bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclic Nucleotide Content of the Rat Anococcygeus During Relaxations Induced by Drugs or by Non-adrenergic, Non-cholinergic Field Stimulation
Authors: Mirzazadeh Shokoufeh , Hobbs Adrian J , Tucker John F , Gibson Alan
Published: April 2011

Low concentrations of sodium nitroprusside (0.2 and 1 μM) relaxed carbachol-induced tone of the rat anococcygeus but did not affect the content of either cGMP or cAMP; higher concentrations (10, 100 and 1000 μM) produced greater relaxation (> 60%) and a rise in cGMP but not cAMP. In the presence of the cGMP-phosphodiesterase inhibitor M&B 22948 (10 μM), 1 μM sodium nitroprusside produced greater relaxation and a selective increase in cGMP. Forskolin (0.5–250 μM) caused relaxation and a selective increase in cAMP; the concentration-response relationships of the two effects were similar. Non-adrenergic, non-cholinergic (NANC) field stimulation (10 Hz; 20 s trains) reduced tone by 52% but had no effect on cyclic nucleotide content; in the presence of 10 μM M&B 22948 or 1 μM sodium nitroprusside, NANC stimulation produced a greater degree of relaxation and increased cGMP but not cAMP content. The results show that NANC stimulation acts like sodium nitroprusside, causing a selective increase in cGMP, and this supports the proposal that NANC transmission in the rat anococcygeus involves an endogenous nitrate; the possibility that multiple pools of cGMP exist in the anococcygeus is discussed.
Different Influence of Endothelium in the Mechanical Responses of Human and Cat Isolated Cerebral Arteries to Several Agents
Authors: Conde M Victoria , Marco Emilio J , Fraile M Luz , Benito J Miguel , Moreno M Jesús , Sanz M Luz , De Pablo Angel L López
Published: April 2011

The present work was undertaken to elucidate the role of the vascular endothelium in the changes of isometric tension elicited by different compounds in isolated cylinders of human and cat cerebral arteries and cat pulmonary arteries. Endothelium removal by rubbing significantly reduced the relaxing response to acetylcholine (ACh) of isolated segments of all the arteries. The same treatment did not modify the contraction elicited by 5-hydroxytryptamine (5-HT) in the human and cat cerebral segments but increased the contractile effect of the amine in cat pulmonary arteries. The mechanical responses to vasopressin, ATP and adenosine in isolated segments of cat cerebral arteries were unaffected after removing the endothelial layer. L-Arginine, but not D-arginine (10−5 M), enhanced significantly the relaxation induced by increasing doses of ACh in unrubbed cat cerebral arteries whereas it did not modify the response to ACh in rubbed ones. However, L-arginine had no effect on the dose-response curve to 5-HT in both kinds of preparation and did not change the tone in precontracted unrubbed cat cerebral segments. These results suggest that the endothelium of the cerebrovascular bed plays a minor role in regulating the mechanical response induced by several vasoactive agents, although it retains its ability to produce an endothelium-derived relaxing factor.
Structure-pharmacokinetic Relationships among the N1, N3-Alkylxanthines in Rats
Authors: Apichartpichean Ruttikorn , Hasegawa Takaaki , Nadai Masayuki , Kuzuya Takafumi , Nabeshima Toshitaka
Published: April 2011

The pharmacokinetics of four N3-alkylxanthine and four N1-methyl-N3-alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1, N3-alkylxanthine in plasma and urine was determined by HPLC. A one-compartment model adequately described the plasma concentration time data. The steady-state volume of distribution (Vss) was calculated using model-independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P < 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1-position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non-renal (hepatic) clearance increased with increasing lipophilicity.
Transdermal delivery of insulin by ultrasonic vibration
Authors: Tachibana Katsuro , Tachibana Shunro
Published: April 2011

Ultrasonic vibration has been used to deliver insulin through the skin of hairless mice fasted overnight and partially immersed in an aqueous solution of insulin (20 units mL−1). The skin surface was exposed to ultrasonic vibration in two ultrasonic energy ranges (3000–5000 Pa and 5000–8000 Pa) at 48 kHz for 5 min. Blood glucose concentration was measured before and after exposure to insulin and ultrasonic vibration. In the group subjected to the lower energy vibrations, blood glucose fell rapidly to reach 34 ± 11.9% of control values in 120 min, while when the animals were exposed to higher energy vibrations, the fall in blood glucose was 22.4 ± 3.9% of control values at 120 min. The values remained low for the length of the experiment (240 min). Those exposed to insulin alone or ultrasonic vibration alone revealed no significant change in blood glucose concentration. It is postulated that ultrasonic vibration may alter skin permeability resulting in the absorption of insulin. That the blood glucose decrease was greater at the higher of the two energy ranges, suggests this factor could control insulin delivery.
Akinesia due to catecholamine depletion in mice is prevented by caffeine. Further evidence for an involvement of adenosinergic system in the control of motility
Authors: Popoli Patrizia , Caporali Maria Grazia , De Carolis Arsenia Scotti
Published: April 2011

The administration of reserpine with α-methyl-p-tyrosine (2.5 and 200 mg kg−1 i.p., 24 and 3 h before the test, respectively) induced a marked akinesia in mice. This effect was significantly and dose-dependently reversed by the methylxanthine, caffeine. The anti-akinetic effect of caffeine within a pattern of catecholamine depletion has been interpreted as a dopamine mimetic activity of this drug. The possible involvement of the adenosine system in this effect of caffeine is discussed.
Effects of ginsenoside-Rb2 on adenine nucleotide content of rat hepatic tissue
Authors: Yokozawa Takako , Fujitsuka Naoki , Yasui Teruhito , Oura Hikokichi
Published: April 2011

