bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative inotropic effect induced by diethylamiloride (DEA) in rabbit myocardium
Authors: PEREZ M D , FUEYO J , BARRIGON S
Published: April 2011

The effects of the Na+/H+ exchange blocking drug diethylamiloride (DEA) on mechanical function have been studied in the rabbit isolated, arterially perfused interventricular septum. At concentrations of 10−6-10−5 M, DEA induced a significant, dose-dependent, negative inotropic effect (a 54% decrease from control values at the highest concentration), which was slow to develop. After a 45 min washout, recovery was almost complete (95 ± 3.4%). At concentrations > 5 × 10−5 M, DEA induced a rapid and marked decrease in developed tension, associated with a progressive decrease in excitability and incomplete recovery. Resting tension was not significantly modified at any of the concentrations tested. At > 10−6 M DEA enhanced significantly the transient negative inotropic effect of the brief intracellular acidosis induced by removal of NH4Cl perfusion, both by decreasing the minimal value of developed tension and by increasing the time required to produce this effect. These effects suggest that the dose-dependent DEA negative inotropic effect could be mediated by a progressive intracellular acidosis produced by inhibition of the Na+/H+ exchange system.
The Parenteral Controlled Release of Liposome Encapsulated Chloroquine in Mice
Authors: Titulaer H A C , Eling W M C , Crommelin D J A , Peeters P A M , Zuidema J
Published: April 2011

Free (0.6 mg), and liposome encapsulated chloroquine (0.6, 3 mg), were injected intraperitoneally, intramuscularly and subcutaneously in mice. Intraperitoneal administration of liposome-encapsulated chloroquine resulted in high and long lasting concentrations of chloroquine in the blood compared with intraperitoneal administration of free chloroquine. After administration of the liposome-encapsulated chloroquine the concentrations in the spleen were also higher, indicating that chloroquine liposomes reached the blood compartment intact after intraperitoneal administration. After intramuscular and subcutaneous administration the chloroquine liposomes acted as a local depot, giving a slower release from the subcutaneous fat layer than from the muscle depot. After the 0.6 mg dose a burst effect was found at about 7 h in most of the animals; this was not found after the 3 mg dose. This finding and the slower release after the 3 mg dose than after the 0.6 mg dose could be explained by the formation of aggregates after the injection.
The Use of Enzyme-linked Immunosorbent Assays to Study the Plasma Disposition of Sheep Polyclonal and Rat Monoclonal Digoxin-specific Fab Fragments in the Rabbit
Authors: Timsina M P , Hewick D S
Published: April 2011

The plasma disposition of sheep polyclonal digoxin-specific Fab (fragment antigen-binding) fragments has been studied in rabbits after their intravenous injection (1 mg kg−1) using enzyme-linked immunosorbent assays exploiting both the species-specificity (ELISAi) and the digoxin-specificity (ELISA2) of digoxin-specific Fab fragments. The log concentration versus time profiles were best described by a biexponential plasma disposition when either assay was used. Although the plasma concentrations determined by ELISA, and ELISA2 at each sampling time were not significantly different, there was a tendency for certain ELISA2 values to be higher. This resulted in the ELISA2-derived data giving a significantly longer distribution half-life (t 1/2α), but similar values for elimination half-life (t 1/2β), apparent volume of distribution at steady state (Vdss), and clearance. Using ELISA2, which was generally the more sensitive assay, to compare the plasma disposition of the sheep polyclonal digoxin-specific Fab fragments with rat monoclonal digoxin-specific Fab fragments, it was shown that the rat product had a shorter t 1/2α (11 vs 22 min), a t 1/2β which was not significantly different (253 vs 168 min), but a faster clearance (1.2 vs 0.7 mL kg−1 min−1), associated with a much larger Vdss (321 vs 108 mL kg−1). The extracellular fluid volume, using thiocyanate as a marker, was about 216 mL kg−1 for the nine rabbits used. This suggests that the rat preparation penetrates more extensively into the extracellular space and may indicate that some degree of extracellular binding or cell penetration is occurring.
The importance of nucleus accumbens in nicotine-induced locomotor activity
Authors: Fung Yiu K
Published: April 2011

Bilateral injections of either nicotine (200 μg) or cytisine (30 or 60 μg) into the nucleus accumbens elicited locomotor hyperactivity in rats. Pretreatment with mecamylamine (2 mg kg−1, s.c.) was effective in attenuating the stimulatory effect of either nicotine or cytisine. This study suggests that nicotinic agonists such as nicotine and cytisine produce their locomotor excitatory effects through stimulation of the mesolimbic dopaminergic pathway.
Release of Chlorpheniramine Maleate from Fatty Acid Ester Matrix Disks Prepared by Melt-extrusion
Authors: Prapaitrakul W , Sprockel O L , Shivanand P
Published: April 2011

Chlorpheniramine maleate was incorporated into disks consisting of glyceryl fatty acid esters, polyethylene glycol fatty acid esters or a combination of the two. A melt-extrusion process was used to prepare the matrix disks containing the drug. The release of the drug into distilled water, pH 1·2 buffer, and pH 7·5 buffer showed the expected square root of time dependence. An increase in the fatty acid ester hydrophilic-lipophilic balance (HLB) from 1 to 14 resulted in a 10-fold increase in the drug release rate from 0·25 ± 0·01 to 25·84 ± 1·29 mg cm−2 h−½ The maximum release rate was seen from the fatty acid ester with a melting point of 44°C. The pH of the dissolution medium had a small impact on the rate of drug release, but the rate of agitation had no significant influence on the rate of drug release. By blending a fatty acid ester of a high melting point (64°C) and a low HLB value of 2 with esters of lower melting points (33 to 50°C) or higher HLB values (10 to 14), it was possible to modify the release from 10·0 ± 0·70 to 21·5 ± 0·57 mg cm−2 h−½
Absorption of Iron from Iron Succinyl-protein Complexes by Mouse Small Intestine
Authors: Simpson R J , Raja K B , Peruzzi M , Cremonesi P
Published: April 2011

