 32°C were 1.98 and 55.8 μg mL−1 respectively. 8-MOP showed Fickian diffusion, with its flux being linearly related to the concentration of drug in the donor solution. The permeability coefficient of 8-MOP through human skin from different concentrations of aqueous solutions and a 2.6 μg mL−1 bath lotion (as used in clinics) were statistically identical with mean values of 1.76 ± 0.12 × 10−2 and 1.70 ± 0.32 × 10−1 cm h−1 respectively (P ≥ 005). An ethanol/water (1:1 w/v) receptor solution did not improve the clearance of 8-MOP from the dermis when compared with an aqueous vehicle. Complete removal of the stratum corneum by tape stripping from full-thickness membranes produced a threefold increase in the flux of 8-MOP thus suggesting that the main barrier to 8-MOP permeation resides in the stratum corneum although the aqueous epidermal and dermal tissue provide a significant resistance to transdermal drug permeation. The equilibrium uptake of 8-MOP into psoriatic plaques and the 8-MOP aqueous/plaque partition coefficient were found to be more than twofold greater than for normal stratum corneum. The absorption of 8-MOP from the total applied topical dose (396 mg) was assessed as ∼0.25% and only 2.5% of an oral dose, a significant reduction in the possible toxic hazard. The peak concentration of 8-MOP permeating through the skin was observed at about 35 min after limited exposure for 15 min.

Our results suggest that following a 15 min bath in the drug solution, there may be a need for an interval of about 20 min before patients are irradiated to ensure the optimization of photosensitizer with UVA irradiation (PUVA) therapy. Alternatively, UV irradiation could be applied at a lower flux over a longer time.
Carboxymethylcellulose-sodium Based Transdermal Drug Delivery System for Propranolol
Authors: Krishna Rajesh , Pandit J K
Published: April 2011

Propranolol, a β-adrenoceptor blocker, suffers from a high degree of first-pass metabolism resulting in very low bioavailability (<10%) following administration with conventional oral formulations. To circumvent this significant therapeutic hurdle, we formulated a carboxymethylcellulose-sodium (CMC-Na) based transdermal system for propranolol and evaluated the patch for its in-vitro and in-vivo performance.

In-vitro permeation studies using the excised hair-free rat skin model resulted in 66.54% permeation at the end of 24 h in a modified Franz diffusion cell. This zero-order permeation profile was characterized by a drug permeation rate of 52.87 ± 11.63 μg cm−2 h−1. Skin irritation studies in rats (n = 5), evaluated for flare-and-wheal with respect to a formalin control, indicated that the drug-containing patch evoked only a mild response over a 7-day period. Preliminary in-vivo studies in male albino rabbits (n = 3), indicated that plasma drug levels averaged 11.75 ± 3.40 ng mL−1 in a 24-h study period before patch removal.
Improving the Oral Bioavailability of Sulpiride by a Gastric-retained Form in Rabbits
Authors: Kohri Naonori , Naasani Imad , Iseki Ken , Miyazaki Katsumi
Published: April 2011

To improve the limited oral bioavailability of sulpiride, a gastric-retained form was developed and evaluated using gastric-emptying-controlled rabbits.

The AUC value after oral administration of sulpiride as an aqueous solution was less than that after oral administration of sulpiride original powder. The dissolution was not important as a rate limiting factor for sulpiride oral absorption. Sulpiride was absorbed predominantly from the upper part of the small intestine of the rabbit.

A gastric-retained tablet prepared from Carbopol 934P, with sustained-release characteristics, was found to be suitable for improving and extending the oral bioavailability of sulpiride.
Urinary Excretion Profile of Torasemide and its Diuretic Action in Dogs
Authors: Sogame Yoshihisa , Okano Kanemichi , Hayashi Kazutaka , Uchida Takeshi , Tsuda Yoshio
Published: April 2011

The plasma concentration profile, urinary excretion rate and diuretic response were studied in anaesthetized dogs after an intravenous administration of torasemide or furosemide.

The urinary excretion rate of furosemide decreased rapidly after administration. The plasma concentration, which is related to the urinary excretion profile, also decreased rapidly. The diuretic response, which reflected the excretion rate, occurred rapidly after administration but lasted for a short time. The urinary excretion rate of torasemide was much lower than that of furosemide and decreased slowly after administration. The plasma concentration also decreased slowly. The diuretic response to torasemide occurred more slowly but lasted longer than the response to furosemide.

These results suggest that the diuretic response profile of either diuretic depends on their urinary excretion rate, and that the difference in the diuretic response between torasemide and furosemide may be explained by the different transfer rate of the drugs from the plasma to the nephron.
The Effects of Cyclophosphamide on the Pharmacokinetics of Triiodothyronine in the Male Rat
Authors: Angley Manya T , Sansom Lloyd N , Smeaton Timothy C , Stupans Ieva
Published: April 2011

In the present study, the possibility that cyclophosphamide or a cyclophosphamide metabolite may be accelerating the clearance of triiodothyronine has been examined.

Following administration of exogenous triiodothyronine to saline-and cyclophosphamide-treated rats, the area under the plasma-concentration time curve (AUC), apparent clearance (CLapp) and half-life of triiodothyronine were measured. AUC (34.43 ± 12.34 compared with 33.32 ± 9.92 nmol hL−1), CLapp (36.30 ± 12.89 compared with 37.51 ± 11.16 mLh−1) and half-life (7.50 ± 1.39 compared with 6.40 ± 0.96 h) were not significantly different in the control rats compared with the cyclophosphamide-treated rats.

