bluuebunny/crossref_metadata_2025 huggingface dataset:
Glutaraldehyde Cross-linked Bovine Casein Microspheres as a Matrix for the Controlled Release of Theophylline: In-vitro Studies
Authors: Latha M S , Jayakrishnan A
Published: April 2011

A controlled release dosage form of theophylline in the form of microspheres using the milk protein casein as the matrix is described. Glutaraldehyde cross-linking of an aqueous alkaline solution of the protein containing the drug, dispersed in a mixture of dichloromethane/hexane having ca. 1% of an aliphatic polyurethane as the suspension stabilizer, led to the formation of the drug-loaded microspheres. Drug incorporation efficiency of around 80% could be achieved by the technique. Release profiles of the drug were examined in simulated gastric and intestinal fluids at 37°C. It was observed that the release was diffusion-controlled and followed the Higuchi model. Release characteristics were influenced by the cross-linking density, particle size and the extent of loading. Data obtained indicate that the natural milk protein casein could be used as a matrix for sustained release oral dosage forms.
A Study of the Percutaneous Absorption-enhancing Effects of Cyclodextrin Derivatives in Rats
Authors: Vollmer U , Müller B W , Peeters J , Mesens J , Wilffert B , Peters T
Published: April 2011

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) and 2,6-dimethyl-β-cyclodextrin (D-β-CyD) were studied for transdermal penetration enhancement of the cytochrome P450 inhibitor liarozole by an in-vivo transdermal absorption rat model. The mode of action of penetration enhancement was investigated by differential scanning calorimetry (DSC). In-vivo, HP-β-CyD, as a 20% aqueous solution, increased the absorption of liarozole approximately threefold and a 20% aqueous solution of D-β-CyD decreased the percutaneous absorption of liarozole in blood by a factor of 0·6. However, pretreatment with D-β-CyD (20%, 4 h) enhanced the transdermal absorption 9·4-fold. In the DSC experiments the thermal profile of human stratum corneum was practically unchanged after treatment with HP-β-CyD, but treatment with D-β-CyD revealed an interaction of D-β-CyD with the protein and lipid fraction. Thus the results from DSC and those from the permeability experiments revealed that D-β-CyD acts as a transdermal absorption enhancer by changing the stratum corneum barrier whereas HP-β-CyD influences the partitioning behaviour of the drug in the skin.
Metabolism and Transport of the Pentapeptide Metkephamid by Brush-border Membrane Vesicles of Rat Intestine
Authors: Langguth Peter , Bohner Viviane , Biber Jürg , Merkle Hans P.
Published: April 2011

Intestinal metabolism and transport of the pentapeptide metkephamid (Tyr-d-Ala-Gly-Phe-N-Me-Met-NH2) were studied using isolated brush-border membranes from the rat. Analysis of the metabolic fragments of enzymatic hydrolysis revealed that cleavage of the N-terminal peptide bond leads to the formation of tyrosine and a tetrapeptide d-Ala-Gly-Phe-N-Me-Met-NH2. The inactivation was due to aminopeptidase N activity and could be inhibited by peptidase inhibitors puromycin, bacitracin and certain dipeptides. Transport studies demonstrated uptake of the intact pentapeptide into the intra vesicular space of the vesicles. The transport was a first-order process; no participation of known intestinal peptide carrier systems in the transport of metkephamid could be shown. Modelling of simultaneous metabolism and transport kinetics suggests strategies to improve the fraction absorbed of a peptide by either decreasing its affinity to the metabolizing enzymes (increase Km) or decreasing the concentration of the metabolizing enzymes e.g. by delivering the peptide to an absorption site with reduced enzymatic activity (decrease Vmax) or increasing its absorption velocity.
Antihypertensive Action of Geraniin in Rats
Authors: Cheng Juei-Tang , Chang Shu-Shi , Hsu Feng-Lin
Published: April 2011

The effects of geraniin, one of the ellagitannins purified from the leaves of Sapium sebiferum, on blood pressure were investigated in the spontaneously hypertensive rat (SHR). A single intravenous bolus injection of geraniin into anaesthetized SHRs lowered the arterial mean blood pressure in a dose-dependent manner without affecting the heart rate. A similar action was also observed in the normotensive (WKY) rat that received this compound at a higher dose. Geraniin did not modify the baroflex sensitivity in the phenylephrine-challenged SHR. This tannin reduced the plasma noradrenaline in a dose-dependent fashion which was not influenced by adrenalectomy. Failure of the antagonists, idazoxan and yohimbine for α2-adrenoceptors as well as haloperidol and domperidone for dopamine receptors, to reverse the antihypertensive actions of geraniin ruled out the possible mediation of these receptors. Moreover, geraniin attenuated the pressor responses to exogenous noradrenaline and Bay K 8644 to a similar degree, indicating the direct effect of this compound on vascular activity in rats. These results suggest that geraniin possesses the ability to lower systemic blood pressure through the reduction of noradrenaline release or by direct vasorelaxation.
Antithyroid Action of Ketoconazole: In-vitro Studies and Rat In-vivo Studies
Authors: Comby Francis , Lagorce Jean-François , Buxeraud Jacques , Raby Claude
Published: April 2011

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol−1), and to inhibit lactoperoxidase (IC50 2 × 10−4 m). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.
Inhibition of Platelet Thromboxane Formation and Phosphoinositides Breakdown by Diisoeugenol
Authors: Lin Chien-Huang , Kuo Yeh-Hsiong , Lin Yun-Lian , Teng Che-Ming
Published: April 2011