In comparison with non-diabetic rats, the tissue ATP content of diabetic rats is lower and the AMP content higher. However, daily intraperitoneal administration of ginsenoside-Rb2 for several days resulted in an increase of tissue ATP content and a decrease of AMP content, characterized by an increase in the adenine nucleotide content, as well as improvement of energy charge. Thus, ginsenoside-Rb2 administration caused a change in the pattern of metabolism, activating the ATP supply system.
Effects of dextran sulphate on renal dysfunctions induced by gentamicin as determined by the kidney perfusion technique in rats
Authors: Kikuchi Shinji , Aramaki Yukihiko , Nonaka Homare , Tsuchiya Seishi
Published: April 2011

The effect of dextran sulphate on accumulation of gentamicin within the renal cortex and on renal functional changes induced by gentamicin has been investigated using the rat renal perfusion technique. Gentamicin accumulation decreased by the co-administration of dextran sulphate, the degree being proportional to dextran sulphate concentration. The filtered load of gentamicin was unaffected by dextran sulphate. The perfusion of kidney with gentamicin brought about a decrease in the reabsorption of Na+ and an increase in the rate of urine flow with no effect on that of glomerular filtration. The addition of dextran sulphate in the perfusate resulted in the resumption of these levels to those of the control. Dextran sulphate thus apparently interacts with gentamicin in the lumen of proximal tubules to inhibit the reabsorption of gentamicin by proximal tubular cells, and prevents the renal dysfunctions induced by gentamicin.
The Influence of Myrj 59 on the Solubility, Toxicity and Activity of Amphotericin B
Authors: Tasset C , Préat V , Roland M
Published: April 2011

The effect of Myrj 59 (a polyoxyethyleneglycol derivative of stearic acid) on amphotericin B (Am B) solubility, toxicity and activity has been investigated. We showed that Myrj 59 could solubilize the antibiotic. Moreover, it also decreased and abolished the haemolytic activity of the drug by increasing the resistance of the red blood cells and impairing the interaction of Am B with the cellular membrane cholesterol, but it did not modify the in-vitro antifungal activity of the drug. On the other hand, Myrj 59 did not decrease the acute in-vivo toxicity of the drug (LD50 and nephrotoxicity). In a previous study we have shown that a polyoxyethyleneglycol derivative of cholesterol could solubilize Am B and was able to decrease the in-vitro and in-vivo toxicity of the antibiotic without altering its in-vitro antifungal activity. The results of the present study suggest that the cholesterol moiety of the surfactant is not necessary to decrease the in-vitro lytic activity of the drug but could play a role in the reduction of the in-vivo toxicity.
Competitive Protein-binding Radioassay of Thiamine in Simple Solutions and in Multivitamin Pharmaceuticals
Authors: Kozik Andrzej , Wróabel Radoslawa , Turyna Izabela
Published: April 2011

A competitive inhibition radioassay of thiamine is described using a gel obtained by coupling a buckwheat-seed thiamine-binding protein to CNBr-activated Sepharose. The sample to be analysed is incubated with gel suspension and [14C]thiamine and after centrifugation the radioactivity of the supernatant is measured. The method is simple and specific, and applicable over a thiamine concentration range 0.5-5 μM with a coefficient of variation typically below 5%. The gel is reusable and stable for several months. Applicability of the method for direct determination of thiamine in multivitamin pharmaceuticals is demonstrated.
Suppression of the Purgative Action of Rhein Anthrone, the Active Metabolite of Sennosides A and B, by Indomethacin in Rats
Authors: Yagi Teruyo , Miyawaki Yoshie , Nishikawa Atsuko , Yamauchi Kazuko , Kuwano Shigeaki
Published: April 2011

Rhein anthrone (12.48 mg kg−1) produces watery and mucoid diarrhoea approximately 20 min after intracaecal administration to rats. Pretreatment with the prostaglandin (PG) biosynthesis inhibitor indomethacin (10 mg kg−1, i.p.) only delayed and did not completely block the onset of the induced diarrhoea. Rhein anthrone stimulated PGE2 release into the rat colonic lumen and the increased release was depressed by indomethacin. Rhein anthrone also accelerated large intestinal transit and this acceleration could be partly inhibited by indomethacin, which was probably responsible for the delay in the onset of diarrhoea. Indomethacin prevented the enhanced water, K+ and mucus secretion and the reduced Na+ absorption in the colon which were induced by rhein anthrone. The net water secretion could not be reversed to net absorption and the mucus secretion was only slightly depressed by indomethacin. Thus, our findings suggest that other mechanisms, together with the PG-dependent mechanism, are involved in the purgative action of rhein anthrone in rats.
Moment Analysis of Drug Disposition in Rat Kidney: Role of Basolateral Membrane Transport in Renal Transepithelial Transport of p-Aminohippurate
Authors: Saito Yoshihiro , Tanigawara Yusuke , Okamura Noboru , Shimizu Hiromasa , Kamiya Akira , Hori Ryohei
Published: April 2011