The absorption of iron from iron succinyl-protein complexes was investigated in mice. 59Felabelled succinyl-casein and -albumin complexes, [59Fe]ferritin and 59FeSO4, at doses of 20 or 200 μg of iron, were administered orally to normal mice or mice with absorption enhanced by chronic hypoxia. 59Fe from iron succinyl-protein was well absorbed in normal mice (> 10% of dose) and showed enhanced absorption in hypoxic mice (> 40% of dose). Intestinal uptake was predominantly by the duodenum for all compounds studied. In-vivo absorption of 59Fe from an iron succinyl-protein complex was studied using tied-off segments of mouse duodenum, jejunum or ileum of normal or hypoxic mice. Incubation for up to 15 min in duodenum or 60 min in ileum showed very little absorption of 59Fe. No enhancement of absorption was seen in hypoxic mice. It was concluded that absorption of the intact iron succinyl-protein complex cannot explain absorption seen after oral dosing.
Role of the Endothelium and Smooth Muscle Tone in the Dilator Response of the Rabbit Coeliac Artery to Histamine
Authors: Tayo ‘Fola
Published: April 2011

The role of the endothelium and vascular tone was studied on histamine-induced relaxation and contraction of the rabbit coeliac artery. Histamine contracted the tissue via the release of noradrenaline (NA), an action blocked by prazosin and mepyramine but not influenced by endothelial removal. Tachyphylaxis readily developed to histamine-induced contractions. After a moderate tone (40–55%) was induced with NA, histamine relaxed the tissues concentration-dependently. This relaxation was absent when the endothelium was removed indicating that the receptors involved are located on the endothelium. When the tone was increased to 80–85% with NA, relaxation could only be demonstrated after blocking H1-receptors. Removal of the endothelium did not influence this response. The relaxant effect of histamine in both preparations, however, was blocked by metiamide indicating that it is H2-receptor mediated. In the rabbit coeliac artery, endothelial H2-receptors are readily activated at moderate tone while muscular H2-receptors are stimulated at high tone after blocking H1-receptors. The predominance of H2-receptors in this artery may serve the physiological function of vasodilation in the blood vessels of the stomach.
The Effect of Nifedipine Alone or Combined with Cytotoxic Chemotherapy on the Mouse NC Carcinoma In-vitro and In-vivo
Authors: Gaffen J D , Stamford I F , Chambers E , Tavares I A , Bennett A
Published: April 2011

Effects of the calcium antagonist nifedipine on the response of the murine NC carcinoma has been examined alone and together with cytotoxic chemotherapy in-vitro and in-vivo. The cytotoxic drug combination of methotrexate and melphalan, or nifedipine alone (0·2–25 μg mL−1), caused a concentration-related reduction of NC cell growth in culture. At the lower concentrations, combination of the cytotoxic drugs with nifedipine resulted in an addition of the separate drug effects, but with drug concentrations that on their own approached maximal effectiveness the combined response was less than additive. NC tumours were excised from mice 14 days after inoculation s.c. with NC cells, weighed, and extracted for prostanoids. Mouse survival was determined up to day 121, and cancer spread was recorded postmortem. Nifedipine 1, 5 or 10 mg kg−1 had little or no effect on the tumour weight, tumour prostanoid content, metastasis to the lymph nodes or lungs, or on the increase of mouse longevity by the cytotoxic drugs.
Characterization of the variation between batches of Fast-Flo lactose using low frequency dielectric spectroscopy
Authors: Craig Duncan Q M , Davies Carole F , Boyd James C , Hakes Linda B
Published: April 2011

The dielectric response of four batches of lactose has been measured over a frequency range of 104 to 10−2 Hz. The spectra corresponding to three of the batches were identical, while the fourth showed a marked reduction in response. This particular batch has also been reported to exhibit longer disintegration times than the other three when formulated as a tablet. The potential use of dielectric spectroscopy as a means of screening batches of pharmaceutical materials is discussed.
Sulphate conjugation enhances reversible binding of drug to human serum albumin
Authors: Mizuma Takashi , Komori Michiyo , Ueno Masaharu , Horikoshi Isamu
Published: April 2011

Reversible binding of model compounds, their conjugated metabolites (sulphates and glucuronides), and also derivatives of the compounds, to human serum albumin (HSA) has been examined using an ultrafiltration method. p-Nitrophenol (P-NP), α-naphthol (α-NA) and β-naphthol (β-NA) were used as model compounds. Reversible binding of 500 μm  p-NP sulphate to 4% HSA (96·6 ± 0·35%, mean ± s.d. n = 3) was significantly higher (P < 0·001), whereas reversible binding of p-NP glucuronide to 4% HSA (33·3 ± 9·82%) was much lower (P < 0·001) than that of 500 μm  p-NP (90·9 ± 0·60%). Reversible binding of 500 μm  p-NP glucopyranoside to 4% HSA (25·8 ±2·82%) was comparable with that of the glucuronide, with which it is structurally similar. In contrast, reversible binding of 500 μm  p-NP phosphate, an anionic compound like p-NP sulphate, to 4% HSA (61·4 ± 5·28%) was significantly lower than that of p-NP (P < 0·001). Similar results were observed in reversible binding of sulphates of α-NA and β-NA. Significant differences of dissociation constants for HSA binding were observed between the parent compound (α- or β-NA) and its sulphate conjugate (P < 0·005 for α-NA and α-NA sulphate, P < 0·001 for β-NA and β-NA sulphate), but the number of binding sites was the same. These results indicated that sulphate conjugation enhances reversible binding of a parent compound to HSA by increasing the binding affinity of the parent compound to HSA. This enhancement appeared to be advantageous for preventing random distribution of this metabolite to organs in the body.
Inhibition of Dapsone-Induced Methaemoglobinaemia by Cimetidine in the Rat During Chronic Dapsone Administration
Authors: Coleman M D , Tingle M D , Park B K
Published: April 2011