Diisoeugenol inhibited the platelet aggregation and ATP release of rabbit platelets caused by ADP, arachidonic acid, platelet-activating factor (PAF), collagen and thrombin. Prolongation of the incubation time of platelets with diisoeugenol did not cause further inhibition and the aggregability of platelets could not be restored after washing. In human platelet-rich plasma, diisoeugenol inhibited the biphasic aggregation and ATP release induced by adrenaline and ADP in a concentration-dependent manner. Thromboxane B2 formation caused by arachidonic acid, collagen and thrombin was markedly inhibited by diisoeugenol in a concentration-dependent manner. Diisoeugenol also inhibited the formation of inositol monophosphate caused by collagen, PAF and thrombin. The cAMP level of washed platelets was not changed by diisoeugenol. It is concluded that the antiplatelet effect of diisoeugenol is due to the inhibition of thromboxane formation and phosphoinositides breakdown.
Salmeterol inhibits anaphylactic histamine release from guinea-pig isolated mast cells
Authors: Gentilini Grazia , Di Bello Maria Grazia , Raspanti Silvia , Bindi Daniela , Mugnai Sabrina , Zilletti Lucilla
Published: April 2011

Salmeterol (1 Nm-100μm) showed an inhibitory action on anaphylactic histamine release from mast cells, isolated from pleural and peritoneal cavities of actively sensitized guinea-pigs and stimulated by incubation with allergen. The effect is concentration-dependent and is reduced by the β-adrenoceptor antagonist propranolol (1 μm). This study supports the hypothesis of an antiinflammatory property of salmeterol, which concerns cells involved in the early phases of asthma.
Gastrointestinal Effects of Diazepam-withdrawal are Linked to Activation of Central Cholecystokinin-ergic Pathways in Rats
Authors: Bonnafous Cécile , Martinez Jose , Bueno Lionel
Published: April 2011

The influence of flumazenil-precipitated diazepam withdrawal on intestinal myoelectric activity and colonic transit was evaluated, in diazepam-dependent rats. Administered intraperitoneally, flumazenil (15 mg kg−1) induced a strong stimulation of the duodenal spiking activity lasting 197 ± 20 min, and accelerated colonic transit corresponding to a significantly (P < 0·05) increased value of the geometric centre (3.52 ± 0.23 vs 2·44 ± 0·1 for the control). Both devazepide and L365260 administered intracerebroventricularly at a dose of 10 μg kg−1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 μg kg−1) only L365260 was able to antagonize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit when administered intracerebroventricularly at a dose of 10 μg kg−1, whereas similar blockade was obtained at a dose of 5 μg kg−I with L365260, and 10 ng kg−1 with PD135–158. It is concluded that in rats precipitated diazepam-withdrawal altered intestinal motility and colonic transit and that these effects are mediated by central release of cholecystokinin (CCK) or activation of CCK-ergic neurons.
The Adenosine Agonist NECA Inhibits Intestinal Secretion and Peristalsis
Authors: Coupar Ian M , Hancock Debra L
Published: April 2011

This study aimed to determine whether the antidiarrhoeal effect of the mixed A1/A2 adenosine agonist NECA (5′-N-ethylcarboxamido adenosine) is due to inhibition of intestinal fluid transport or to contractility. Intestinal secretion was stimulated in anaesthetized rats by intra-arterial infusions of PGE2 (4 μg min−1) or vasoactive intestinal peptide (0·8 μg min−1). NECA reversed PGE2-induced secretion in the jejunum (ED50 16 μg kg−1) and ileum (ED50 21 μg kg−1, i.v.) and inhibited VIP-induced secretion in the jejunum (ED50 21·5 μg kg−1). NECA inhibited twitch responses (0·1 Hz, 1 ms, IC50 11·2Nm) but not tetanic contractions at 10 Hz of the transmurally stimulated guinea-pig ileum. Likewise, NECA (10 μm) did not inhibit frequency-related contractions over the range of 2·5 to 40 Hz of rat jejunum or ileum. However, NECA was shown to be a potent inhibitor (30 Nm) of the peristaltic reflex in the rat ileum. The results indicate that adenosine receptors are involved in modulating peristalsis as well as the secretory activity of the mucosa in the rat small intestine.
Evidence for Functional δ-Opiate Receptors in the Rat Intestine
Authors: Hancock Debra L , Coupar Ian M
Published: April 2011

The selective δ-opiate agonists d-Ser2, Leu5, Thr6-enkephalin (DSLET), d-Ala2, d-Leu5-enkephalin and d-Pen2, d-Pen5-enkephalin caused inhibition of the cholinergic contraction produced by transmural stimulation of the rat isolated jejunum. Dynorphin A, which is an agonist at both κ- and δ-opioid receptors also inhibited the cholinergic contraction, as did leu- and met-enkephalin. The selective μ-receptor agonist d-Ala2-NMe-Phe4, Gly-ol5-enkephalin was the least potent of all peptides tested. In general, the order of potency of the peptides was similar to that reported for the δ-receptor-rich mouse vas deferens with potency values similar to those recorded previously for the hamster vas deferens. The selective δ-opioid antagonist naltrindole caused parallel shifts to the concentration-effect curve to DSLET giving a pA2 value of 10·15. The results indicate that the previously identified δ-binding sites in the rat jejunum may correspond to functional δ-opiate receptors involved in attenuating acetylcholine release.
The Action of 1,2,3,5,6,11b-Hexahydro-[1]benzothieno [3,2-g]indolizine Hydrochloride (ADT 16) on Peripheral and Central Responses Mediated by 5-Hydroxytryptaminergic and Adrenergic Systems of the Rat
Authors: Leitch I M , Rawlow A , King R G , Boura A L A , Bremner J B , Browne E J
Published: April 2011