As cyclophosphamide does not appear to alter the elimination of triiodothyronine, it is likely that cyclophosphamide or a cyclophosphamide metabolite is acting at the hypothalamo-pituitary axis, reducing the synthesis or release of thyroid stimulating hormone and consequently decreasing the levels of triiodothyronine and thyroxine.
Prediction of In-vivo Blood Level with Controlled-release Dosage Forms. Effect of the Gastrointestinal Tract Time
Authors: Ouriemchi E M , Vergnaud J M
Published: April 2011

The process of in-vivo drug transfer is very complex in the case of oral dosage forms with controlled release. A numerical model taking all the known facts into account, including the release of the drug controlled by diffusion through the dosage form along the gastrointestinal tract, the kinetics of absorption in the blood compartment and the kinetics of elimination was constructed.

Various parameters intervene in an important manner for a given drug: the size of the dosage form which is associated with the rate of release of the drug, and the dose frequency in multidosing.

Some emphasis is placed upon the gastrointestinal tract time which appears to be the main and first parameter to be considered in preparing a dosage form.
The In-vivo Cardiovascular Effects of a Putative Class III Anti-arrhythmic Drug, AM 92016
Authors: Hagerty M J , Wainwright C L , Kane K A
Published: April 2011

AM 92016(1-(4-methanesulphonamidophenoxy)-3-(N-methyl-3–4-dichlorophenethylamino)-2-propanol benzoic acid salt), an oxypropanolamine analogue of sotalol, has been shown to possess Class III antiarrhythmic properties in-vitro at concentrations showing 1000 times more potency than sotalol. The aim of this study was to characterize the effects of AM 92016 in-vivo.

When administered to anaesthetized guinea-pigs, AM 92016 (10 μg kg−1-5 mg kg−1) significantly increased heart rate, systolic arterial blood pressure, left ventricular systolic pressure and the contractile index dp/dtmax. AM 92016 also significantly decreased the QT interval of the electrocardiogram from 135 ± 10 to 105 ± 4 ms (5 mg kg−1). The time to onset of the first arrhythmia and ventricular fibrillation, induced by intravenous infusion of ouabain, was shortened in the presence of AM 92016. Ouabain-induced ventricular fibrillation occurred at 18 ± 5 and 12 ± 3 min (P < 005) in control and AM 92016-(1 mg kg−1) treated guinea-pigs, respectively. An infusion of AM 92016 (2.5 μg kg−1 min−1) to anaesthetized pigs significantly increased the total number of arrhythmias occurring following coronary artery occlusion from 266 ·26 in control pigs to 535 ± 148 (P < 005) in those receiving AM 92016. The time to onset of ventricular fibrillation was also significantly reduced in anaesthetized pigs from 24 ± 1 to 18 ± 3 min in the presence of AM 92016. The drug did not change haemodynamics in the anaesthetized pig.

We conclude that AM 92016 exhibited proarrhythmic rather than antiarrhythmic activity when administered in-vivo to either guinea-pigs or pigs.
Effects of Adenosine on NANC Bronchoconstriction in Anaesthetized Guinea-pigs
Authors: Nieri P , Martinotti E , Lazzeri N , Breschi M C
Published: April 2011

The present work assesses the effects of the acute administration of adenosine on tachykinergic bronchoconstriction induced in different ways (exogenously administered capsaicin or substance P and vagal electrical stimulation) in anaesthetized and curarized guinea-pigs.

Adenosine (30–3000 μg kg−1, i.v.) enhanced significantly and dose-relatedly the airway narrowing induced by a single dose of capsaicin (0.5-2 μg kg−1, i.v.), both in normal and in vagotomized animals. A smaller and less dose-dependent enhancement by the nucleoside of the pulmonary resistance increase induced by substance P (5–15 μg kg−1, i.v.) was observed. This effect was almost completely prevented by the H1 antagonist diphenhydramine (1 mg kg−1, i.v.), which also unmasked an inhibitory action of adenosine at the highest doses. Diphenhydramine, on the contrary, did not significantly modify the potentiation by adenosine of capsaicin-mediated bronchoconstriction. Finally, the nucleoside dose-dependently inhibited the atropine-resistant bronchospasm following vagal electrical stimulation.

The use of the selective adenosinic agonists R-N6-[2-phenylisopropyl]adenosine (1–100 μg kg−1, i.v.) and 5′-N-methylcarboxamidoadenosine (1–100 μg kg−1, i.v.) before the administration of capsaicin, revealed the ability of the first to reproduce the enhancement induced by adenosine, while the second had an inhibitory effect.

It is concluded that adenosine has both excitatory and inhibitory modulatory effects on airway responsiveness to excitatory non-adrenergic non-cholinergic (e-NANC) stimuli. The excitatory effects, revealed with substance P and capsaicin, support the hypothesis that adenosine may play a role as an asthma mediator.
Is Activation of Lysosomal Enzymes Responsible for Paracetamol-induced Hepatotoxicity and Nephrotoxicity?
Authors: Khandkar Milind A , Parmar Dipak V , Das Mita , Katyare Surendra S
Published: April 2011

Paracetamol overdose (300 mg kg−1) in mice resulted in a time-dependent increase in the liver weight; no change was seen for the kidney. The total acid phosphatase activities in the two tissues increased significantly 0.5 h after paracetamol overdose and remained elevated up to 3 h. Free as well as total cathepsin D activities increased significantly in both the tissues within 2-2.5 h of paracetamol treatment. Simultaneously tyrosine positive materials in the two tissues increased. RNAse II and DNAse II activities were low in liver and kidneys of the controls. Paracetamol treatment elevated both free and total RNAse II activity in the two tissues by 0.5 h. Maximum activity of DNAse II (free and total) was seen at 2.5 h after paracetamol administration.