The determining step in transepithelial transport of p-aminohippurate (PAH) in renal tubular secretion has been elucidated in the rat isolated perfused kidney. The method was based upon a multiple indicator dilution experiment and non-compartmental moment analysis. Single-pass dilution curves were obtained from venous and urinary effluents after simultaneous intra-arterial injections of Evans blue with albumin, [3H]inulin and [14C]PAH. Probenecid was used as a transport inhibitor and dissolved in both perfusate and injection solution. The urinary excretion of PAH decreased depending on the probenecid concentration, while that of inulin was not affected. No correlation was observed between the amount of secretion and the mean residence time of secreted PAH in renal epithelial cells (T̈cell). Since T̈cell ought to be affected by the rate of secretion from cells to lumen, it was suggested that the secretion rate was independent of the amount secreted. In contrast, the amount of PAH excreted via tubular secretion showed a linear correlation with the volume of distribution in the kidney and the apparent rate constant for tubular uptake of PAH. Since these kinetic parameters reflect the transport from blood into cells across the basolateral membranes of renal epithelial cells, the present results demonstrated that basolateral membrane transport is a determining step in the transcellular transport of PAH and that the major effect of probenecid is the inhibition of transport from blood into cells.
Peripheral Pharmacokinetic Handling and Metabolism of L-Dopa in the Rat: The Effect of Route of Administration and Carbidopa Pretreatment
Authors: Rose S , Jenner P , Marsden C D
Published: April 2011

The effect of carbidopa (L-α-methyldopa hydrazine; 25 mg kg−1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxy-phenylalanine (L-dopa; 50 mg kg−1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-∞) after L-dopa i.a. and increased AUC0-∞ after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment. The rat model displays similar peripheral pharmacokinetics and metabolism of L-dopa to those reported in human studies, and may be used for further investigations into the pharmacokinetic handling of the drug.
Pentazocine-induced Catecholamine Efflux from the Dog Perfused Adrenals
Authors: Fukumitsu Kazuo , Sumikawa Koji , Hayashi Yukio , Kinouchi Keiko , Yoshiya Ikuto
Published: April 2011

This study has been undertaken to determine whether pentazocine induces catecholamine efflux from the adrenal medulla as a mechanism for its sympathomimetic effect. Dog isolated adrenals were perfused retrogradely with modified Locke's solution. The efflux of catecholamines from dog perfused adrenals was increased from the resting output of 0.18 ± 0.04 μg min−1 (mean ± s.e.), to 0.47 ± 0.13 μg min−1 by the administration of pentazocine (50 μM). The pentazocine-induced catecholamine efflux was dose-dependent in the 50–400 μM dose range. This effect of pentazocine was not inhibited by either a combination of atropine and (+)-tubocurarine, or verapamil, in contrast to acetylcholine-induced catecholamine release. There was no significant difference in potency among stereoisomers, i.e. (+)-, (—) and (+)-pentazocine, in inducing catecholamine efflux. Naloxone did not influence the effects of either (+)-or (—)-pentazocine. The interaction of pentazocine with acetylcholine-induced catecholamine release was also examined. Both (+)-and (—)-pentazocine inhibited acetylcholine-induced catecholamine release dose-dependently, and these inhibitory effects were not reversed by naloxone. Acetylcholine-induced catecholamine release was accompanied by increased dopamine-β-hydroxylase release, whereas pentazocine-induced catecholamine efflux was not. These results suggest that pentazocine directly acts on the adrenal medulla to induce catecholamine efflux via a non-exocytotic mechanism, and that opioid receptors do not play a role in this action.
An Investigation into the Effects of Aminoguanidine Treatment on the Plasma and Blood of Free-fed and Dietary-restricted Rats
Authors: Preedy Victor R , Hammond Barry
Published: April 2011

An investigation has been made into the effect of oral aminoguanidine (50–60 mg kg−1 day−1) on the blood biochemistry of male Wistar rats which either had free access to food or were dietary-restricted (50% of the food consumed by the free access group). In control rats (i.e. without aminoguanidine treatment) three weeks of food restriction caused significant increases in plasma sodium and albumin and the erythrocyte count, haematocrit and haemoglobin. There were reductions in plasma calcium, phosphate, alkaline phosphatase activity, urea, triglycerides, creatinine, glucose and the red cell volume. Similar effects of food restriction were observed in aminoguanidine-treated rats. Aminoguanidine ingestion in free-fed animals caused a reduction in plasma creatinine concentration. In dietary-restricted rats, aminoguanidine ingestion reduced plasma sodium and total plasma proteins (largely as a result of a decline in albumin), and increased plasma urea concentrations. Aminoguanidine was added to plasma of control rats in-vitro to determine whether it interfered with the assay of urea and creatinine. At concentrations of 0.1 to 10 mg mL−1, aminoguanidine had no effect on urea determinations. However, aminoguanidine significantly reduced the apparent concentration of plasma creatinine by between 7 to 81%. The changes in plasma analytes in aminoguanidine-treated rats may be indicative of minor hepatic perturbations or kidney function, but the data also imply that prior nutritional state is a determinant of aminoguanidine effects.
Disposition of Hexobarbitone and Antipyrine in DOCA-hypertensive Rats
Authors: Ben-Zvi Z , Hreash F , Kaplanski J
Published: April 2011