Some acute pharmacological effects have been examined of racemic ADT 16 (1,2,3,5,6,11b-hexahydro[1]benzothieno[3,2-g]indolizine hydrochloride), on peripheral and central responses mediated by 5-HT and adrenergic systems in the rat. In-vitro, ADT 16(10–1000 Nm), similarly to mianserin, antagonized the inhibitory responses to B-HT 920 of the electrically-stimulated rat isolated prostatic vas deferens. High concentrations of ADT 16 (10 μm), also resembled those of mianserin by potentiating twitch responses to electrical stimulation of the tissue. Contractile responses to phenylephrine of rat isolated epididymal vas deferens were antagonized by ADT 16 (0·3–1 μm). In the rat stomach fundus strip, ADT 16 (1–3 μm) antagonized contractions due to 5-HT. ADT 16 (0·1–1 μm) had no effect on responses to acetylcholine of the guinea-pig isolated ileum. In-vivo, in spinalized, decerebrated rats, fenfluramine- or clonidine-induced facilitation of flexor reflex activity of the anterior tibialis muscle was attenuated by ADT 16 (3 and 10 mg kg−1, i.v., and 3 mg kg−1, i.v. respectively). In the anaesthetized rat, l-3,4-dihydroxyphenylalanine (l-dopa)- or l-5-hydroxytryptophan (l-5-HTP)-induced increases in the frequency of spontaneous twitches of the anterior digastricus muscle were attenuated by ADT 16 (1 and 3 mg kg−1, i.v.; n = 4). It is concluded that ADT 16, similarly to mianserin, is a novel peripherally and centrally active antagonist of 5-HT and adrenergic responses in the rat.
Digoxin-specific Fab fragments impair renal function in the rat
Authors: Moran Robert J , Struthers Allan D , Hewick David S
Published: April 2011

The effect on renal function, and the plasma and urinary disposition, of digoxin-specific antibody fragments (DSFab), were studied using the rat as an experimental model. After 24 h, DSFab (2 mg kg−11, i.v.) caused decreases in urine volume and creatinine clearance of 34 and 33%, respectively, when measured in the same rats. However, only the creatinine clearance was significantly changed when compared with a separate saline-treated control group. Plasma and urinary creatinine concentrations were unaffected by DSFab treatment. Since creatinine clearance approximates to glomerular filtration rate (GFR), it appears that a dose of DSFab equivalent to about one-fifth of the usual clinical dose, causes a reduction in GFR of about one-third. In patients undergoing digitalis therapy, a degree of renal impairment is common and it is possible that this may be exacerbated by treatment with DSFab. DSFab had an elimination half-life of 178 min, an apparent volume of distribution (Vd) of 106 mL kg−1 and a plasma clearance of 0·42 mL kg−1 min−1. If it is assumed that the plasma volume of a rat is approximately 35 mL kg−1, the measured Vd suggests appreciable penetration of DSFab into the extracellular fluid at this dose. Seventy-two hours after injection, only 7·6% of the administered dose of DSFab was found in the urine.
Distribution and Protein Binding of FK506, a Potent Immunosuppressive Macrolide Lactone, in Human Blood and Its Uptake by Erythrocytes
Authors: Nagase Kazuko , Iwasaki Kazuhide , Nozaki Katsuko , Noda Kohsei
Published: April 2011

The distribution of FK506 in the blood was estimated in-vitro. At a drug level of 5 ng mL−1, FK506 mainly distributed in erythrocytes (95–98%) in dog, monkey and human blood, and its distribution was affected by drug concentration, temperature, and haematocrit values. In erythrocytes most of FK506 was distributed in cytoplasmic components and was bound strongly to a protein having a molecular weight of 10–11 kDa. The molecular weight of this protein agrees with FK506-binding protein found in various cells. Greater than 98·8% of FK506 was bound to the plasma proteins in all species studied. FK506 bound to various plasma proteins such as lipoproteins, globulins, α1-acid glycoprotein and albumin.
The Protective Effect of Nimodipine, a Calcium Antagonist, and Its Influence on Soman Clearance in the Anaesthetized Rabbit
Authors: Karlsson Britt , Fredriksson Sten-Åke , Sellström Åke , Algers Güran
Published: April 2011

The effect of pretreatment with a vasoactive compound, nimodipine, on soman intoxication in peripheral organs of rabbits was studied by measuring changes in the cholinesterase and acetylcholinesterase activity and by measuring clearance of soman in blood using gas chromatography/high resolution mass spectrometry. In animals receiving soman only, initial blood concentrations were approximately 100 ng mL−1 and were still detectable after 5 min. The clearance rate of soman in blood markedly increased following nimodipine pretreatment such that soman was below the detection limit (0·002–0·003 ng mL−1) in all samples. Soman injection caused a significant inhibition of the acetylcholinesterase activity in serum, and in brain. In rabbits pretreated with nimodipine, no significant inhibition of acetylcholinesterase activity occurred after soman injection. In view of the effects of nimodipine on soman clearance and on the acetylcholinesterase and cholinesterase inhibition during soman intoxication, we suggest that nimodipine has profound circulatory effects, which during soman intoxication, increase the vascular perfusion through the body and thereby increase the detoxifying capacity.
The effect of Ca2+ antagonists on spontaneous motility from sheep duodenum
Authors: Murillo María Divina , Plaza Miguel Angel , De Pedro María José , Arruebo María Pilar
Published: April 2011