Dapsone undergoes N-acetylation to monoacetyl dapsone as well as N-hydroxylation to a hydroxylamine which is responsible for the haemotoxicity (i.e. methaemoglobinaemia; Met Hb) of the drug. Since dapsone is always given chronically, we have investigated the ability of cimetidine to inhibit Met Hb formation caused by repeated dapsone administration. The drug was given (i.p.) to four groups (n = 6 per group) of male Wistar rats, 300–360 g. Group I received 10 mg kg−1 at 1, 24, 48 and 72 h. Group II received 10 mg kg−1 at 1, 8, 24, 32, 48, 56, 72 and 80 h. Groups III and IV received the drug as for groups I and II, respectively, as well as cimetidine (50 mg kg−1) 1 h before each dose of dapsone. Twice daily dapsone administration (Group II) resulted in a significantly greater (P < 0.05) Met Hb AUC (757 ± 135 vs 584 ± 115% Met Hb h), dapsone AUC (140 ± 17.5 vs 113 ± 130 μg h mL−1) and monoacetyl dapsone AUC (48.2 ± 18.3 vs 10.8 ± 4.6 μg h mL−1) compared with a single daily dapsone dose (group I). The administration of cimetidine before the once daily dose of dapsone (group III) resulted in a significant (P < 0.05) fall in Met Hb (302 ± 179 vs 584 ± 115% Met Hb h) and an increase in both the dapsone (151 ± 22.2 vs 113 ± 13.0 μg h mL−1) and monoacetyl dapsone AUC values (33.6 ± 5.8 vs 10.8 ± 4.0 μg h mL−1) compared with a single daily dose of dapsone (group I). Administration of cimetidine before the twice daily dose of dapsone (group IV) resulted in no significant change in Met Hb or monoacetyl dapsone levels, despite a marked increase in the AUC after dapsone compared with control (303 ± 53.2 vs 140 ± 17.5 μg h mL−1  P < 0.05; group II). The administration of a single dose of monoacetyl dapsone alone resulted in rapid production of methaemoglobinaemia (17.1 ± 7.2%) at 1 h; however, prior administration of cimetidine did not significantly affect methaemoglobin levels over 24 h (287.6 ± 77.9 vs 316.4 ± 120.2% Met Hb h). These studies indicate that although cimetidine may reduce Met Hb formation during chronic dapsone administration, dose reduction of dapsone is required to avoid haemotoxicity because of the increased accumulation of both parent drug and its monoacetyl metabolite.
Effects of Tableting Pressure on Hydration Kinetics of Theophylline Anhydrate Tablets
Authors: Otsuka Makoto , Kaneniwa Nobuyoshi , Kawakami Katsumi , Umezawa Osamu
Published: April 2011

The effects of tableting pressure on hydration kinetics of types I and II theophylline anhydrate tablets at 95% relative humidity, 35°C, have been studied by using various kinetic equations. Relations between tablet expansion and hydration were studied. Samples of 2 cm diameter tablets (1 g) were compressed at 5, 10 and 20 MPa. The hydration of types I and II tablets decreased with increased tableting pressure. The time required for 50% hydration of 2 cm diameter tablets, compressed at various pressures suggests that the tablet hydration rate was affected by the tableting pressure. Types I and II tablets expanded 11.37-16.75% in volume during hydration to the monohydrate. The thickness expansion of the tablets exceeded the diameter expansion as the tablet structure was not uniform owing to the orientation of particles during the compression. The final expansion ratio of the tablets increased with increased tableting compression pressure. The Hancock Sharp constant (m) and fitting of the kinetic data to a suitable model suggested that the hydration of theophylline anhydrate tablets followed the two-dimensional phase boundary equation (type I tablets) or the three-dimensional phase boundary equation (type II tablets).
Response of canine cerebral arteries to endothelin-1
Authors: Garcia J L , Monge L , Gómez B , Diéguez G
Published: April 2011

The effects of endothelin-1 (10−10-10−7 M) were isometrically recorded in 4 mm cylindrical segments from the middle cerebral artery of dogs. Cumulative application of endothelin-1 produced marked, sustained contraction of arteries in a concentration-dependent-manner, the maximal response being about 2.6 times higher than that achieved with KCl (50 mM). The contraction by endothelin-1 was unaffected either by endothelium removal or by the cyclo-oxygenase inhibitors indomethacin (10−6 M) and meclofenamate (10−6 M). In a Ca2+ -low (25 μM) solution the endothelin-1-induced arterial contraction was decreased. Therefore, the cerebral vasoconstriction induced by endothelin-1 could be caused by activation of specific receptors located on smooth muscle cells which would lead to the influx of extracellular calcium and vascular musculature contraction.
Comparison of the effects of hydralazine and nifedipine on contractions and 45Ca influx of rat aorta
Authors: Orallo Francisco , Gil-Longo José , Bardán Belén , Calleja José M
Published: April 2011