The disposition of antipyrine and hexobarbitone, and their effects on drug metabolizing hepatic enzymes have been investigated in DOCA-hypertensive rats. Antipyrine pharmacokinetic parameters were the same in hypertensive and control animals. Hexobarbitone sleeping time was longer in hypertensive rats compared with controls, while the activity of hepatic hexobarbitone hydroxylase was the same in both groups. Hepatic aminopyrine-N-demethylase activity was elevated in hypertensive rats while aniline hydroxylase and aryl hydrocarbon hydroxylase were lower. Glucuronyl transferase was the same in both groups. The sensitivity of the central nervous system of hypertensive rats to hexobarbitone was not altered, as determined by hexobarbitone concentration in blood and in brain. The total hepatic blood flow (arterial and portal) was significantly increased. Thus it is suggested that the difference in the disposition of the two drugs is probably not due to drug metabolizing enzyme activity. It is likely that the increase in total hepatic blood flow and rapid saturation of hepatic hexobarbitone metabolizing enzymes have significant roles in the slower metabolism and increased activity of hexobarbitone in hypertensive rats as compared with control rats.
Relative anti-inflammatory effect of oral dexamethasone-β-D-glucoside and dexamethasone in experimental inflammatory bowel disease in guinea-pigs
Authors: Friend D R , Phillips S , Mcleod A , Tozer T N
Published: April 2011

The relative anti-inflammatory effect of dexamethasone and a prodrug, dexamethasone-β-D-glucoside, has been assessed in guinea-pigs with experimentally-induced inflammatory bowel disease (IBD). The glucoside prodrug is designed to reach the large intestine following oral administration. The active agent is liberated when the prodrug is hydrolysed by glycosidases of colonic bacteria. Guinea-pigs were administered degraded carrageenan in their drinking water to produce experimental IBD. Starting on day 15, dexamethasone (1.3 μmol kg−1) or dexamethasone-β-D-glucoside (1.3 or 0.65 μmol kg−1) was administered by gastric intubation once daily for 5 days. Relative to control animals, the drug and prodrug treatments significantly (P < 0.05) reduced the total number of caecal ulcers. While there was no difference statistically between the drug and prodrug treatments, the data suggest that a lower dose of dexamethasone, administered as its glucoside prodrug, could reduce side-effects without reduced efficacy. These results support the hypothesis that localized delivery of dexamethasone to the large bowel can improve pharmacotherapy of IBD by reducing the side-effects associated with corticosteroids.
Disposition of the hypolipidaemic agent, 6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid, in Sprague-Dawley rats
Authors: Hall Iris H , Wong Oi T , Wyrick Steven D , Simlot Rupendra , Shrewsbury Robert P
Published: April 2011

The disposition of [2-14C] 6-amino-2-mercapto-5-methyl-pyrimidine-4-carboxylic acid has been determined in rats following intravenous and oral administration. A two-compartment pharmacokinetic model fitted to the blood and urinary data predicted its maximum terminal (β) half-life to be 38 h. Urinary and faecal excretion accounted for approximately 30 and 8% of the administered radioactivity, respectively. The parent compound accounted for 88% of the urine radioactivity after oral administration. In a tissue distribution study, the largest percentages of radioactivity were found in the skin and carcass; by 24 h, all other organs contained less than 1% of the administered radioactivity. The drug was highly water soluble, not extensively bound to plasma proteins, nor taken up by red blood cells. The drug uptake by human fibroblasts or rat aorta cells appeared to be by passive diffusion.
Protection of acetylcholinesterase by meptazinol in mice exposed to di-isopropyl fluorophosphate. Comparison with physostigmine
Authors: Galli Alessandro , Mori Francesca
Published: April 2011

The protective action of meptazinol against acute diisopropyl fluorophosphate (DFP) intoxication has been evaluated in mice by measuring the effects on the DFP LD50 of the pretreatment of the animals with increasing doses of the drug. Meptazinol at the doses 15, 30 and 45 mg kg−1 injected 15 min before DFP caused a dose-dependent increase in the DFP LD50, resulting in protection ratios equal to 2.1, 4.8 and 9.7, respectively, in the absence of atropine and 2.5, 4.7 and 8, respectively, in the presence of atropine sulphate (17.4 mg kg−1) therapy. Under the same experimental conditions, the protective ratio of 0.1 mg kg−1 physostigmine sulphate was 2.2 and 7.3 in the absence and presence of atropine therapy, respectively. In separate experiments, the time course of acetylcholinesterase (AChE) activity recovery was evaluated in the brain and diaphragm of mice pretreated with meptazinol (30 mg kg−1) or physostigmine (0.1 mg kg−1) 15 min before poisoning with DFP (8 mg kg−1). Ten minutes after poisoning, residual AChE activity in the brain averaged 4, 47 and 15% of that in controls in animals pretreated with atropine alone, atropine plus meptazinol or atropine plus physostigmine, respectively. Twenty four hours after poisoning, brain AChE activity averaged 31 and 47% of that in controls in mice protected by meptazinol and physostigmine, respectively. The data from the diaphragm closely paralleled those from the brain. It is concluded that high doses of meptazinol exert antidotal action against acute DFP poisoning in the mouse comparable in efficacy with that of physostigmine combined with atropine. This action is most probably due to the ability of meptazinol to protect AChE from irreversible inactivation by DFP.
Prediction of drug loss from PVC infusion bags
Authors: Atkinson H C , Duffull S B
Published: April 2011

PVC: water partition coefficients for a series of 13 drugs have been calculated from literature data and a high degree of correlation with octanol: water partition coefficients demonstrated. The resulting model, log PPVC= −0.35 + 0.69 log P, (r2 = 0.88) has been prospectively tested with 10 drugs. All the test drugs were within the 95% confidence intervals associated with predicted log PPVC values consistent with a valid model. In practice, predicted log PPVC values may be used to estimate drug loss from the aqueous phase of PVC bags at equilibrium. Equations are described which enable calculation of likely drug loss from 100, 500 and 1000 mL PVC bags. It is recommended that this approach is used to identify drugs which are unlikely to be significantly absorbed into PVC.
Effect of Physical and Chemical Properties on Drug Release From Selected Thermosoftening Vehicles
Authors: Kopcha Michael , Lordi Nicholas G
Published: April 2011