The results suggest that concerted action of cathepsin D, RNAse II and DNAse II may be responsible for paracetamol-induced hepatotoxicity and nephrotoxicity.
A Qsar Study Of Anti-Inflammatory N-Arylanthranilic Acids
Authors: Duffy J C , Dearden J C , Rostron C
Published: April 2011

A detailed quantitative structure-activity relationship (QSAR) analysis of a series of 112 anti-inflammatory N-arylanthranilic acids has been performed to determine which physicochemical properties of these compounds are responsible for their anti-inflammatory activity. The results indicate that activity is modelled best by molecular shape parameters. The angle between the planes of the two benzene rings, dictated by the substitution pattern of the compounds, also appears relevant to activity. Dipole moments show some significance, but log P and other physicochemical parameters correlate poorly with activity. The best QSAR obtained was:

log(1/MED) = 1.601B1(2) + 0.576B1(3) − 1.187B3(4) + 0.522B1(6) − 1.681 μ(bond)(2) − 0.208 μ(bond)(5) − 0.265 μ (bond)(6) − 0.226

n = 112, r = 0.855, r2 (adj) = 0.716, F = 40.33, s = 0.511, r(CV)2 = 0.665

where B1 and B3 are Verloop substituent width parameters and μ(bond) is bond dipole (position in parentheses).
Synthesis and Antithrombotic Effect of Xanthone Derivatives
Authors: Lin Chun-Nan , Hsieh Hsin-Kaw , Liou Shiou-Jyh , Ko Horng-Huey , Lin Hsien-Cheng , Chung Mei-Ing , Ko Feng-Nien , Liu Hong-Wen , Teng Che-Ming
Published: April 2011

A series of xanthone derivatives was synthesized and tested in-vitro for their ability to inhibit aggregation of rabbit washed platelets and human platelet-rich plasma (PRP) induced by various inducers.

2-Prenyloxyxanthone showed the most potent inhibition of rabbit washed platelet aggregation induced by arachidonic acid (IC50 = 10.2 μM). Of the compounds tested in human PRP, 2-[3 (propylamino)-2-hydroxypropoxy]xanthone (4) hydrochloride salt exhibited the most potent inhibition of platelet aggregation induced by adrenaline (IC50 = 4.4 μM), whereas in evaluation of mouse antithrombotic activity, compound 4 exhibited the most potent protection of mice from thrombotic challenge. Compound 4, 2-[3-(isopropylamino)-2-hydroxypropoxylxanthone hydrochloride salt and 2,5 dihydroxyxanthone suppressed the secondary aggregation induced by adrenaline in human PRP.

We conclude that the antiplatelet effects of these compounds are mainly due to an inhibitory effect on thromboxane formation.
A Pig Collagen Peptide Fraction. A Unique Material for Maintaining Biological Activity During Lyophilization and During Storage in the Liquid State
Authors: Gaffney P J , Edgell T A , Dawson P J , Ford A W , Stocker K
Published: April 2011

There is frequent use of human and animal proteins as stabilizers during lyophilization of a variety of biological substances with a view to long term stable storage. This report describes the comparative excellent stabilizing effect of a porcine collagen peptide fraction (CPF) during the lyophilization and subsequent storage of three commonly used biological substances, alkaline phosphatase, tissue plasminogen activator and thrombin.

The CPF was heated to 150°C for one hour before use. The CPF was shown to have some advantage during lyophilized storage over human serum albumin. Solutions of thrombin stored in CPF at room temperature and at 37°C for one week retained nearly all activity, while storage of thrombin in human serum albumin solution at 37°C lost nearly all biological activity.

These preliminary data suggest that porcine CPF is a safe and advantageous stabilizer for addition to biological products with a view to long-term lyophilized storage and short-term liquid storage.
The Effect of pH on the In-vitro Dissolution of Three Second-generation Sulphonylurea Preparations: Mechanism of Antacid-sulphonylurea Interaction
Authors: Lehto Pasi , Laine Kari , Ivistö Kari T K , Neuvonen Pertti J
Published: April 2011

Simultaneously administered magnesium hydroxide or sodium bicarbonate can increase the rate and extent of absorption of non-micronized glibenclamide and glipizide. To clarify the mechanism of this interaction we have studied the effect of pH on the dissolution of two different formulations of glibenclamide (micronized and non-micronized) and one formulation of glipizide.

One tablet of each sulphonylurea preparation was placed in a dissolution chamber containing continuously mixed dissolution medium at pH 2, pH 6 or pH 9; 5 mL of the medium was replaced every 2 min. The amount of glibenclamide dissolved from the non-micronized formulation within 2 h, was 1.2, 4.5 and 76% at pH 2, pH 6 and pH 9, respectively (P < 001), whereas 21, 29 and 100% was dissolved from the micronized formulation (P < 001). The amount of glipizide dissolved within 2 h at pH 2, pH 6 and pH 9 was 3.9, 24 and 92%, respectively (P < 001).