Longitudinal smooth muscle of the sheep duodenum showed a rhythmic spontaneous activity with an average frequency of 5·6 ± 0·55 phasic movements min−1 and a mean value of the amplitude of phasic contractions of 0·956 ± 0·1 g. When the strips were incubated in Ca2+-free medium, the spontaneous motility amplitude (SMA) was reduced to 37 ± 8·2% of control values. In Ca2+-free medium plus EDTA (1 or 2 Mm), the SMA was strongly reduced to 21·9 ± 8·3 and 1·8 ± 1·8%, respectively. Verapamil, nifedipine and diltiazem diminished the SMA. The EC50 value for verapamil was 10−9 M., whereas that for diltiazem was 2 × 10−9 M and for nifedipine was 3 × 10−14 M. Trifluoperazine and TMB-8 reduced the SMA with EC50 values of 7 × 10−6and 3 × 10−5  m, respectively. The spontaneous activity in the sheep duodenum seemed to be mediated by influx extracellular Ca2+, which enters through potential-dependent channels and intracellular Ca2+ release.
Effects of Nω-nitro-l-arginine and capsaicin on neurogenic vasomotor responses in isolated mesenteric arteries of the monkey
Authors: Tsuchiya Kimiyuki , Urabe Masanobu , Yamamoto Ryuich , Asada Yujiro , Lee Tony J-F
Published: April 2011

Monkey isolated mesenteric arterial rings denuded of endothelium constricted upon transmural nerve stimulation (TNS) in the absence of active muscle tone. The constriction was potentiated by Nω-nitro-l-arginine (3 × 10−5  m), but not by the d-enantiomer (3 × 10−5  m). The potentiation was reversed by l-arginine (3 × 10−4  m). The neurogenic vasoconstriction of mesenteric arteries was also augmented by capsaicin, but to a lesser extent than that induced by Nω-nitro-l-arginine. Indomethacin (10−5  m) did not affect TNS-induced vasoconstriction. These findings suggest that nerve-derived nitric oxide or a related substance may play a greater role than do capsaicin-sensitive vasodilator transmitters in neurogenic regulation of mesenteric arterial tone in the monkey. The transmitter mechanisms for vasodilation in mesenteric circulation vary among species.
Comparative Study of Buccoadhesive Formulations and Sublingual Capsules of Nifedipine
Authors: Save Tanuja , Shah Meena U , Ghamande A R , Venkitachalam Padma
Published: April 2011

The pharmacodynamics of nifedipine administered via the oral mucosa was investigated in hypertensive patients. The effect of two buccoadhesive formulations, tablets and films, was compared with the commercially available sublingual capsule in a complete cross-over study in six patients. All three formulations elicited onset of action 10 min after administration. The sublingual capsule and the buccoadhesive film revealed peak response at 30 min. The buccoadhesive tablet, however, exhibited a delayed peak response at 45 min. Analysis of variance indicated that, although time-dependent differences in the formulations were suggested, there was no significant difference in the overall effect produced by the three formulations. The results of the study suggest that the buccoadhesive formulations of nifedipine were comparable in performance with the sublingual capsule.
Diltiazem Facilitates Endothelin Clearance from the Blood Stream to Reduce Toxic Elevation of Plasma Endothelin Level in Rodents
Authors: Ashizawa Naoki , Okumura Hiroshi , Matsuura Akihiro , Kobayashi Fujio
Published: April 2011

Pretreatment with diltiazem at a dose of 2 mg kg−1 intravenously protected against sudden death induced by intravenous administration of endothelin-1 (ET-1, 5 nmol kg−1), with an apparent decrease in the plasma immunoreactive-ET-1 (IR-ET-1) in mice. These effects, which were also observed in anaesthetized rats, disappeared in rats with bilateral ligation of the renal arteries. In the latter, the exogenous ET-1-induced elevation of plasma IR-ET-1 tended to be higher than that in the sham-operated controls. Furthermore, in anaesthetized rats, diltiazem inhibited ET-1-induced decreases in renal blood flow and increased renal accumulation of IR-ET-1. These results indicate that part of the clearance of ET-1 from the bloodstream occurs in the kidney, and that diltiazem enhances the elimination of the peptide, presumably by improvement in the renal circulation, this action leading to alleviation of the toxic effects of ET-1.
Sesquiterpene Components of Volatile Oils as Skin Penetration Enhancers for the Hydrophilic Permeant 5-Fluorouracil
Authors: Cornwell P A , Barry B W
Published: April 2011

Twelve sesquiterpene compounds, derived from natural volatile oils, were investigated as putative skin penetration enhancers for human skin. Pretreatment of epidermal membranes with sesquiterpene oils, or solid sesquiterpenes saturated in dimethyl isosorbide, increased the rate of absorption of the model hydrophilic permeant, 5-fluorouracil (5-FU). Enhancers with polar functional groups were generally more potent than pure hydrocarbons. Furthermore, enhancers with the least bunched structures were the most active. The largest effect was observed following pretreatment with nerolidol, which increased pseudo-steady-state 5-FU flux over 20-fold. Molecular modelling suggested that terpenes with structures suitable for alignment within lipid lamellae were the most potent enhancers. Sesquiterpene enhancers had long durations of action implying that they did not wash out of the skin easily. This study attempted to improve enhancer clearance by replacing the aqueous donor and receptor phases by ethanol: water (1:1) solutions. Ethanol increased the permeability coefficient for 5-FU 13-fold, demonstrating that, in aqueous solution, it is a moderately potent penetration enhancer. Sesquiterpene and ethanol enhancement effects were approximately additive. Sesquiterpene effects were almost fully maintained for at least 4·5 days following pretreatment, illustrating poor reversibility. Stratum corneum/water drug partitioning studies suggested that an important mechanism of action of the enhancers was to increase the apparent drug diffusivity in the stratum corneum. Increases in drug partitioning into the entire stratum corneum following enhancer pretreatment were relatively small. Diffusivity increases were directly related to overall rises in permeability. This study has shown that sesquiterpene compounds, which are of low toxicity and cutaneous irritancy, can promote 5-FU absorption across human skin. Sesquiterpene compounds, therefore, show promise as clinically-acceptable skin penetration enhancers.
Effect of Policosanol on Isoprenaline-induced Myocardial Necrosis in Rats
Authors: Noa Miriam , Herrera M , Magraner J , Más Rosa
Published: April 2011