The release profile of several drugs, (chlorpheniramine maleate, salicylic acid, hydrochlorothiazide, p-hydroxy benzoic acid, sulphafurazole, anhydrous theophylline) and the marker (D&C yellow No. 10) was detailed to determine the effect of physical and chemical properties on release from selected thermosoftening matrices (Gelucire 50/02 and 50/13). At a concentration of drug or marker of 2·5% w/w, hydrochlorothiazide showed the slowest release from G50/02, due to its low aqueous solubility, while theophylline showed the highest release owing to its low mol. wt and moderate aqueous solubility. Release reflected two of the selection criteria, aqueous solubility and mol. wt, set forth for the drug/markers used in the study. The hydrophobic matrix, G50/02, offered no enhancement in drug release and functioned in a manner commensurate with other hydrophobic matrices. No hydrogen bonding was noted between any of the drugs or markers and the matrix. As drug or marker concentration increased from 2·5 to 15% w/w, potential hydrogen bonding was noted between p-hydroxy benzoic acid and the matrix. Theophylline no longer had the highest release being replaced by chlorpheniramine maleate and D&C yellow No. 10. With Gelucire excipient G50/13, chlorpheniramine maleate showed the highest release; it dissolved within the matrix at experimental temperature and lowered the matrix melting point. The matrix swelled upon exposure to the dissolution medium and it was from this swollen layer that release occurred. Sulphafurazole, hydrochlorothiazide, salicylic acid and p-hydroxy benzoic acid exerted a similar effect to chlorpheniramine maleate on the matrix. No hydrogen bonding was observed between the drugs and matrix. As drug or marker concentration was further increased, chlorpheniramine maleate and D&C yellow No. 10 demonstrated the highest release; all other drugs formed a cluster. Apparent diffusion coefficients for G50/02 and G50/13 matrices were in agreement with published data confirming the predictive ability of the experimental design and postulated mechanistic models of release from hydrophilic and lipophilic matrices.
The Effect of Moderate Haemodilution with Fluosol-DA or Hespan on the Nonmicrosomal Acetylation of Sulphadimidine in the Rat
Authors: Shrewsbury Robert P , Hong Donald D , White Lisa G , Gordon Teressa R
Published: April 2011

The effects of Fluosol-DA (Fluosol) and Hespan haemodilution on the nonmicrosomal acetylation of sulphadimidine were studied in male rats. Fluosol increased the acetylsulphadimidine percent excreted in urine, the metabolic formation rate constant (kf), and the formation clearance (CLF) for 72 h after haemodilution without any significant changes in the sulphadimidine apparent volume of distribution (Vd) or total body clearance (CL). Hespan haemodilution increased the acetylsulphadimidine percent excreted in urine only at 48 h while significantly decreasing the sulphadimidine clearance, urinary excretion rate constant (ku), and renal clearance (CLR) for 72 h. The enhanced N-acetyltransferase activity after Fluosol haemodilution may have therapeutic consequences for concomitantly given drugs metabolized by this enzyme.
Effects of Opioid and α2-Adrenoceptor Agonists on the Isolated Ileum of Morphine-dependent Guinea-pigs During Withdrawal and After Clonidine Treatment
Authors: Colado M I , Martin M I
Published: April 2011

The present study was undertaken to investigate the effect of clonidine administration to opiate-dependent guinea-pigs after morphine withdrawal on subsequent twitch responses of the longitudinal muscle-myenteric plexus preparations to electrical field stimulation. The results indicate that clonidine, administered immediately after morphine removal, causes tolerance to the inhibition exerted by opioid and α2-adrenoceptor agonists on the electrically-evoked twitches. Such a finding suggests that the mechanism of action of clonidine involves not only its well-known effects on locus coeruleus neurons but also that it has specific actions on the myenteric plexus. This work shows the existence of interactions between opioid and α-adrenoceptor on the cholinergic neurons present in the isolated ileum.
Contractile Response of Human Omental Arteries to Endothelin
Authors: Vila J M , De Aguilera E Martín , Irurzun A , Aldasoro M , Flor B , Lluch S
Published: April 2011

The effects of endothelin have been studied in isolated arterial segments (0·8–1 mm in external diam.) of human omental arteries obtained during the course of abdominal operations (15 patients, 7 men and 8 women). Paired segments, one normal and the other de-endothelized, were mounted for isometric recording of tension in organ baths. Endothelin produced concentration-dependent contractions with an EC50 value of 5·4 × 10−9  m. Removal of endothelium did not affect significantly endothelin-induced contractions (EC50, 6·7 × 10−9  m). Removal of extracellular calcium or addition of the calcium channel blocker nicardipine (10−6  m) diminished but did not abolish responses to endothelin. These results indicate that endothelin exerts powerful contractile effects on human isolated omental arteries which are independent of the presence of an intact endothelial cell layer; this contraction cannot be explained solely by voltage-dependent calcium channels.
Further Characterization of the Protective Effect of 8-Cyclopentyl-1,3-dipropylxanthine on Glycerol-induced Acute Renal Failure in the Rat
Authors: Panjehshahin M R , Munsey T S , Collis M G , Bowmer C J , Yates M S
Published: April 2011