We conclude that the elevated pH of the gastric contents is the most likely explanation for the interactions previously demonstrated between antacids and sulphonylureas after their concomitant ingestion.
Bioavailability Study of Glycyrrhetic Acid after Oral Administration of Glycyrrhizin in Rats; Relevance to the Intestinal Bacterial Hydrolysis
Authors: Takeda Shuichi , Ishihara Kazuhisa , Wakui Yoko , Amagaya Sakae , Maruno Masao , Akao Teruaki , Kobashi Kyoichi
Published: April 2011

To clarify the metabolic fate of glycyrrhizin when orally ingested, we investigated the bioavailability of glycyrrhetic acid, the aglycone of glycyrrhizin, after intravenous or oral administration of glycyrrhetic acid (5.7 mg kg−1, equimolar to glycyrrhizin) or glycyrrhizin (10 mg kg−1) at a therapeutic dose in rat.

Plasma concentration of glycyrrhetic acid rapidly decreased after its intravenous administration, with AUC of 9200 ± 1050 ng h mL−1 and MRT of 1.1 ±0.2 h. The AUC and MRT values after oral administration were 10600± 1090 ng h mL−1 and 9.3 ±0.6 h, respectively. After oral administration of glycyrrhizin, the parent compound was not detectable in plasma at any time, but glycyrrhetic acid was detected at a considerable concentration with AUC of 11700 ± 1580 ng h mL−1 and MRT of 19.9 ± 1.3 h, while glycyrrhetic acid was not detected in plasma of germ-free rats at 12 h after oral administration of glycyrrhizin. The AUC value of glycyrrhetic acid after oral administration of glycyrrhizin was comparable with those after intravenous and oral administration of glycyrrhetic acid, indicating a complete biotransformation of glycyrrhizin to glycyrrhetic acid by intestinal bacteria and a complete absorption of the resulting glycyrrhetic acid from intestine. Plasma glycyrrhizin rapidly decreased and disappeared in 2 h after intravenous administration. AUC and MRT values were 2410 ± 125 μg min mL−1 and 29.8 ± 0.5 min, respectively. Plasma concentration of glycyrrhetic acid showed two peaks, a small peak at 30 min and a large peak at 11.4 h, after intravenous administration of glycyrrhizin, with an AUC of 15400±2620 ng h L−1 and an MRT of 18.8 ± 1.0 h. The plasma concentration profile of the latter large peak was similar to that of glycyrrhetic acid after oral administration of glycyrrhizin, which slowly appeared and declined.

The difference of MRT values (19.9 and 9.3 h) for plasma glycyrrhetic acid after oral administration of glycyrrhizin and glycyrrhetic acid suggests the slow conversion of glycyrrhizin into glycyrrhetic acid in the intestine.
In-vivo Microdialysis Measurement of 5-Hydroxytryptamine and its Metabolites, 5-Hydroxyindoleacetic Acid and N-Acetyl 5-Hydroxytryptamine, in Rat Blood: Effects of Histamine-receptor Antagonists
Authors: Sakurai Eiichi , Monura Akio , Yamakami Jun , Hikichi Noboru
Published: April 2011

The blood concentrations of 5-hydroxytryptamine (5-HT) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and N-acetyl 5-HT were assayed by in-vivo microdialysis and a highly sensitive HPLC procedure that was originally developed to analyse CNS mediators. We investigated the effects of histamine-receptor antagonists on 5-HT metabolism and its release into the blood of rats.

The mean basal levels of 5-HT, 5-HIAA and N-acetyl 5-HT in the blood measured by in-vivo microdialysis were 77.2 ± 9.4, 20.3 ± 1.5 and 1.89 ± 0.15 pmol mL−1, respectively. These levels were not significantly affected by an intraperitoneal injection of saline, and remained at constant levels for at least 8 h after administration of saline. After an intraperitoneal injection of 5-HT hydrochloride (0.5 mg kg−1), 5-HT was soon detected in the blood of the jugular vein. 5-HIAA also quickly appeared in the blood and declined monoexponentially from 60 min after injection. In contrast, N-acetyl 5-HT slowly appeared in the blood and it reached a maximal level at 270 min. The 5-HT and N-aceryl 5-HT levels in dialysates from rat jugular vein were significantly increased by intraperitoneal pyrilamine (2.0 mg kg−1), (+)-chlorpheniramine (2.0 mg kg−1) and cimetidine (20.0 mg kg−1). However, there was no increase in the 5-HIAA concentration after an intraperitoneal injection of these histamine-receptor antagonists, demonstrating that the 5-HT released from various cells containing 5-HT was predominantly metabolized to N-acetyl 5-HT by N-acetyltransferase. Moreover, thioperamide did not affect the basal levels of 5-HT, 5-HIAA or N-acetyl 5-HT.

Because the recovered 5-HT, 5-HIAA and N-acetyl 5-HT in the dialysate is directly proportional to the free fraction in the blood, in-vivo microdialysis is a reliable method of examining 5-HT metabolism and its release into the blood.
Determination of Captopril in Human Blood by an Enzyme-linked Immunosorbent Assay
Authors: Jehanli Ahmed M T , Arafat Towfiq , Al-Shami Munzir
Published: April 2011

An immunoassay for the quantitation of the angiotensin-converting enzyme inhibitor, captopril in human plasma is described.

Antisera very specific for captopril were produced by immunization with captopril conjugated to bovine serum albumin or porcine thyroglobulin via the drug's thiol group. The antibodies were used to develop an enzyme-linked immunosorbent assay (ELISA) with a detection limit of 0.3 ng mL−1 and intra- and inter-assay coefficients of variation of 7 and 12%, respectively. Apart from stabilizing captopril by the addition of N-ethyl maleimide, the assay was used to detect the drug in human plasma without further extraction or purification.

