bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surprising Pharmacological Activity of Analogues Designed by Substitution of Position 3 in Arginine Vasopressin (AVP) and 8-D-Arginine Vasopressin with l-2-Naphthylalanine
Authors: Lammek Bernard , Konieczna Ewa , Trzeciak Henryk I , Kozlowski Artur , Szymkowiak Jacek , Stojko Rafal , Kupryszewski Gotfryd 
Published: April 2011

Abstract
In an attempt to develop more active and selective analogues of arginine vasopressin (AVP), two peptides have been designed, synthesized and tested for vasopressor (V1-receptors) and antidiuretic (V2-receptors) activities. We also estimated the uterotonic and anti-uterotonic activities of these compounds in-vitro.
The first peptide, [(l-2-Nal)3] AVP is a highly active V2-agonist. The second analogue, [(l-2-Nal)3, (d-Arg)8]VP is among the most potent antagonists of the vasopressor response to AVP. Moreover, it is the first V1-antagonist devoid of anti-uterotonic activity.
High antipressor potency of the second peptide was achieved without modification of position 1.
Antihypertensive Drugs Reduce Noradrenaline-induced Hypertrophy of Cultured Myocardial Cells
Authors: Lähteenmäki T A , Sievi E , Vapaatalo H 
Published: April 2011

Abstract
The cellular mechanisms of cardiac hypertrophy are still largely unknown. In-vivo studies have demonstrated that antihypertensive drugs can regress hypertrophy independently of reductions in blood pressure. The antihypertrophic effects of metoprolol, propranolol, felodipine, verapamil and captopril were studied in neonatal cardiac myocyte culture. Prazosin was used as a positive control. Hypertrophy was defined as an increase in protein content measured by [3H]leucine incorporation.
Noradrenaline induced a 1.5-fold increase in protein synthesis over 48 h. Prazosin prevented the hypertrophic effect of noradrenaline. Adrenergic β-receptor blocking agents and calcium antagonists reduced myocyte hypertrophy in a dose-dependent manner. The angiotensin-converting enzyme inhibitor captopril was ineffective.
These results indicate that adrenergic β-receptor blockers and calcium antagonists may have direct nonhaemodynamic effects on the growth of cultured cardiac myocytes.
Preventive Effects of Unsei-in and Oren-gedoku-to, Chinese Traditional Medicines, Against Rat Paw Oedema and Abdominal Constriction in Mice
Authors: Wang L M , Mineshita S 
Published: April 2011

Abstract
Oren-gedoku-to and Unsei-in are complex mixtures of ingredients derived from plants. These two drugs are clinically most frequently used in the treatment of Behçet's disease, we have investigated the anti-inflammatory and analgesic actions of Oren-gedoku-to and Unsei-in using a battery of tests; rat paw oedema induced by five different agents; abdominal constriction; mouse ear swelling; and dye leakage tests, designed to clarify the therapeutic potential of these medicines.
The findings in this study that these medicines are able to inhibit the rat paw oedema, suppress the abdominal constriction and inhibit the increased dye permeability confirm the analgesic and anti-inflammatory effects of these compounds.
From these results there seems a clear rationale for exploring the effectiveness of these Chinese medicines in the treatment øf chronic and acute inflammatory diseases.
Kinetic Evidence for Facilitated Peritoneal Transport of Benzoic acid in Rats
Authors: Nakashima Emi , Matsushita Ryo , Kanada Naomi , Ichimura Fujio 
Published: April 2011

Abstract
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

Abstract
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

Abstract
Propranolol, a β-adrenoceptor blocker, suffers from a high degree of first-pass metabolism resulting in very low bioavailability (&lt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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 &lt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 001), whereas 21, 29 and 100% was dissolved from the micronized formulation (P &lt; 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 &lt; 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

Abstract
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.