In the rat, treatment with the alkylxanthine 8-cyclopentyl-1,3-dipropylxanthine (CPX) at a dose of 0·1 mg kg−1 antagonizes adenosine-induced falls in renal blood flow and reduces the severity of glycerol-induced acute renal failure. Treatment of glycerol-injected rats with 0·03 mg kg−1 of CPX resulted in no significant improvements in a range of indices of renal function. However, treatment with 0·1 or 0·3 mg kg−1 doses of CPX did significantly ameliorate acute renal failure although there were no significant differences in the degree of protection of renal function afforded by these two doses. In glycerol-injected rats, 0·1 or 0·3 mg kg−1 CPX administered either as a single dose or repeated doses every 12 h for two days did not inhibit renal phosphodiesterase. Thus the beneficial effects of CPX can be produced by doses that have no effect on renal phosphodiesterase activity whereas 0·1 mg kg−1 of CPX has been shown previously to antagonize the actions of adenosine. The findings provide further evidence that the beneficial effect of CPX in glycerol-induced acute renal failure is a consequence of adenosine antagonism and not phosphodiesterase inhibition.
Improved transdermal delivery of prostaglandin E1 through hairless mouse skin: combined use of carboxymethyl-ethyl-β-cyclodextrin and penetration enhancers
Authors: Uekama Kaneto , Adachi Hirotoshi , Irie Tetsumi , Yano Tadanori , Saita Masaru , Noda Kanji
Published: April 2011

The optimal prescription of transdermal preparations of prostaglandin E1 (PGE1) for treatment of peripheral vascular diseases has been investigated. The chemical stability of PGE1 in fatty alcohol/propylene glycol (FAPG) ointment was markedly improved by carboxymethyl-ethyl-β-cyclodextrin (CME-β-CyD). Application of a PGE1 ointment containing the penetration enhancer, 1-dodecylazacycloheptane-2-one (Azone) or 1-[2-(decylthio)ethyl]azacyclopentane-2-one (HPE-101), onto the skin of hairless mice showed the increase of blood flow in the skin due to the vasodilating action of PGE1. In particular, the ointment containing a PGE1-CME-β-CyD complex supplemented with HPE-101 showed the most prominent increase of the blood flow. Compared with other ointments, this ointment was found to show significantly greater transfer of HPE-101 into in-vitro preparations of the skin of hairless mice. Transfer of PGE1 into the skin was thought to be facilitated by this increased transfer of HPE-101. These results suggest that a combination of CME-β-CyD and HPE-101 is useful for designing PGE1 ointments for topical application with good chemical stability and percutaneous permeability.
Toloxatone pharmacokinetics in the plasma and cerebrospinal fluid of the rabbit
Authors: Vistelle R , Lamiable D , Zinsou M , Leon A , Wiczewski M
Published: April 2011

The pharmacokinetics of toloxatone (5 and 10 mg kg−1, i.v.) was studied in anaesthetized rabbits. There was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic parameters with the increase of the dose. The terminal half-life was short (47·4 ± 2·8 and 41·5 ± 4·2 min for 5 and 10 mg kg−1, respectively). The total clearance was 79 ± 18 mL min−1 after a dose of 5 mg kg−1 and 106 ± 40 mL min−1 after a dose of 10 mg kg−1. The volume of distribution was 5·8 ± 2·8 (5 mg kg−1) and 5·4 ± 1·8 L (10 mg kg−1). The average percentage of toloxatone bound to plasma protein was 30% and was not affected by concentrations within the investigated range. In cerebrospinal fluid (CSF), the highest concentrations of toloxatone were obtained within 15 min after the end of the injection. The CSF level of toloxatone was equal to that of plasma unbound toloxatone and declined at a rate similar to toloxatone in plasma. These results suggest that the toloxatone passage through the blood-brain barrier may be completed by passive diffusion. In addition, the unbound plasma concentration would accurately reflect the toloxatone concentration in CSF and could be a useful tool for drug monitoring.
Contractions induced by phenylephrine and noradrenaline are differently affected by endothelium-dependent relaxation in rat aorta
Authors: Auguet M , Tricoche R , Braquet P
Published: April 2011

In rings of rat aorta precontracted with phenylephrine (10 μm) or noradrenaline (10 μm), addition of carbachol (10 μm) produced an endothelium-dependent relaxation. However, regardless of the concentration of agonist tested, both the intensity and duration of the relaxation were significantly less when noradrenaline, rather than phenylephrine, was used as the precontracting agent. The different responses observed do not appear to be related to destruction of endothelium-derived relaxing factor by autoxidation of noradrenaline since neither EDTA (30 μm) nor superoxide dismutase (30 units mL−1) improved the relaxation to carbachol. In addition, in endothelium-free rings, the noradrenaline (1 μm)-induced contraction was less sensitive than the phenylephrine (1 μm)-induced contraction to sodium nitroprusside (0·1 μm) or to 8-Br-cGMP (300 μm). With phenylephrine-, but not noradrenaline-, induced contraction, the relaxation triggered by carbachol was significantly reduced by pretreatment of the aortic rings with chloroethylclonidine (50 μm), which inactivates a subpopulation of α1-adrenoceptors. Thus, the results confirm that both alkylation sensitive and resistant α1-adrenoceptors exist in rat aorta and indicate that EDRF may discriminate between these two α1-adrenoceptor subtypes which are differently affected by phenylephrine and noradrenaline.
Analysis of the effects of adenosine in skinned bovine coronary artery
Authors: Ramagopal Mudumbi V , Mustafa S Jamal
Published: April 2011