Our immunoassay provides a very sensitive and rapid (four hours) alternative for the study of captopril pharmacokinetics.
Protective Effect of Butylated Hydroxyanisole on Adriamycin-induced Cardiotoxicity
Authors: Vora Jayesh , Khaw Ban-An , Narula Jagat , Boroujerdi Mehdi
Published: April 2011

Adriamycin has a wide spectrum of antitumour activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen free radicals. The objective of the present study was to investigate the influence of the antioxidant, butylated hydroxyanisole co-therapy on the cardiotoxicity of adriamycin, in-vivo.

The aqueous solubility of butylated hydroxyanisole was enhanced by inclusion complex formation with hydroxypropyl-β-cyclodextrin. The extent of drug-induced myocardial damage in rats was assessed using intravenous “in-labelled antimyosin Fab and chronological changes in serum creatine kinase levels. There was a dose-related increase in myocardial antimyosin uptake in rats, which reached a plateau at an adriamycin dose of 10 mg kg−1. The antimyosin uptake at this dose (% dose g−1 = 0.1942 ± 0.0150, n = 8) was significantly reduced by co-administration of butylated hydroxyanisole with adriamycin (10 mg kg−1 of each) to 0.1462 ± 0.0116 (n = 5, P < 0.05).

Assessment of cardiotoxicity in the rats was also performed by measuring serial changes in serum creatine kinase levels. Increasing doses of adriamycin caused an increase in serum creatine kinase levels with peak values obtained between 2 and 8 h after dosing. These values decreased upon co-administration of butylated hydroxyanisole with adriamycin at 10 mg kg−1, each and 30 mg kg−1, each by 29 and 41%, respectively. On the other hand, butylated hydroxyanisole did not inhibit the tumouricidal activity of adriamycin as investigated in-vitro using the NMU rat mammary adenocarcinoma cell-line.

The significant reduction in anthracycline cardiotoxicity by butylated hydroxyanisole coadministration may result from its scavenging action on adriamycin-mediated free-radical formation or its enhancement of activity of enzymes involved in the metabolism of adriamycin.
Involvement of Prostaglandins and 5-Hydroxytryptamine in the Contractile Effect of Platelet-activating Factor in Rat Isolated Gastric Corpus
Authors: Martínez-Cuesta M A , Barrachina M D , Moreno L , Calatayud S , Esplugues J
Published: April 2011

The present study characterizes the nature of the response to the platelet-activating factor (PAF) in isolated gastric corpus with and without mucosa.

PAF (10-8 M) induced contraction of rat isolated gastric corpus strips followed by desensitization of this tissue. Incubation of strips with the specific PAF-receptor antagonist WEB 2086 (5 × 10-8 − 5 × 10-5 M), the prostaglandin blocker indomethacin (10-6 M) and the 5-hydroxytryptamine antagonist methysergide (10-5 M) reduced significantly the contraction induced by PAF. Neither of the histamine H1/H2 antagonists diphenhydramine (10-6 M) or cimetidine (10-5 M) affected the contraction induced by PAF. In contrast with the whole gastric corpus, in mucosa-free strips, the contractile effect of PAF was not modified by methysergide.

The present study supports the view that the effect of PAF is mediated by activation of specific PAF receptors and the release of prostaglandins and 5-hydroxytryptamine in isolated gastric corpus. Furthermore, our results suggest a role of the gastric mucosa via the release of 5-hydroxytryptamine which contributes to the contractile effect of PAF in the gastric smooth muscle.
Membrane-bound Phosphodiesterases in Rat Myocardium
Authors: Kaasik Allen , Ohisalo Jorma J
Published: April 2011

Isoenzyme-specific phosphodiesterase (PDE) inhibitors are potential positive inotropic drugs. For evaluating such drugs in experimental models and to understand the physiological roles of the different isoenzymes, it is necessary to know what isoenzymes are present in the tissues studied. Rat myocardium has been reported to be devoid of the particulate cGMP-inhibited cAMP-PDE (type III isoenzyme). Here we re-evaluate the isoenzyme profile of rat myocardium.

The cAMP-PDE isoenzyme patterns were studied by ion-exchange chromatography using siguazodan and rolipram, specific inhibitors of type III and IV isoenzymes, respectively. In contrast to earlier reports, type III isoenzyme was abundant in the particulate fraction. PDE III-specific antibodies depressed PDE activity and stained bands in Western blot with molecular masses 64 and 71 kDa. Type III isoenzyme of myocardial membranes was found to be unstable at 37°C which may explain why earlier investigators have failed to demonstrate its presence.

The data presented in this paper show that rat heart particulate fraction contains two low Km PDE isoenzymes, type III and type IV, in equal activities. Thus, in contrast to previous reports, this paper clearly shows the presence of considerable amounts of membrane-bound type III PDE isoenzyme in rat myocardium.
Trifluoperazine is More Effective than Chlorpromazine in Releasing Oxygen from Haemoglobin and Myoglobin
Authors: Bhattacharyya Jaya , Bhattacharyya Maitree , Chakraborti Abhay Sankar , Chaudhuri Utpal , Poddar Ramendra Kumar
Published: April 2011

The extent of oxygen release from two heme proteins, haemoglobin and myoglobin have been studied in the presence of trifluoperazine and chlorpromazine (5–1000 μM).

At a molar ratio (drug: protein) of 1.5, the release of oxygen from haemoglobin was 4 and 15% in the presence of chlorpromazine and trifluoperazine respectively, while from myoglobin the corresponding values were 20 and 40%.