Policosanol is a mixture of higher aliphatic primary alcohols isolated from sugar cane (Saccharum officinarum L.) and octacosanol represents its main component. This study was conducted to examine the effects of policosanol on myocardial necrosis induced by subcutaneous injection of isoprenaline in rats. A significant reduction (P < 0·01) of infarct size, polymorphonuclear cells and mast cells was observed in animals treated with policosanol at 5 or 25 mg kg−1, while animals receiving only acetysalicylic acid pretreatment showed a significant decrease in the infarct area (P < 0·05). No significant differences in polymorphonuclear and mast cells were obtained when compared with positive control data. It is concluded that policosanol delays the evolution of infarction, showing a protective effect on the myocardial necrosis induced by isoprenaline in this experimental model.
A Novel 11β-Hydroxysteroid Dehydrogenase Inhibitor Contained in Saiboku-To, a Herbal Remedy for Steroid-dependent Bronchial Asthma
Authors: Homma Masato , Oka Kitaro , Niitsuma Tomoyuki , Itoh Hisao
Published: April 2011

To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11β-hydroxysteroid dehydrogenase (11β-HSD), using rat liver homogenate and Cortisol as a typical substrate. We studied the effects often herbal constituents on 11β-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens< Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11β-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1·8 × 10−4  m). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11β-HSD.
Effect of cardiopulmonary bypass on plasma concentrations of diltiazem and its two active metabolites
Authors: Boulieu R , Bonnefous J L , Lehot J J , Durand P G , Chassignolle J F , Ferry S
Published: April 2011

Diltiazem is often used to prevent myocardial ischaemia during the perioperative period of coronary artery bypass surgery. The purpose of this study was to investigate the effect of cardiopulmonary bypass (CPB) on plasma concentrations of diltiazem and of its two main and active metabolites (N-monodemethyldiltiazem (N-desmethyldiltiazem) and desacetyldiltiazem). The patients were administered their usual treatment during the preoperative days. The last dose was administered immediately before anaesthesia. At the onset of CPB, a significant decrease in the plasma concentrations of diltiazem and its metabolites was observed, whereas the variation was slight and not significant when the plasma concentrations were corrected for haemodilution. These results confirm that the decrease observed at the initiation of the bypass procedure can be ascribed to the haemodilution induced by the CPB. During CPB, the concentrations of diltiazem and its metabolites remained constant suggesting that the rate of metabolism and excretion of the drug was altered during the bypass procedure. At the end of CPB, there was no increase of drug plasma concentrations suggesting that no redistribution of diltiazem from tissues to plasma occurred. Furthermore, this study shows that only 33% of subjects have therapeutic levels of diltiazem before anaesthesia, and that all subjects have subtherapeutic levels during and after the CPB. These results suggest that a higher chronic oral dose of the drug should be given in patients undergoing cardiac surgery with CPB.
Adipose tissue storage of drugs as a function of binding competition. In-vitro studies with distribution dialysis
Authors: Minder S , Daniel W A , Clausen J , Bickel M H
Published: April 2011

Distribution dialysis was used to study binding competition between homogenates of adipose tissue and of lean tissues. The concentration ratios adipose/X (X = blood, muscle, lung, liver) of eight lipophilic drugs were determined in the absence and in the presence of a competing binding system X. With drugs which do not undergo storage in adipose tissue in-vivo, yet have a high volume of distribution, such as imipramine or desipramine, there was strong binding competition, and the balance of distribution was shifted from adipose to lean tissues. In the case of indomethacin with a low volume of distribution this shift was from adipose tissue to blood. With diazepam there was a marked binding competition which was not, however, sufficient to shift the balance of distribution away from adipose tissue. Binding competition was negligible with thiopentone. In contrast, with the equally lipophilic hexethal a moderate binding competition was observed. This is consistent with a decreased adipose tissue storage of the latter barbiturate. It is concluded that binding competition exists not only between blood and tissues but also among individual tissues. It is suggested that occurrence and extent of adipose tissue storage of drugs are determined by binding competition between lean and adipose tissues and, more generally, that distribution of lipophilic drugs is largely a function of binding competition.
Effect of lignocaine on eicosanoid synthesis by pieces of human gastric mucosa
Authors: Goel R K , Tavares I A , Nellgard P , Jonsson A , Cassuto J , Bennett A
Published: April 2011

Lignocaine can affect prostaglandin synthesis in various tissues, and it has anti-inflammatory activity. No studies have been made previously on human isolated gut tissues. When concentrations of 5, 50 and 250 μg mL−1 lignocaine were incubated with human gastric mucosa/submucosa at 37°C for 30 min, only the highest concentration reduced the levels of prostaglandin E, thromboxane B2 and 6-keto-PGF1α in the incubates, and leukotriene C4/D4 was unaffected. Therapeutically relevant amounts of lignocaine given parenterally would therefore seem unlikely to alter gastric mucosal prostanoids, but high doses can be given orally because of extensive first-pass metabolism in the liver.
The In-vitro Effects of Insulin and the Effects of Acute Fasting on Cardiac β-Adrenoceptor Responses in the Short-term Streptozotocin-diabetic Rat
Authors: Austin Clare , Chess-Williams Russell
Published: April 2011