We have investigated the mechanism of adenosine-induced relaxation in relation to its effects on intracellular organelles in Triton X-100- and saponin-skinned bovine coronary arteries. In intact coronary arteries, high K+ and prostaglandin F2α caused sustained contractions, whereas caffeine produced transient contractions. Triton X-100 treatment abolished these contractions. However, Triton X-100-skinned coronary arteries were responsive to added free calcium. There was no significant difference between calcium concentration-response curves obtained in the absence and presence of adenosine (50 μm). Unlike Triton X-100, in saponin-skinned arteries, caffeine produced transient contractions but high K+ and prostaglandin F2α did not. Adenosine had no effect on caffeine-induced contractions in saponin-skinned coronary arteries. These data suggest that adenosine had no direct inhibitory effect on either the contractile apparatus or calcium release from sarcoplasmic reticulum in coronary arteries.
An in-vitro study of chloroquine transport in the rat submaxillary gland
Authors: Onyeji C O , Dixon P A F , Ogunbona F A
Published: April 2011

The uptake and efflux of chloroquine by the rat submaxillary gland in-vitro were studied under various incubation conditions. Variations in the extracellular pH significantly affected both the uptake and efflux of the drug. Increasing chloroquine concentration significantly decreased the uptake. Uptake was also decreased significantly (P < 0·05) when compared with control conditions (pH 7·40, 37·5°C, O2 aeration, 6 × 10−6  m chloroquine) by the following experimental variations: aeration of the incubation medium with N2 instead of O2; decrease of bath temperature from 37·5 to 4°C; addition of metabolic inhibitors, cyanide (10−3  m), iodoacetic acid (10−3  m) and o-nitrophenol (10−3  m). Cimetidine (10−3  m), a known organic cationic inhibitor, had no significant effect on chloroquine uptake when compared with control values. These results show that the uptake of chloroquine by the rat submaxillary gland in-vitro is concentration-dependent and this is indicative of possible saturable binding sites for the drug in the gland. These results suggest that the transfer of chloroquine across the submaxillary gland may be mediated by an active transport process. On the other hand, it is possible that the apparent active transport process implicated in this study could be a consequence of chloroquine ion trapping in the acidic interior of lysosomes.
Influence of inhibition of extraneuronal uptake and of O-methylation on the hyperglycaemia caused by sympathomimetic amines in depancreatized rats
Authors: Proença Jorge , Guimarães Serafim
Published: April 2011

This study aimed at testing whether the O-methylating system (extraneuronal uptake + O-methylation) modulates, in-vivo, β-adrenoceptor-mediated responses. The influences of U-0521 (3,4-dihydroxymethylpropiophenone, an inhibitor of catechol-O-methyl transferase (COMT)) and hydrocortisone (an inhibitor of extraneuronal uptake) on the hyperglycaemia evoked by isoprenaline and adrenaline were compared. Both inhibitors enhanced the increase of the plasma glucose level induced by either isoprenaline (0·36 nmol kg−1 min−1) or adrenaline (0·55 nmol kg−1 min−1). The enhancement caused by U-0521 developed faster than that caused by hydrocortisone, but was of the same magnitude. This is the first report of supersensitivity to sympathomimetic amines caused by inhibition of either COMT or extraneuronal uptake in-vivo and for a response not involving smooth muscle cells.
Evaluation of Ion-exchange Microspheres as Carriers for the Anticancer Drug Doxorubicin: In-vitro Studies
Authors: Chen Yan , Burton Mark A , Codde James P , Napoli Sylvia , Martins Ian J , Gray Bruce N
Published: April 2011

A comparison study of doxorubicin loading, release characteristics and stability within sodium and hydrogen forms of ion-exchange resin microspheres has been performed. It was demonstrated that resins in the Na+ form, although having lower drug loading capacity, showed similar release profiles to resins in the H+ form but still maintain all the drug activity. Resins in the H+ form, despite having high drug loading capacity, caused drug degradation within microspheres due to their strong acidic nature. Therefore, in comparison with the H+ form, resins in the Na+ form can be considered as better carriers for doxorubicin in terms of sustaining the release of drug and maintaining drug activity. Other factors such as the degree of resin cross-linkage and drug/resin mixing time have also been examined in relation to drug loading and release characteristics. Overall, this study demonstrated the significance of the characteristics of matrix materials and their influence on the drug activity and microsphere performance in-vitro.
Effects of Proteolytic Enzyme Inhibitors as Absorption Enhancers on the Transdermal Iontophoretic Delivery of Calcitonin in Rats
Authors: Morimoto Kazuhiro , Iwakura Yasushi , Nakatani Emi , Miyazaki Makoto , Tojima Hideki
Published: April 2011

The effects of proteolytic enzyme inhibitors, aprotinin, soybean trypsin inhibitor and camostat mesilate as absorption enhancers on the transdermal iontophoretic delivery of salmon calcitonin (SCT) have been examined in rats. The dermal absorption of SCT was evaluated with hypocalcaemic effect. Application of SCT (12·5 int. units/rat) onto abdominal skin did not produce any hypocalcaemic effect. This produced a small hypocalcaemic effect with cationic iontophoresis (drug phase, anode; reference phase, cathode; high frequency pulses of 1 V at 10 kHz, 2h). Furthermore, camostat mesilate (1 Mm) and aprotinin (106 int. units mL−1) enhanced the hypocalcaemic effects on the application of SCT with iontophoresis. These hypocalcaemic effects were highest with the pH 4·0 preparation compared with those of the pH 5·5, pH 7·0 and pH 8·0 preparations. However, soybean trypsin inhibitor did not change the hypocalcaemic effects. This was because the soybean trypsin inhibitor is a relatively high molecular weight peptide (mol. wt 8000) and an anion at used pH, and therefore was not absorbed through rat skins with cation iontophoresis.
Effect of Cocaine on Tritium Overflow Evoked from Vasa Deferentia Previously Loaded with [3H]Noradrenaline by Stimulation Using Different Types of Electrode
Authors: Bedwell A M , El-Mas M , Hughes I E
Published: April 2011