The effect of the vasodilator hydralazine has been compared with nifedipine on KCl-(K+) (60 mM) and noradrenaline-(NA) (10 μM) induced 45Ca uptake and contractile responses in rat aorta arterial strips without endothelium. Hydralazine (0.5–10 mM) was equally effective in relaxing K+ - (IC50 = 2.2 ± 0.17 mM) and NA-(IC50 = 3.06 ± 0.25 mM) induced tension, the degree of relaxation depending on the dose. Nifedipine totally inhibited K+-(IC50 = 3.16 ± 0.28 nM) induced contractions with lower doses than were necessary to relax (up to 54.0 ± 4.1% with supramaximal concentrations) NA-induced contractions (IC50 = 1.48 ± 0.12 μM). In the experiments in a calcium-free medium, nifedipine (1 μM) had no effect on the NA-(10 μM) induced contractions whereas hydralazine (1 mM) strongly inhibited them. Nifedipine did not affect the basal uptake of 45Ca but the induced uptakes were reduced to 66.3 ± 3.2% (K+) and 65.5 ± 4.1% (NA) of their basal values. Hydralazine did not affect the basal uptake of 45Ca nor that induced by the two vascoconstrictor agents. These results suggest that nifedipine acts on the cell membrane by blocking the movements of calcium through the voltage-dependent and receptor-operated calcium channels, whilst hydralazine has an intracellular effect.
Plasma volumes, blood volumes, and plasma protein concentrations after moderate haemodilution with Fluosol-DA or normal saline in the rat
Authors: Shrewsbury Robert P
Published: April 2011

Plasma volumes, blood volumes, and plasma total protein, albumin, and bilirubin concentrations have been determined in rats for 72 h following 20 or 40 mL kg−1 haemodilution with Fluosol-DA or 0.9% Nad. Haemodilution with 20 mL kg−1 of either haemodiluent had no influence on the measured values. Plasma and blood volumes did not change after Fluosol-DA haemodilution at 40 mL kg−1, but albumin and bilirubin concentrations were decreased for 72 h. Only bilirubin concentrations were decreased for 72 h following haemodilution with 40 mL kg−1 of 0.9% NaCl. It was concluded that changes in a drug's plasma protein binding, and not the plasma or blood volume, are responsible for the reported alterations in a drug's apparent volume of distribution after haemodilution.
Effect of Chronic Nicotine Treatment and Withdrawal on Rat Striatal D1 and D2 Dopamine Receptors
Authors: Kirch Darrell G , Taylor Timothy R , Creese Ian , Xu Shou-Xi , Wyatt Richard Jed
Published: April 2011

The effects on rat striatal dopamine receptors after chronic nicotine administration (3 and 12 mg kg−1 day−1), and after withdrawal from chronic nicotine (12 mg kg−1 day−1), were studied. After 21 days of continuous minipump infusion, the control (saline) and nicotine-treated rats were killed. The nicotine-withdrawal rats were killed on day 28, 7 days after pump removal. Radioligand studies were performed to determine D1 ([3H]SCH23390) and D2 ([3H]spiperone) striatal dopamine receptor affinity (Kd) and maximum binding (Bmax). Dopamine inhibition of antagonist binding at 3 concentrations and the effect of 0·3 Mm GTP on binding affinity were examined. No statistically significant differences between control and nicotine treatment or withdrawal groups were noted in either D1 or D2 receptor Kd or Bmax. Although nicotine has been shown to affect nigrostriatal dopamine release, chronic treatment does not appear to alter overall striatal dopaminergic receptor binding parameters.
Calcium-calmodulin-dependent Activation of Adenylate Cyclase in Prostaglandin-induced Electrically-monitored Intestinal Secretion in the Rat
Authors: Hardcastle J , Hardcastle P T , Ayton B , Chapman J , Macneil S
Published: April 2011

The calcium-calmodulin antagonist 5-iodo-C8-W7 inhibited the PGE2-induced stimulation of cAMP production by isolated enterocytes from rat small intestine. It also reduced the secretory response of intestinal sheets to PGE2, measured as a rise in short-circuit current. It did not however, inhibit the electrical responses to forskolin and dibutyryl cAMP, nor to acetylcholine, a secretagogue whose effect is not mediated by cAMP. It is concluded that the receptor-mediated activation of adenylate cyclase and the subsequent secretory response are dependent upon calcium-calmodulin.
Time Course of PAF Formation by Gastrointestinal Tissue in Rats After Castor Oil Challenge
Authors: Pintoy A , Autore G , Mascolo N , Sorrentino R , Biondi A , Izzo A A , Capasso F
Published: April 2011

When castor oil was administered by gavage to rats, the duodenum and jejunum, but not the stomach, produced large amounts of platelet activating factor 3–7 h after oil challenge with a peak at 3 h. Intraluminal release of acid phosphatase was also markedly increased in the duodenum and jejunum of castor oil-treated rats, especially 3–5 h after oil challenge. No increase was observed in the stomach. There was a correlation between elevated release of acid phosphatase and intestinal hyperaemia.
Effect of Calcium Channel Blockers on Postprandial Gastrointestinal Motility in the Dog
Authors: De Ponti Fabrizio , Einaudi Arturo , Cosentino Marco , D'Angelo Luigi , Frigo Gian Mario , Crema Antonio
Published: April 2011

We have compared the ability of nifedipine and lacidipine, a new 1,4-dihydropyridine, to interfere with postprandial gastrointestinal motility. Five conscious dogs, fitted with 8 bipolar electrodes along the gastrointestinal tract, were studied. Gastrointestinal spike activity was evaluated by means of a computer system. Lacidipine (8 μg kg−1) was administered as an i.v. bolus immediately followed by a 10 μg kg−1 h−1 i.v. infusion for 3 h, starting 30 min before a standard meal. This dose of lacidipine decreased systolic blood pressure by approximately 20%. Nifedipine was used at equihypotensive doses (30 μg kg−1 i.v. bolus followed by 300 μg kg−1 h−1 i.v. infusion). Lacidipine had no effect on either gastric or intestinal postprandial spike activity. Nifedipine significantly delayed the appearance of the fed pattern and reduced the number of spikes in the small bowel, while it had no effect on gastric spike activity. We conclude that equihypotensive doses of lacidipine and nifedipine differ in their effects on the gastrointestinal tract, lacidipine having a better cardiovascular selectivity profile than nifedipine, and that the sensitivity to nifedipine varies in different parts of the gut.
Investigation of the 5-HT receptor mediating relaxation in guinea-pig proximal colon
Authors: Elswood C J , Bunce K T
Published: April 2011