The findings were attributed to the greater extent of local conformational change around tryptophan moieties of each of the proteins induced by trifluoperazine.
Effect of Bakuchiol on Leukocyte Functions and Some Inflammatory Responses in Mice
Authors: Ferrándiz María Luisa , Gil Blanca , Sanz María Jesús , Ubeda Amalia , Erazo Silvia , González Ernesto , Negrete Rosa , Pacheco Sergio , Payáa Miguel , Alcaraz Maráa José
Published: April 2011

The effects of bakuchiol, a meroterpenoid isolated from the leaves of Psoralea glandulosa L., on phospholipase A2 (PLA2) activity from different sources, human neutrophil responses, zymosan air pouch and topical inflammation in mice, were investigated.

This natural product was a weak inhibitor of secretory and intracellular PLA2 but dose-dependently reduced the formation of LTB4 and TXB2 by human neutrophils and platelet microsomes, respectively. In addition, bakuchiol inhibited degranulation in human neutrophils, whereas superoxide generation was not affected. In mice, bakuchiol decreased cell migration, myeloperoxidase activity and eicosanoid levels in the air pouch inflammation induced by zymosan. After topical administration, this compound was effective as an inhibitor of oedema and myeloperoxidase activity in the 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear oedema and significantly reduced the PGE2 content and ear oedema in the arachidonic acid-induced response.

Bakuchiol is a natural anti-inflammatory agent able to control leukocytic functions such as eicosanoid production, migration and degranulation in the inflammatory site.
Transient Relaxation of Plasmid DNA in Escherichia coli by Fluoroquinolones
Authors: Matsuo Miki , Ohtsuka Yoshihisa , Kataoka Kazuhiro , Mizushima Tohru , Sekimizu Kazuhisa
Published: April 2011

We examined the influence of fluoroquinolones (norfloxacin, enoxacin, ofloxacin, levofloxacin, and sparfloxacin) on DNA supercoiling of plasmids in Escherichia coli cells by analysis with agarose gel electrophoresis in the presence of chloroquine.

All the fluoroquinolones tested immediately induced DNA relaxation. The relaxed DNA was re-supercoiled, and the process was sensitive to chloramphenicol, suggesting that newly synthesized proteins participate in the reaction. The concentrations of fluoroquinolones required for DNA relaxation were much higher than those required for cell killing.

The bactericidal effect of fluoroquinolones is apparently related to mechanisms other than DNA relaxation.
The Blood-brain Barrier: Principles for Targeting Peptides and Drugs to the Central Nervous System
Authors: Begley David J
Published: April 2011

The presence of the blood-brain barrier (BBB), reduces the brain uptake of many drugs, peptides and other solutes from blood. Strategies for increasing the uptake of drugs and peptide-based drugs include; structural modifications to increase plasma half-life; improving passive penetration of the BBB by increasing the lipophilicity of the molecule; designing drugs which react with transporters present in the BBB; and reducing turnover and efflux from the central nervous system (CNS).
Potential Protein Kinase C Inhibitors. 8,9,10,11α:-Tetrahydro-7αH-7,11-methano-12,12-dimethylcycloocta[de]naphthyl-9-amines
Authors: Wilson Martin P , Bowman Ralph E , Smith H John , Nicholls Paul J , Hewlins Michael J E
Published: April 2011

The synthesis of the 9α- and 9β-epimers of 8, 9, 10, 1 1α-tetrahydro-7αH-7, 11-methano-12, 12-dimethylcycloocta [de] naphthyl-9-amine is described.
Reaction between Ferriprotoporphyrin IX and the Antimalarial Endoperoxide Artesunate Gives an Intermediate Species with Enhanced Redox Catalytic Activity
Authors: Adams Paul A , Berman Peter A
Published: April 2011

The kinetics of the reaction between ferri(Fe(III) protoporphyrin IX (haemin) and the potent sesquiterpene endoperoxide antimalarial artesunate are shown to be consistent with a three-step, two-intermediate mechanism, with the final product possessing a degraded tetrapyrrole ring system. Microscopic rate constants for the mechanism have been evaluated. The redox catalytic capability of the haem artesunate complex is shown to be approximately fourfold that of haemin alone, suggesting a possible mechanism of action of the drug.
Receptor Binding Affinities and Biological Activities of Linear and Cyclic Melanocortins in B16 Murine Melanoma Cells Expressing the Native MC1 Receptor
Authors: Sahm Ulrike G , Olivier George W J , Branch Sarah K , Moss Stephen H , Pouton Colin W
Published: April 2011

Cyclic α-melanocyte-stimulating hormone (α-MSH) analogues produced by disulphide bridging (e.g. [Cys4,Cys10]α-MSH) are known to be almost equipotent to the native hormone in amphibian skin bioassays and as a consequence have been proposed as a paradigm for the active conformation of native MSH at the pigment cell MC1 receptor. However this proposal has been somewhat speculative as there is no published data comparing biological activity of cyclic MSH analogues with data on receptor binding. This study addresses this problem by comparing tyrosinase stimulatory activity with their receptor binding affinity in B16 murine melanoma cells expressing the native MC1 melanocortin receptor.

Cyclic [Cys4,Cys10] α-MSH showed almost the same affinity for the MC1 receptor as α-MSH, but the linear analogue [Cys4,Cys10]α-MSH bound less strongly. Both had biological activities similar to that of the natural ligand. Introduction of D-Phe into the ring in position 7 increased both affinity and activity of the cyclic compound.