In mouse and guinea-pig vasa deferentia previously incubated with [3H]noradrenaline, electrical stimulation applied through parallel electrodes (transmurally) increased overflow of tritium 2- to 5-fold above the resting value. Electrical stimulation applied using methods involving more substantial conduction of nerve impulses in neuronal elements in the tissues evoked a tritium overflow which was smaller (70%) than that evoked by transmural stimulation. Cinchocaine (25 μm), tetrodotoxin (0·5 μm) or the absence of calcium effectively abolished evoked overflow in both tissues whichever method of stimulation was used. In mouse vas deferens, cocaine (10 μm) did not alter overflow evoked by either transmural or axonal stimulation while 100 μm produced a reduction. In guinea-pig vas deferens, cocaine (10 μm) produced a statistically significant increase in evoked overflow of about 50% or more with both transmural and axonal stimulation. As in mouse vas deferens, 100 μm cocaine produced a reduction. It is concluded that the action of cocaine is independent of these methods of stimulation and that some difference in the arrangement of the noradrenergic nerves in the two species may account for the differential effect of cocaine observed.
Effects of (±)-, (+)- and (—)-Celiprolol on the Rat Left Atria and Portal Vein
Authors: Doggrell Sheila A
Published: April 2011

Differing effects of (±)-celiprolol at β-adrenoceptors have been reported. The effects of (±)-, (+)- and (—)-celiprolol on the contractile responses of the rat left atria and portal vein have therefore been studied. (±)-Celiprolol did not augment the responses of the atria to electrical stimulation and is therefore not an agonist at β1-adrenoceptors. Prolonged treatment with (±)-celiprolol attenuated the contractile activity of the vein and this effect was blocked by ICI 118,551 and is therefore mediated by agonism at β2-adrenoceptors. The pA2 values for (±)-, (+)- and (–)-celiprolol at the β1-adrenoceptors of the atria were 8·0, 6·0 and 8·6, respectively. On the portal vein, (±)- and (–)-celiprolol produced non-parallel rightward shifts of log isoprenaline attenuation curves with a reduction in isoprenaline maximum responses. This effect of (±)-celiprolol on the vein was not due to slowly reversible antagonism, as the inhibitory effect of (±)-celiprolol was readily reversible.
Anorectic Activity of Fluoxetine and Norfluoxetine in Rats: Relationship Between Brain Concentrations and In-vitro Potencies on Monoaminergic Mechanisms
Authors: Caccia S , Bizzi A , Coltro G , Fracasso C , Frittoli E , Mennini T , Garattini S
Published: April 2011

The present study was aimed at establishing the importance of brain monoamine uptake and release mechanisms in the anorectic activity of fluoxetine, relating them to the actual brain concentrations of the parent drug and its metabolite norfluoxetine after anorectic doses in rats. Both compounds showed anorectic activity when administered intraperitoneally, norfluoxetine being slightly more active (ED50 = 22·9 μmol kg−1) than fluoxetine (ED50 = 35·0 μmol kg−1) despite the fact that the metabolite is about ten times less potent than the parent drug in inhibiting 5-hydroxytryptamine (5-HT) uptake. Comparing the brain concentrations of norfluoxetine, in terms of maximum concentrations (Cmax) and area under the curve (AUC), after the ED50 of fluoxetine or synthetic norfluoxetine, it also appeared that the metabolite plays a major role in the anorectic effect of the parent drug in rats. Brain Cmax of fluoxetine (48·7 μm) and norfluoxetine (21·7 and 27·3 μm after metabolite and drug, respectively) were several times those blocking 5-HT uptake in-vitro (0·5 μm), making it unlikely that fluoxetine (directly or through its metabolite) reduces food intake by specifically blocking 5-HT neuronal uptake. Brain Cmax of fluoxetine but particularly norfluoxetine were more compatible with those capable in-vitro of affecting catecholaminergic mechanisms, such as inhibition of dopamine and noradrenaline uptake and enhancement of dopamine release. These results together with recent in-vitro findings that the parent compound and its active metabolite induce tritium release from hippocampal synaptosomes previously loaded with [3H]5-HT suggest that mechanisms other than inhibition of 5-HT uptake are involved in the anorectic action of these compounds in rats.
Evidence against Substance P as a neurotransmitter at the neuroepithelial junction in rat colonic mucosa
Authors: Burleigh David E , Yull Derek N
Published: April 2011

Substance P (SP) caused a concentration-dependent increase in short-circuit current of rat isolated colonic mucosal preparations (ED50 10 Nm). The SP antagonist [d-Arg1, d-Pro2, d-Trp7,9, Leu11]SP (50 μm) did not increase short-circuit current. Tetrodotoxin (3·1 μm) reduced the effect of a maximum concentration of SP (300 Nm). This reduction was increased when tetrodotoxin was given with [d-Arg1, d-Pro2, d-Trp7,9, Leu11]SP. Increases in short-circuit current produced by electrical field stimulation were not reduced by [d-Arg1, d-Pro2, d-Trp7,9, Leu11]SP. It is concluded that SP is not a transmitter at the neuroepithelial junction in rat colonic mucosa.