5-Hydroxytryptamine (5-HT) induced concentration-related relaxations (EC50 = 9·1 μm) of guinea-pig proximal colon pretreated with ketanserin (1 μm) and ondansetron (10 μm). This 5-HT-induced effect was neuronally mediated since it was blocked by tetrodotoxin (0·3 μm). 5-Carboxamidotryptamine was a full agonist and ten times more potent than 5-HT. α-Methyl-5-HT was a partial agonist. 2-Methyl-5-HT was without effect. Methysergide and metergoline were antagonists of 5-HT producing parallel shifts at 0·1 μm but unsurmountable antagonism at higher concentrations. pKB values of 8·0 and 7·3 were calculated for methysergide and metergoline, respectively. This study has identified a 5-HT-induced relaxation of guinea-pig proximal colon which is mediated via a neuronal 5-HT1-like receptor. However, the subtype has yet to be established.
Inhibition by diltiazem of left ventricle collagen proliferation during renovascular hypertension development in rats
Authors: Baxter C F
Published: April 2011

Diltiazem administered in drinking water (0·7 mg mL−1) to Goldblatt two kidney-one clip rats over 16 weeks did not prevent the development of hypertension and left ventricular hypertrophy (LVH). When the collagen content of the left ventricles was assayed (as hydroxyproline), it was found that the fibrosis, characteristic of LVH, was inhibited by diltiazem treatment, despite the fact that hypertension and LVH had developed. This study provides some indirect evidence for the notion that the collagen and myocyte compartments of the myocardium are under separate influences during LVH development in renovascular hypertension.
Visual recovery using small dilating eye drops
Authors: Gray R H , Franklin S J , Reeves B C
Published: April 2011

It is well established that reduced size dilating eye drops of 1% tropicamide and 10% phenylephrine (micro drops) are effective for clinical purposes. Excellent pupil dilatation (mydriasis) is achieved and pupil constriction does not occur in response to light. In this study, the effect of micro drops of 1% tropicamide on distance and near visual recovery was compared with standard drops in a group of 20 healthy volunteers. For each person studied, one eye was selected at random to be tested first with the standard drop size, and then after a minimum of one week, the same eye was again tested using a drop of the same drug one fifth standard size. An iris photograph, Snellen visual acuity at 6 m, and reading visual acuity was obtained for each test procedure: before drop instillation and at 30 min, 1, 2 and 4 h after drug instillation. Use of the micro drops caused a small but statistically significant improvement in the rate of recovery of distance and near visual acuity. These findings, allied to the known beneficial effects of reduced systemic absorption using micro drops, lend further weight to the argument that mydriasis may be achieved more safely, with fewer side effects, and with earlier return of normal vision when reduced size drops are used. It is hoped that practical micro drop dispensers will be developed.
Dispositional study of opioids in mice pretreated with sympathomimetic agents
Authors: Dambisya Yoswa M , Chan Kelvin , Wong Chak-Lam
Published: April 2011

Brain and plasma levels of morphine and codeine were determined by an assay method involving solid-phase extraction and ion-pair reversed phase HPLC. Detection was by a variable wavelength UV-detector (for codeine) and an amperometric electrochemical detector (for morphine) coupled in series. Ephedrine or phenylpropanolamine pretreatment did not interfere with the plasma disposition of morphine, evidenced by overlapping plasma concentration-time profiles. Brain opioid levels were equally unaffected by sympathomimetic pretreatment. The relative ratios of brain to plasma concentrations at the time corresponding to the respective peak anti-nociceptive activity for morphine and codeine revealed no significant differences. It is concluded that single doses of ephedrine and phenylpropanolamine do not affect the disposition of morphine and codeine in mice.
Anorectic activity of fluoxetine and norfluoxetine in mice, rats and guinea-pigs
Authors: Anelli M , Bizzi A , Caccia S , Codegoni A M , Fracasso C , Garattini S
Published: April 2011

The present study aimed to establish the role of the metabolite norfluoxetine in the anorectic activity of fluoxetine, and to relate the anorectic doses (ED50) to the brain concentrations of the parent drug and its metabolite. Fluoxetine showed anorectic activity at increasing intraperitoneal doses (ED50 = 391, 34·7 and 21·7 μmol kg−1 in mouse, rat and guinea-pig, respectively) and norfluoxetine was slightly more active (24·3, 22·9 and 19·1 μmol kg−1, respectively) in all three species. In terms of maximum concentration (Cmax) and area under the curve (AUC) within the experimental period (0–90 min), brain concentrations varied widely and were poorly related to the dose; guinea-pig appeared to be much more sensitive to fluoxetine than was mouse or rat. Administered norfluoxetine was present in the brain of the three species in approximately the same order as fluoxetine, i.e. lower in guinea-pig than in mouse or rat. The Cmax and AUC of norfluoxetine after fluoxetine administration was 50–60% of the values after an equiactive dose of norfluoxetine in mouse and guinea-pig, and more than 80% in rat.
The effect of thymidine on the antibacterial and antiviral activity of zidovudine
Authors: Shepherd A J , Barr P , Lewin C S
Published: April 2011