This study demonstrates that in-vitro incubation with insulin results in a reduction of the sensitivity of cardiac tissues from streptozotocin-diabetic rats to isoprenaline. Following incubation with insulin, the sensitivity of left atria and papillary muscles from diabetic animals was not significantly different from those of control animals. Insulin incubation had no effect on the sensitivity of diabetic tissues to forskolin or on ventricular β-adrenoceptor number. Reduction of blood glucose in the absence of insulin by fasting, did not affect the sensitivity of tissues from diabetic animals to isoprenaline. These results suggest that insulin itself can directly reduce β-adrenoceptor sensitivity without altering receptor number.
Vasorelaxant Effects of Oxpentifylline and Theophylline on Rat Isolated Aorta
Authors: Marukawa Seishiro , Hatake Katsuhiko , Wakabayashi Ichiro , Hishida Shigeru
Published: April 2011

The mechanism of the relaxation response of rat aorta to the phosphodiesterase inhibitors oxpentifylline and theophylline was studied. Oxpentifylline induced a greater vasorelaxation response in the intact strips than in those without endothelium. The endothelium-dependent relaxation response to oxpentifylline was inhibited by nitro-l-arginine but not by indomethacin, and the endothelium-independent relaxation response was potentiated by the combination with isoprenaline but not sodium nitroprusside. Theophylline induced a similar relaxation response in vascular strips with and without endothelium. The relaxation response to theophylline was not inhibited by indomethacin or nitro-l-arginine in intact strips, but was potentiated by combination with isoprenaline or sodium nitroprusside in the denuded strips. These results suggest that the two phosphodiesterase inhibitors oxpentifylline and theophylline induce vasorelaxation by different mechanisms. Oxpentifylline can induce both endothelium-dependent relaxation, which is probably mediated by an endothelium-derived relaxing factor, and endothelium-independent relaxation, which may be due to an inhibitory action on phosphodiesterase of vascular smooth muscle. In contrast, theophylline can induce endothelium-independent relaxation alone, without modulation by the endothelium.
Lack of Circadian Variation in the Sensitivity of Rat Terminal 5-HT1B Autoreceptors
Authors: Singh Ashish , Redfern Peter
Published: April 2011

The sensitivity of terminal 5-HT1B autoreceptors in the cerebral cortex and hippocampus to both agonist and antagonist was determined at four different time points in the light: dark cycle of the rat to evaluate whether changes in their responsiveness underlie the circadian rhythm in 5-hydroxytryptamine (5-HT) release. No significant circadian differences were evident in the apparent pIC50 values calculated for 5-HT to inhibit K+-evoked tritium effiux or in the apparent pA2 values calculated for methiothepin to antagonize the effect of 5-HT, at the different time points, in either brain region. These findings suggest that the sensitivity of terminal 5-HT1B autoreceptors in rat cerebral cortex and hippocampus does not change in a circadian pattern, during the light: dark cycle, and argues against such a change influencing the circadian variation in 5-HT release.
SR 48968 selectively prevents faecal excretion following activation of tachykinin NK2 receptors in rats
Authors: Croci Tiziano , Emonds-Alt Xavier , Manara Luciano
Published: April 2011

We tested the ability of SR 48968, (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl)benzamide, a non-peptide antagonist highly selective for tachykinin NK2 receptors, to prevent defecation induced in rats by several agents. The tachykinin agonists substance P, [MePhe7]neurokinin B and [β-Ala8]neurokinin A (4–10) all promoted defecation and increased faecal water content, the last compound being over ten times more potent than the other two (intraperitoneal dose inducing the excretion of I g faeces dry weight = 6·7 μg kg−1). SR 48968 given either orally (p.o.) or subcutaneously (s.c.) was similarly potent in dose-dependently inhibiting faecal output stimulated by the selective NK2-agonist [β-Ala8]neurokinin A (4–10) (doses causing 50% inhibition 0·4 μg kg−1, p.o. and 0·3 μg kg−1, s.c). This inhibition was long-lasting (more than 18 h after 1 μg kg−1 SR 48968 either s.c. or p.o.). At the higher doses tested, SR 48968 also significantly prevented the increase in faecal water content produced by [β-Ala8]neurokinin A (4–10). In rats treated with SR 48968, stimulation of faecal output by the α2-adrenergic antagonist idazoxan and by salmonella endotoxin (LPS), but not by the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin, 5-HT, carbachol or platelet-activating factor, was partially prevented. The present results suggest that activation of intestinal NK2 receptors, either directly by the selective agonist [β-Ala8]neurokinin A (4–10) or indirectly through the release of endogenous neurokinin A (by idazoxan or LPS), promotes defecation, presumably as a consequence of increased gut motility or secretion, or both. SR 48968 should therefore be useful for studying the role of neurokinin A-dependent mechanisms in health and disease, including those of the gastrointestinal system, and possibly for developing new therapeutic agents.
Involvement of nitric oxide in the response to 5-hydroxytryptamine in the rat in-vivo
Authors: Franks C M , Hardcastle J , Hardcastle P T
Published: April 2011

The involvement of nitric oxide (NO) in the effects of 5-HT on intestinal secretion and cardiovascular function in anaesthetized rats was investigated using NG-nitro-l-arginine methyl ester (l-NAME), a specific NO-synthase antagonist, and its optical isomer d-NAME. l-NAME significantly reduced the prolonged hypotensive response to 5-HT. It also caused a small rightward shift in the colonic 5-HT dose-response curve. This suggests that NO plays a significant role in the prolonged hypotensive response to 5-HT, and may make a small contribution to the secretory response of the colon, but not that of the jejunum, in the rat in-vivo.
The Effect of Process and Formulation Variables on the Properties of Spray-dried β-Galactosidase
Authors: Broadhead J , Rouan S K Edmond , Hau I , Rhodes C T
Published: April 2011