The study suggests that the intrinsic efficacy of cyclic [Cys4,Cys10]α-MSH analogues is similar to native α-MSH. Our studies support the proposal that the cyclic structure serves as a good model for the active conformation of linear α-MSH.
P2T Purinoceptor Antagonists. A QSAR Study of Some 2-Substituted ATP Analogues
Authors: Tomkinson N P , Marriott D P , Cage P A , Cox D , Davis A M , Flower D R , Gensmantel N P , Humphries R G , Ingall A H , Kindon N D
Published: April 2011

FPL67085MX represents the first in a class of novel, highly potent and selective P2T purinoceptor antagonists which are inhibitors of adenosine diphosphate (ADP)-induced platelet aggregation in-vitro.

In an early series of compounds we studied the effect of variation of the adenine 2-substituent on potency and derived quantitative structure-activity relationships (QSARs) between the properties of the molecules and their biological activity. This work has recently been revisited using comparative molecular-field analysis (CoMFA) and the comparison of the predictions from the two methods is discussed along with their relative merits in terms of compound design.

The model suggests that the receptor for these molecules has a narrow lipophilic cleft, which is occupied by the adenine 2-substituent.
Airway Reactivity to Inhaled Spasmogens 18–24 h after Antigen-challenge in Sensitized Anaesthetized Guinea-pigs
Authors: Johnson Alexia , Broadley Kenneth J
Published: April 2011

The anaesthetized allergic guinea-pig was used to assess changes in airway reactivity to four different inhaled spasmogens: methacholine, 5-hydroxytryptamine (5-HT), histamine and the thromboxane A2 mimetic, 9,11-dideoxy-9α,11α-methano-epoxy-PGF2α (U-46619). Reactivity was determined 18 to 24 h after challenge of ovalbumin-sensitized guinea-pigs with inhaled ovalbumin. This time coincides with the appearance of a late-phase bronchoconstriction in these animals. Sensitivity to the spasmogen was assessed from the concentration-response curve for the increase in pulmonary inflation pressure (PIP) in ovalbumin- and saline-challenged sensitized animals.

When methacholine, 5-HT or histamine were the spasmogens there was no hyper-reactivity. The geometric mean EC50 values (i.e. the concentrations inducing half the maximum effect) obtained from the dose-response curves for methacholine (73 (42–129) and 94 (66–134) μg mL−1), 5-HT (1.5 (0.81–3.03) and 1.1 (0.51–2.24 μg mL−1) and histamine (39 (21–75) and 72 (32–162) μg mL−1) did not differ significantly (P > 0.05) between saline- and ovalbumin-challenged animals, respectively. However, when U-46619 was the spasmogen, ovalbumin-induced airway hyper-reactivity was observed as a leftwards shift of the concentration-response curve and the EC50 value for ovalbumin-challenged animals (8.1 (5.1–13) ng mL−1) was significantly (P < 0.05) less than the value for control animals (39 (21–75) ng mL−1).

Our findings suggest that airway hyper-reactivity is not ‘non-specific’, but instead depends on the chosen spasmogen. The absence of hyper-reactivity with certain spasmogens was not a result of poor delivery, because all spamogens caused a bronchoconstriction by the inhaled route. It was also not associated with the model because ozone has been shown to induce hyper-reactivity to inhaled methacholine and 5-HT. Because airway hyper-reactivity to both inhaled histamine and agonists at muscarinic receptors is regularly seen in man, the anaesthetized guinea-pig might not be the ideal model for assessing airway hyper-reactivity after antigen challenge and its modification by anti-asthma drugs.
Intestinal Absorption of Stable Cyclic Glycylphenylalanine: Comparison with the Linear Form
Authors: Mizuma Takashi , Masubuchi Satoshi , Awazu Shoji
Published: April 2011

The absorption, especially the stability and transportability, of the cyclic peptide cyclic glycylphenylalanine (cyclo(Gly-Phe)) and the linear peptides glycylphenylalanine, glycyl-d-phenylalanine and phenylalanylglycine have been studied in rat small intestine.

Linear peptides were degraded on the mucosal side and only glycyl-d-phenylalanine appeared on the serosal side. However, cyclo(Gly-Phe) was stable on the mucosal side and appeared on the serosal side. Furthermore, the absorption clearance of cyclo(Gly-Phe) was higher than that of glycyl-d-phenylalanine. In the presence of the peptidase inhibitor bestatin, the degradation of linear peptides was reduced and linear peptides appeared on the serosal side, but only phenylalanylglycine, which is transported by the oligopeptide transporter, was absorbed faster than cyclo(Gly-Phe). The absorption clearance of cyclo(Gly-Phe) was reduced as its concentration was increased from 125 μm to 500 μm. Furthermore, the absorption clearance of cyclo(Gly-Phe) at 125 μm was reduced at 4°C or in the presence of glycylsarcosine and cephalexin, which are transported by the oligopeptide transporter.

These results indicated that cyclo(Gly-Phe) was stable enough to be absorbed and was transported in part by the oligopeptide transporter rather than completely by passive diffusion.
Comparison of the Effects of Cimetidine and Ranitidine on the Pharmacokinetics of Disopyramide in Man
Authors: Jou Ming-Jeng , Huang Shung-Chieh , Kiang Fu-Mei , Lai Miao-Ying , Chao Pei-Dawn Lee
Published: April 2011

The widely prescribed antiulcer agents cimetidine and ranitidine have the potential to affect the absorption, metabolism or renal excretion of disopyramide. This study investigated the effect of a single oral dose of cimetidine or ranitidine on the pharmacokinetics of disopyramide and mono-N-dealkyldisopyramide in six healthy volunteers. The treatment was conducted in a randomized cross-over design. Serum levels and urinary recoveries of disopyramide and mono-N-dealkyldisopyramide were assayed by HPLC.