The effect of thymidine and deoxyadenosine on the antiviral and antibacterial effect of zidovudine was studied in human immunodeficiency virus type 1 (HIV-1) Escherichia coli and Salmonella typhimurium. In quantitative assays, 10 μg mL−1 thymidine was shown to increase the 50% inhibitory concentration (IC50) of zidovudine for HIV-1 by approximately 100-fold and to reduce zidovudine (1 μm)-induced protection of C8166 cells from 204 to 0·18 log syncytial-forming units. Thymidine also antagonized the antibacterial effect of zidovudine for two E. coli and three S. typhimurium species in a dose-dependent manner; 10 μg mL of thymidine increased the minimum inhibitory concentration of zidovudine for E. coli strains by 10–40-fold and for S. typhimurium strains by three-fold. Deoxyadenosine reduced the minimum inhibitory concentration of zidovudine against all five bacterial strains but had no effect on the IC50 of zidovudine for HIV-1, nor did it significantly reverse the antagonism of the antibacterial and antiviral activity of thymidine. The induction of the SOS response in E. coli was reversed in a dose-dependent manner by thymidine while the presence of deoxyadenosine increased induction of the SOS response by zidovudine at suboptimal concentrations.
Effects of long-term laxative treatment on neuropeptides in rat mesenteric vessels and caecum
Authors: Milner Pamela , Belai Abebech , Tomlinson Annette , Hoyle Charles H V , Sarner Shula , Burnstock Geoffrey
Published: April 2011

In order to investigate the toxic effects of long-term treatment with anthraquinone laxatives, rats were fed either chocolate alone, or chocolate adulterated with senna or danthron (1,8-dihydroxyanthraquinone) for 5 months. Mesenteric blood vessels and the outer muscle layers of the caecum, together with the myenteric plexus, were examined using ultrastructural, histochemical, immunohistochemical and immunoassay techniques. There was no ultrastructural evidence of degeneration in either the mesenteric vessels or the caecum. In the mesenteric vessels, levels of neuropeptide Y were significantly reduced in the danthron-fed rats, but levels of substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were unaffected by all treatments. In the caecum, VIP-, SP- and CGRP-immunoreactivity and catecholamine-fluorescence were unchanged by the laxative treatments.
Illicitly Imported Heroin Products (1984 to 1989): Some Physical and Chemical Features Indicative of Their Origin
Authors: O'Neil Philip J , Pitts Jane E
Published: April 2011

Samples taken from seizures of imported illicit heroin preparations of known geographical origin have been examined. The typology developed in two previous surveys of illicit heroin products is applicable to many of the samples studied in this work, although significant changes have occurred in the chemical profile of illicit heroin products from certain geographical regions. It remains possible, however, to give an opinion as to the origin of many samples of illicit heroin of unknown provenance. The observation in the previous surveys that unrelated samples of illicit heroin possess unique chemical profiles has been confirmed by the present results.
Opioid Properties of Some Isomeric Derivatives of Phencyclidine
Authors: Casy A F , Dewar G H , Al-Deeb O A A
Published: April 2011

The phencyclidine analogues (±)-α-, (±)-β-, and (+)-α- and (–)-α-4-hydroxy-3-methyl-4-phenyl-l-(1-phenylcyclohexyl)piperidine, all with known relative and absolute stereochemistry, have been prepared, and their analgesic potencies related to corresponding prodines. In contrast to the prodines, the (±)-α-phencyclidine analogue was a more potent analgesic than its diastereoisomer, while in agreement with observations in the prodine series, the 3R, 4S-α-enantiomer displayed substantially greater potency than its mirror image form.
Investigation of the Interaction Mode of Phenothiazine Neuroleptics with α1-Acid Glycoprotein
Authors: Miyoshi Toshimi , Sukimoto Katsuaki , Otagiri Masaki
Published: April 2011

The interaction of phenothiazine neuroleptics with α1-acid glycoprotein (AGP) and desialylated AGP (asialoAGP) has been investigated by fluorescence, circular dichroism spectroscopy and by equilibrium dialysis. The binding parameters of phenothiazines obtained from fluorescence agreed closely with those obtained from circular dichroism and equilibrium dialysis. The binding affinities (nK) to AGP were slightly higher than binding affinities to asialoAGP. Attempts to correlate binding affinities with partition coefficients suggested that hydrophobic forces were mainly involved in the binding of phenothiazine neuroleptics to AGP and asialoAGP. However, electrostatic interaction was also found to be involved as suggested by experimental data obtained from the influence of oleic acid and caesium chloride on the drug binding to the two proteins.
Effects of Anaesthetic Agents on Pressor Response to β-Blockers in the Rat
Authors: Abdelrahman Aly , Wang Yong-Xiang , Pang Catherine C Y
Published: April 2011

It has been shown that paradoxical pressor response to a β-adrenoceptor antagonist occurs in conscious rats pretreated with an α-adrenoceptor antagonist. This study examines the influence of anaesthetic agents on mean arterial pressure (MAP) response to a η-blocker. Cumulative dose-response curves of propranolol (non-selective), ICI 118,551 (β2-selective) and atenolol (β1-selective) were constructed in phentolamine-treated rats anaesthetized with urethane, pentobarbitone or halothane. I.v. injections of all three β-blockers caused dose-dependent increases in MAP in urethane-anaesthetized rats. In halothane-anaesthetized rats, propranolol and atenolol did not alter MAP while ICI 118,551 caused a small dose-dependent increase in MAP. In the presence of pentobarbitone, none of the β-blockers raised MAP. In the second series of experiments, a single i.v. bolus dose of propranolol was given in phentolamine-treated rats anaesthetized with pentobarbitone, amobarbitone, ketamine or chloralose. Propranolol did not affect MAP in rats anaesthetized with pentobarbitone, amobarbitone and chloralose but it partially reversed the hypotensive effect of phentolamine in ketamine-anaesthetized rats. In the third series, propranolol or atenolol was i.v. injected in pentobarbitone-anaesthetized rats treated with both phentolamine and adrenaline. Both propranolol and atenolol raised MAP. Our results show that anaesthetic agents differentially affect the MAP response to a β-blocker.
The Optical Resolution of Racemic Chlorpheniramine and Its Stereoselective Pharmacokinetics in Rat Plasma
Authors: Sakurai Eiichi , Yamasaki Seiji , Iizuka Yukisumi , Hikichi Noboru , Niwa Hiroshi
Published: April 2011