The objective of this study was to evaluate the joint effects of various processing and formulation variables on the properties of spray-dried β-galactosidase using statistically designed experiments. The key response variables evaluated were product yield, residual enzymatic activity, moisture content and particle size and appearance. The residual enzymatic activity and product yield were significantly affected by the processing variables. The highest product yields were obtained when the drier outlet temperature was relatively high, resulting in extensive protein denaturation. Subsequent experiments, therefore, compared the relative effectiveness of four stabilizers (mannitol, sucrose, arginine hydrochloride and trehalose) in terms of their ability to preserve enzymatic activity during the spray-drying process and during long-term storage. Trehalose was the most suitable stabilizer. The effect of a number of other formulation variables (total solids level, ratio of stabilizer to protein, presence of surfactant and presence of buffer) was also investigated. A final formulation consisting of 6% β-galactosidase and 10% trehalose in deionized water was selected. Spray-drying at inlet and outlet temperatures of 140 and 95°C, respectively, results in greater than 70% yields of a fully active product with a moisture content of 2–5% and a mean particle size of 2–4 μm.
The Role of the Displacement-time Waveform in the Determination of Heckel Behaviour Under Dynamic Conditions in a Compaction Simulator and a Fully-instrumented Rotary Tablet Machine
Authors: Muller Francis X , Augsburger Larry L
Published: April 2011

The Heckel equation has been used widely to characterize the compression behaviour of pharmaceutical powders, yet very little attention has been paid to the role of the displacement-time profile used to generate this relationship. The objective of this study was to evaluate and compare selected standard waveforms with actual and theoretical tablet press waveforms in the Heckel analysis of representative formulations under dynamic conditions in a compaction simulator and to compare such data with that determined on the same formulation using an actual fully-instrumented rotary tablet press. Increased tableting rate and different programmed displacement-time waveforms with the same gross punch-speed changed the Heckel behaviour of all formulations. The results of this study suggest the pressure-volume relationship determined during powder-bed compression is affected by the instantaneous punch-speed profile of the displacement-time waveform for all materials studied, even though they deform by different mechanisms. It appears that the instantaneous punch-speed profile of the particular displacement-time waveform is a confounding factor of Heckel analysis. Compaction simulators programmed to deliver saw-toothed displacement-time traces have the advantage of constant punch-speed and may be a better choice for characterizing a formulation by Heckel indices and the strain-rate sensitivity index. On the other hand, they also carry the liability of not being a realistic representation of tableting on a rotary tablet press.
The Stability of bFGF Against Thermal Denaturation
Authors: Vemuri Sriram , Beylin Irina , Sluzky Victoria , Stratton Pamela , Eberlein Gert , Wang Y John
Published: April 2011

The influence of sulphated ligand and pH on thermal denaturation of basic fibroblast growth factor (bFGF) was investigated by differential scanning calorimetry (DSC), and verified by fluorescence spectrophotometry. Purity of bFGF before and after heat denaturation was assessed by SDS-PAGE analysis. In DSC studies the samples were heated to 95°C. The midpoint of the temperature change in the thermogram was designated as Tm. Sulphated ligand experiments were undertaken in potassium phosphate (pH 6·5) and sodium acetate buffers. Control thermograms (with no ligand) showed a Tm at 59°C in potassium phosphate buffer. Higher Tm values were noted as sulphated ligand concentration was increased. Similarly when heparin was added, the Tm moved to a higher temperature. A ratio as low as 0·3:1 of heparin to bFGF, increased the Tm to 90°C, which is a 31°C shift in Tm. The effect of pH on thermal denaturation of bFGF was studied in a citrate-phosphate-borate buffer system. A shift in Tm from 46 to 65°C was observed as the pH is changed from 4 to 8. Changes in protein conformation as a function of pH were monitored by fluorescence spectroscopy. It was found that a pH range from 5 to 9 is optimal for the stability of bFGF formulations. In a stability study it was noted that heparin protected bFGF from thermal denaturation only at high temperature.
Induction of the Conversion of Xanthine Dehydrogenase to Oxidase in Rabbit Liver by Cu2+, Zn2+ and Selenium Ions
Authors: Sakuma Satoru , Fujimoto Yohko , Iwai Mimi , Fujimoto Kenjiro , Yasuda Maki , Nishida Hiroko , Fujita Tadashi
Published: April 2011

Effects of Cu2+, Zn2+, Fe2+ and selenium ions on the conversion of xanthine dehydrogenase to oxidase in rabbit liver were examined. Under basal conditions, xanthine oxidase activity represented only 16% of the total xanthine oxidase plus dehydrogenase activity. Cu2+ (2–10 μm), Zn2+ (5–30 μm) and selenium ions (5–100 μm) brought about the conversion of xanthine dehydrogenase to oxidase in a dose-dependent manner. The concentrations of Cu2+, Zn2+ and selenium ions required for increasing xanthine oxidase activity by 50% was approximately 4, 10 and 20 μm, respectively. On the other hand, Fe2+ had no effect on the conversion of the enzyme up to 100 μm. These results suggest that Cu2+, Zn2+ and selenium ions have the potential to modulate the conversion of xanthine dehydrogenase to oxidase in rabbit liver.
Analysis of Neurogenic Contractions Induced by ML-1035 and Other Benzamides in the Guinea-pig Non-stimulated Isolated Ileum
Authors: Linnik Matthew D , Butler Brent T , Elsea Sarah H , Ahmed Nahed K
Published: April 2011