Cimetidine significantly elevated the maximum plasma concentration of disopyramide, the area under the plasma concentration-time curve and the total amount of disopyramide excreted unchanged in the urine, but the serum profile of mono-N-dealkyldisopyramide was not significantly affected. The effects of ranitidine on the pharmacokinetics of disopyramide and mono-N-dealkyldisopyramide were not significant. The interaction between cimetidine and disopyramide occurred mainly at the site of absorption.

The results indicate that cimetidine, but not ranitidine, significantly increased the absorption of orally administered disopyramide.
Pharmacokinetics of N4-Octadecyl-1-β-d-Arabinofuranosylcytosine in Plasma and Whole Blood after Intravenous and Oral Administration to Mice
Authors: Rentsch Katharina M , Schwendener Reto A , Schott Herbert , Hänseler Edgar
Published: April 2011

N 4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC) is a new cytotoxic derivative of cytosine arabinoside with improved cytotoxic activity and stability against deamination. Its pharmacokinetics were studied in mice.

The drug was administered intravenously and orally to ICR mice to assess its pharmacokinetic parameters in plasma and whole blood. The lipophilic drug was administered in small unilamellar liposomes 100–400 nm in diameter. The concentrations of NOAC in plasma and erythrocytes were determined by high-performance liquid chromatography (HPLC). When given orally a rather low amount of the delivered NOAC was absorbed as the unchanged drug, resulting in a bioavailability of 11% from the plasma and 12.9% from whole blood. As shown elsewhere, the amount of drug absorbed is sufficient to provide excellent cytotoxic activity in the L1210 leukemia and in human xenograft models after oral administration. The mean residence time of NOAC after intravenous administration was 3.5 h in plasma and 6 h in whole blood giving NOAC a terminal half-life in blood substantially longer than that of cytosine arabinoside. After oral administration the mean residence time was 18 h in plasma and whole blood.

In summary, NOAC has a prolonged half-life after intravenous administration compared with cytosine arabinoside. The distribution of NOAC in blood is highly dependent on its mode of administration.
Pharmacokinetics of Intragastrically Administered Digoxin in Rabbits with Experimental Bile Duct Obstruction
Authors: Wójcicki M , Drozdzik M , Sulikowski T , Gawronska-Szklarz B , Wójcicki J , Rózewicka L , Skowron J , Zielinski S , Musial H D , Zakrzewski J
Published: April 2011

A change in the functioning of the liver as a result of experimental cholestasis could result in a change in the biotransformation of drugs. The aim of this study was to evaluate the effect of extrahepatic cholestasis on the pharmacokinetics of digoxin.

The investigation was performed on male rabbits randomly divided into two groups: sham-operated and animals with bile-duct ligation. Digoxin (0.02 mg kg−1) was administered intragastrically as a single dose. Biomedical and anatomo-pathological tests and pharmacokinetic assays were performed before the operation and on the 6th day after surgery. A significant increase in area under the serum concentration-time curve and in mean residence time, a decrease in total body clearance, a reduction in the volume of distribution and increases in maximum concentration and the time to reach maximum concentration were observed in animals with the bile-duct ligation.

These results suggest reduced elimination of digoxin in animals with obstructive cholestasis.
Stereoselective Passage of Mefloquine Through the Blood-Brain Barrier in the Rat
Authors: Baudry S , Pham Y T , Baune B , Vidrequin S , Crevoisier CH , Gimenez F , Farinotti R
Published: April 2011

The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)-mefloquine and (–)-mefloquine.

When 50 mg kg−1 racemic mixture was administered orally for 22 days, plasma concentrations of the (+) enantiomer were 2–3 times higher than those of the (–) enantiomer whereas the opposite was true in every part of the brain (cerebellum, cortex, hippocampus, hypothalamus and striatum). Different concentrations of mefloquine were found in the different regions of the brain; the lowest concentrations of (±)-mefloquine (270 nmol g−1) were in the cerebellum and the highest (1100 nmol g−1) in the hippocampus. The main metabolite, carboxymefloquine, was detected in plasma but not in the brain.

The results indicate that mefloquine crosses the blood-brain barrier stereoselectively.
Affinity of the Miotic Drug, Dapiprazole, at α1-Adrenoceptor Subtypes A, B and D
Authors: Eltze Manfrid
Published: April 2011

The functional affinities of the α1-adrenoceptor antagonist, dapiprazole, currently being used to reverse diagnostic pupillary dilation, were determined at subtype A in rat vas deferens, at subtype B in guinea-pig spleen and at subtype D in rat aorta and compared with various α1-adrenoceptor subtype-discriminating antagonists.

Dapiprazole had relatively high affinity both at rat vas deferens α1A-adrenoceptors (pA2 = 7.93) and at rat aortic α1D-adrenoceptors (pA2 = 8.26), whereas its affinity at guinea-pig splenic α1B-adrenoceptors (pA2 = 7.13) was lower. The reference antagonists, 5-methylurapidil and the 5-methylurapidil/fiesinoxan hybrid, B8805–033((±)-1,3,5-trimethyl-6[[3[4(2(2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl]-amino]2,4(1H,3H)-pyrimidinedione), were 40- and 1500-fold selective for the A subtype, whereas spiperone and BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione diHCl) were confirmed as selective for the B and D subtypes of α1-adrenoceptors, respectively.

Thus, in functional experiments dapiprazole seems to be moderately selective (approximately 10-fold) for the A and D over the B subtype of α1-adrenoceptors; the possible therapeutic consequence of this is discussed.