An ovomucoid-conjugated column has been developed for the chiral stationary-phase liquid chromatographic resolution of racemic chlorpheniramine with a quantitation limit of 0·05 μg mL−1. The assay was used to study the stereoselective kinetics of chlorpheniramine enantiomers in rats. After bolus intravenous administration of racemic chlorpheniramine maleate (20 mg kg−1), plasma concentration of the (–)-form was higher than that of the (+)-form. In the elimination phase, the concentrations of (+)- and (–)-chlorpheniramine in the plasma declined biexponentially with half-lives of 18·2 and 50·0 min, respectively. Although there was no significant difference in blood-to-plasma concentration ratio of both enantiomers, the apparent total blood clearance of (+)-chlorpheniramine was twice as large as that of the (–)-isomer. Binding of (–)-chlorpheniramine to rat plasma protein was stronger than that of (+)-chlorpheniramine suggesting stereoselective pharmacokinetics may be due to a difference in the plasma protein binding.
An Improved Model for Studies on Transdermal Drug Absorption In-vivo in Rats
Authors: Vollmer U , Müller B W , Wilffert B , Peters T
Published: April 2011

In rats, transdermal drug absorption can be studied under physiological conditions by cannulating the peripheral skin vein, draining the area of the skin which is used for drug application, and collecting the blood. This method leads to decreased blood volume, which causes a reduction in skin blood flow and limits the maximal duration of the experiment. We improved the model by replacing the collected blood with blood from donor animals, so enabling the measurement of transdermal absorption over a period of 5 h under near constant conditions of blood pressure, haematocrit and skin blood flow. The model was applied to the transdermal absorption of [3H]prazosin and [3H]scopolamine and their permeability coefficients, fluxes and lag-times were determined. The model is suitable for measurements of transdermal drug absorption under in-vivo conditions, both for comparison of absorption profiles of different drugs and of the same drug in different formulations.
Phorbol Dibutyrate Induces Contractions in Bovine Cerebral Arteries by an Extracellular Calcium-independent Mechanism
Authors: Encabo Araceli , Ferrer Mercedes , Marín Jesús , Peiró Concepción , Redondo Juliana , De Sagarrat Ma Rosa , Balfagón Gloria
Published: April 2011

The aim of the present study was to analyse the ability of phorbol 12,13-dibutyrate (PDB) to activate protein kinase C (PKC), measured by its capacity to translocate the enzyme from the cytosol to the membrane fraction, as well as to induce vasconstrictive responses in segments from branches of bovine cerebral arteries. PDB (0·1 μm) produced a marked translocation of PKC activity from the cytosolic to the membranous fraction. This drug induced concentration-dependent contractions which were slow in onset. The contraction elicited by PDB was reduced by the PKC inhibitor, staurosporine (1 and 10 Nm), but unaltered by both Ca2+-free medium containing 3 Mm EGTA and the Ca2+-channel antagonist, nifedipine (1 μm). Preincubation of segments with PDB (10 and 30 Nm) reduced the vasoconstriction elicited by 5-hydroxytryptamine (5-HT) in a concentration- and preincubation time-dependent manner. These data indicate that bovine cerebral arteries possess cytosolic and membranous PKC activities, that the vasoconstrictive responses induced by PDB were independent of extracellular Ca2+, that cytosolic C-kinase is translocated to the membrane and probably down-regulated by PDB, and that this enzyme is not involved in 5-HT responses, but is down-regulated by PDB.
Effects of NZ-107 on Airway Inflammation and Cell Activation in Guinea-pigs
Authors: Iwama Takehisa , Nagai Hiroichi , Koda Akihide
Published: April 2011

The effects of NZ-107 on some airway inflammation models and the generation of superoxide anion (O2−) were studied in guinea-pigs. Airway inflammation was caused by intra-tracheal injection of murine recombinant interleukin-5 (mrIL-5, 15 μg/animal), inhalation of platelet-activating factor (PAF, 0·003%) and intra-tracheal injection of leukotriene B4 (LTB4, 10 μg/animal). NZ-107 (4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone) at a dose of 50 mg kg−1, intraperitoneally reduced mrIL-5- and PAF-induced eosinophilia. This compound at a dose of 25 and 50 mg kg−1 also suppressed LTB4-induced eosinophilia and neutrophilia in bronchoalveolar lavage fluid (BALF). On the other hand, prednisolone at a dose of 20 mg kg−1, i.p., prevented the increased number of macrophages, eosinophils and neutrophils induced by mrIL-5, the increased number of eosinophils induced by PAF and the increased number of eosinophils and neutrophils induced by LTB4 in BALF. Furthermore, both drugs reduced mrIL-5- or PAF-induced increase in the number of airway epithelial cells in BALF. The generation of O2− was measured by the method of cytochrome C reduction. NZ-107 (10–100 μg mL−1) attenuated PAF- and FMLP-induced O2− production from macrophages and reduced PAF-induced O2− generation by eosinophils but had no effect on that from neutrophils. These results indicate that NZ-107 prevents the increased number of pulmonary eosinophils and airway epithelial cells and the activation of macrophages and eosinophils, suggesting that NZ-107 may be useful as a remedy for airway inflammatory diseases such as bronchial asthma.
Different Modes of Blockade by p-Phenylene-polymethylene Bis-ammonium Compounds of the Nicotinic Acetylcholine Receptor Channel in Skeletal Muscle Cells of Mice
Authors: Nojima Hiroshi , Kimura Ikuko , Muroi Masashi , Kimura Masayasu
Published: April 2011