4-Amino-5-chloro-substituted benzamides have been shown to increase gastric motility in-vivo and enhance field-stimulated and peristaltic contractions in-vitro. The present experiments examined the contractile response to a series of benzamides in the guinea-pig non-stimulated ileum. Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 μm acetylcholine (% acetylcholine response = 12 ± 2, 19 ± 3, 26 ± 2, 51 ± 3, n= 13, 8, 17, and 21, with EC50 values of 0·85, 1·8, 5·7, and 14·2 μm for cisapride, zacopride, metocloprarmde, and ML-1035 (4-amino-5-chloro-2-((2-methylsulphinyl)-ethoxy)-N-(2-(diethylamino)-ethyl)-benzamide hydrochloride), respectively). ML-1035 contractions were completely blocked by atropine and tetrodotoxin, while ganglionic blockade with hexamethonium was ineffective. Metoclopramide has been reported to sensitize postjunctional muscarinic receptors, however, ML-1035 did not enhance acetylcholine-induced contractions. Tropisetron (ICS 205–930, 1 μm), caused a parallel rightward shift in the concentration-response curve for both ML-1035 and zacopride (EC50 = 14·2 ± 1·3 and 1·8 ± 0·8 μm in the absence, and 26 ± 2·7 and 6·9 ± 2·3 μm in the presence of tropisetron for ML-1035 and zacopride, respectively) with apparent pKB values of 5·9 and 6·0 for the respective compounds. 5-Hydroxytryptaminergic receptor desensitization by 2-methyl-5-hydroxytryptamine (5-HT3) and 5-methoxytryptamine (5-HT4), attenuated the response to ML-1035. We also examined the effect of the benzamides on [3H]acetylcholine release from longitudinal muscle myenteric plexus preparations; however, these compounds had little effect on basal [3H]acetylcholine release. Thus, the pharmacological data indicate that the benzamides can elicit neurogenic contractions in the non-stimulated ileum by activating postganglionic, cholinergic neurons which is independent of an effect on smooth muscle.
Increased Cardiovascular Responsiveness to Central Cholinergic Stimulation in the Genetically Epilepsy-prone Rat
Authors: Trimarchi G R , Imperatore C , Arcadi F A , Saija A , de Sarro A , de Sarro G B , Costa G
Published: April 2011

We sought to determine whether differences in cardiovascular responsiveness to central stimulation of the cholinergic system existed between the genetically epilepsy-prone and outbred Sprague-Dawley rats. We treated the unanaesthetized, restrained rats with the indirect cholinergic agonist physostigmine (25, 50, 100 and 200 μg kg−1, i.v.) and the direct muscarinic agonist arecoline (50, 100 and 200 μg kg−1, i.v.). Blood pressure and heart rate were evaluated. Genetically epilepsy-prone rats demonstrated to be more susceptible to the action of physostigmine than the outbred Sprague-Dawley rats. Conversely, we did not note any difference between the two strains in the extent of the pressor response induced by arecoline. Moreover, we treated both strains with hemicholinium-3 (34·8 nmol, i.c.v.) to deplete endogenous stores of acetylcholine. This treatment did not affect the pressor response to arecoline, whereas it greatly reduced the response to physostigmine. The present results support an increased cardiovascular responsiveness to central cholinergic stimulation in the genetically epilepsy-prone rat which appears to be related to a pre-synaptic rather than a post-synaptic component.
Topically effective ocular hypotensive acetazolamide and ethoxyzolamide formulations in rabbits
Authors: Loftsson T , Friðriksdóttir H , Stefánsson E , Thórisdóttir S , Guðmundsson ö , Sigthórsson T
Published: April 2011

The effect of topically active 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) eye-drop formulations containing solutions of acetazolamide, ethoxyzolamide or timolol on the intra-ocular pressure (IOP) was investigated in normotensive conscious rabbits. Both acetazolamide and ethoxyzolamide were active but their IOP-lowering effect was less than that of timolol. The IOP-lowering effects of acetazolamide and ethoxyzolamide and that of timolol appeared to be to some extent additive. Combination of acetazolamide and timolol or ethoxyzolamide and timolol in one HP-β-CyD formulation resulted in a significant increase in the duration of activity compared with HP-β-CyD formulations containing only acetazolamide, ethoxyzolamide or timolol. Also, it was possible to increase the IOP-lowering effect of acetazolamide by formulating the drug as a suspension in an aqueous HP-β-CyD vehicle.
In-vivo and in-vitro evaluations of a modified-release oral dosage form of nifedipine by hybridization of hydroxypropyl-β-cyclodextrin and hydroxypropylcelluloses in dogs
Authors: Wang Zheng , Hirayama Fumitoshi , Uekama Kaneto
Published: April 2011

To maintain a suitable blood level of nifedipine for a long period of time, double-layer tablets consisting of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and 3% nonionic surfactant (HCO-60) as a fast-release portion and hydroxypropylcelluloses (HPCs) with different viscosity grades (low, medium and high) as a slow-release portion were prepared, and their in-vitro and in-vivo release behaviours were investigated. Among the seven formulations, the tablet having the mean dissolution time of 0·8–1·3 h gave prolonged plasma nifedipine levels without decrease of AUC after oral administration to dogs. Consequently, the double-layer tablet consisting of HP-β-CyD with 3% HCO-60/(HPC-low: HPC-medium) in a weight ratio 1/(1·5:1·5) was selected as an appropriate modified-release formulation because it elicited almost comparable retarding effects with superior oral bioavailability compared with those of a commercially available slow-release nifedipine product.