The structure-activity relationships of five newly synthesized p-phenylene-polymethylene bis-ammonium (PMBA: C6H4[(CH2)nN+R3]2) compounds were investigated on the blockade of the nicotinic acetylcholine receptor (nAChR) channel. The cell-attached patch clamp configuration was used to measure single-channel currents in the endplate region of single flexor digitorum brevis muscle cells of adult mice. The bis-trimethylammonium compounds PMBA-1 (n = 4, R = CH3) and PMBA-23 (n = 6, R = CH3) produced channel opening above 0·3 μm and open channel blockade above 10 and 3 μm, respectively. The bis-triethylammonium compounds PMBA-43 (n = 1, R = CH2CH3) and PMBA-24 (n = 6, R = CH2CH3) showed no channel opening action, but PMBA-21 (n = 4, R = CH2CH3) opened channels weakly at 3 and 10 μm. These bis-triethylammonium compounds exerted different blocking actions on acetylcholine-activated channel currents. Above 10 μm PMBA-43, like tetraefhylammonium, blocked open channels by decreasing the mean open time by rapid partial closing of the channel during the open-phase. At 10 μm, PMBA-21 blocked open and closed channels by decreasing the opening frequency by means of an irregular sequence of short pulses. At 0·3 μm, PMBA-24 blocked closed or nonconducting channels by decreasing the opening frequency without producing changes in mean open time. These results indicate that by lengthening the distance between two nitrogen atoms in the bis-triethylammonium group of PMBA, open channel blockade changes to closed channel blockade. PMBA compounds were classified into three types of nAChR channel blockers: PMBA-43 as an open, PMBA-21 as an open and closed, and PMBA-24 as a closed or nonconducting channel blocker.
In-vitro Permeability to Salicylic Acid of Human, Rodent, and Shed Snake Skin
Authors: Harada Kayo , Murakami Teruo , Kawasaki Eiko , Higashi Yutaka , Yamamoto Shoso , Yata Noboru
Published: April 2011

In-vitro permeability to salicylic acid of human, rodent, and shed snake skin has been examined for the purpose of selecting model membranes for human skin corresponding to different anatomic sites, since a marked regional variation is suggested among the different sites. The greatest permeability to salicylic acid was observed in the scrotum, that of the sole was negligible. The cheek, neck, and inguinal skin seemed more permeable than the breast, back, thigh, lower leg, or foot skin. Shed snake and skin of hairless rat were found to show similar permeability to human breast and thigh skin. Wistar rat and nude mouse skin showed similar permeability to human cheek, neck, and inguinal skin.
Light stability of molsidomine in infusion fluids
Authors: Vandenbossche G M R , De Muynck C , Colardyn F , Remon J P
Published: April 2011

The influence of artificial light, daylight or stimulated sunlight on the stability of molsidomine was investigated. In static experiments an 80 μg mL−1 solution of molsidomine in saline was stored in an unprotected infusion bag. During dynamic experiments the molsidomine solution (80 μg mL−1) was dropped at 12·5 mL h−1 from an unprotected infusion bag, from an infusion bag covered with aluminium-foil, or from an infusion bag protected with a UV-cover. Either unprotected infusion tubing or infusion tubing with a UV-filter were connected to the infusion bags. Static as well as dynamic experiments showed a half-life of about 20 min for the unprotected molsidomine solutions, when placed behind a window during a sunny day. Protection from light of the infusion bag but not of the infusion tubing had only a minor influence on the drug half-life. Protection of the infusion bag and the infusion tubing with a UV-filter increased the half-life to several days. These results confirm that both the infusion bag and the infusion tubing need adequate light protection during molsidomine administration.
Hydrolysis of Partially Saturated Egg Phosphatidylcholine in Aqueous Liposome Dispersions and the Effect of Cholesterol Incorporation on Hydrolysis Kinetics
Authors: Grit Mustafa , Zuidam Nicolaas J , Underberg Willy J M , Crommelin Daan J A
Published: April 2011

Hydrolysis kinetics of partially hydrogenated egg phosphatidylcholine (PHEPC) were studied as a function of pH, temperature, buffer concentration, ionic strength, and the effect of cholesterol incorporation. Results showed that PHEPC has a maximum stability at around pH 6·5. General acid base catalysis was observed for acetate, HEPES and Tris buffers. Increasing the ionic strength of the buffer solutions did not influence the hydrolysis kinetics. The relationship between the observed hydrolysis rate constants and the temperature could adequately be described by the Arrhenius equation. Incorporation of cholesterol did not affect the hydrolysis kinetics. This result indicates that the hydrolysis kinetics of PHEPC do not depend on the changes in bilayer rigidity induced by cholesterol incorporation. Cholesterol is stable under the experimental conditions used in this study; no changes were observed in cholesterol concentration over the experimental time interval.
Hydrolysis and Stability of Acetylsalicylic Acid in Stearylamine-containing Liposomes
Authors: Habib Muhammad J , Rogers James A
Published: April 2011

The hydrolysis and the stabilization of acetylsalicylic acid (ASA) in liposomes at 30°C were studied. The liposomes consisted of dimyristoylphosphatidylcholine (DMPC) and stearylamine. At pH 4·0 and 8·0, the pseudo-first-order rate constants (kobs) in DMPC: stearylamine (2:1 mole ratio) liposomes were approximately 60% of the values in control solutions (kB) if ASA was incorporated via the organic phase. In contrast, when ASA was added via the aqueous phase, kobs = kB at pH 4·0 but kobs < kB at pH 8·0 and kobs increased with the fraction of stearylamine in the liposomes. However, when ASA was added via the organic phase, reactions occurred which resulted in the loss of ASA as a function of the time period between phase admixture and the point of film hydration. A product of the reactions was determined by IR and TLC to be N-stearylacetamide. Both the initial loss of ASA and the increase in stability decreased as the DMPC: stearylamine mole ratio increased. A mechanism of aminolysis occurring in the organic solvent and at liposome surfaces between ASA and stearylamine or DMPC at pH 8·0 has been suggested. It is concluded that the orientation of ASA and the ordered structural environment of the bilayers minimizes the aminolytic and hydrolytic reactions.