bluuebunny/crossref_metadata_2025 huggingface dataset:
Peak Offset Times as an Indication of Stress Relaxation During Tableting on a Rotary Tablet Press
Authors: Dwivedi S K , Oates R J , Mitchell A G
Published: April 2011

During powder compaction on a Manesty Betapress, peak pressures, Pmax, are reached before the punches are vertically aligned with the centres of the upper and lower compression roll support pins. The interval between the time taken to reach this alignment and the time to reach Pmax is defined as the peak offset time, toff. The duration of toff depends on the ability of the compacted powder to relieve stress and is an indication of the predominant mechanisms of particle deformation during consolidation. Thus, at a given Pmax, short toff values are characteristic of materials that consolidate mainly by brittle fracture while longer values indicate an increase in plastic flow. On the Betapress, the decrease in stress during toff occurs under conditions approaching constant strain and toff therefore, is an indirect measure of stress relaxation. Stress relaxation, and hence toff, decreases with increase in Pmax due to the reduction in the porosity of the compact and consequent restriction of plastic flow into the void spaces. In addition to Pmax, the effects of variables such as punch head geometry, press speed and formulation on toff are reported.
Predisposition to Uterine Microbial Contamination in the Guinea-pig Following Administration of Mucolytic Drugs and Steroid Hormones
Authors: Malhi Jaspal S , Gard Paul R , Hanlon Geoffrey W
Published: April 2011

Using guinea-pigs as a mammalian model, the effects of bromhexine hydrochloride, ethinyloestradiol, norethisterone acetate and prednisolone acetate on uterine microbial status were determined. Those drugs known to decrease mucus viscoelasticity predisposed to the entry of vaginal bacteria into the uterus, probably due to reduction of the cervical mucus barrier. Norethisterone acetate, which increases cervical mucus viscoelasticity, reduced these effects. The effects produced by the steroid hormones were independent of their immunosuppressive effects. The results also suggest that prednisolone acetate may exert oestrogenlike actions on cervical mucus.
IgG- and IgE-mediated Histamine Release from Superfused Guinea-pig Airway Tissues
Authors: Van Amsterdam Ronald G M , Santing Ruud E , De Boer Jacob , Brouwer Frans , Zaagsma Johan
Published: April 2011

Anaphylactic histamine release and the inhibition by the β-adrenoceptor agonist fenoterol has been investigated using lung and tracheal tissues from two groups of guinea-pigs, differently sensitized to respond with IgG or IgE antibodies, respectively. A superfusion method was introduced and compared with classical batch incubation. The difference between IgG- and IgE-mediated histamine release during superfusion of both tissues was much greater than the difference obtained during batch-incubations. Fenoterol inhibited IgG-mediated histamine release during superfusion at lower concentrations and to a larger extent than the release from IgE-sensitized tissues. The inhibition by fenoterol was less pronounced after batch-wise incubations, preincubation at 0°C abolished the quantitative difference of IgG- and IgE-mediated histamine release from lung slices as well as the difference in β-adrenergic inhibition. It is concluded that the new superfusion procedure for airway tissues enhances the sensitivity of antigen-induced histamine release for pharmacological modulation, compared with batch-wise incubation. In addition, the effects of 0°C pretreatment show that cooled transport and storage of airway tissue should be considered with care.
The Effect of Fever on Quinine and Quinidine Disposition in the Rat
Authors: Mansor S M , Ward S A , Edwards G
Published: April 2011

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4·49 ± 1·45 vs 1·38 ±0·65 L h−1 kg−1, P < 0001) and volume of distribution (Vd) (42·6 ± 8·8 vs 28·9 ± 10·3 L kg−1, P < 0·05) with a concomitant shortening of the elimination half-life (t½) (7·1 ±2·5 vs 15·9 ± 5·9 h, P < 0·01). With quinidine, however, fever resulted in an increased CL (3·95 ± 1·05 vs 1·89 ± 0·60 L h−1 kg−1, P < 0·002) with no change in Vd and a significant decrease in t½ (5·1 ±0·7 vs 10·1 ±2·8 h, P < 0·001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.
Protein binding of cefpiramide in the plasma of various species
Authors: Ohshima Taeyuki , Hasegawa Takaaki , Johno Ikuo , Kitazawa Shikifumi
Published: April 2011

The plasma protein binding of cefpiramide in man, dog, rabbit and rat was examined. Cefpiramide was more strongly bound to human plasma than to animal plasma and was exclusively bound to albumin. The characteristics of the protein binding of cefpiramide is one of the factors influencing the extrapolation of drug disposition from animals to man.
Chronic electroconvulsive shock alters hypothermic response of B-HT 920 and SKF 38393 in rats
Authors: Verma Anita , Kulkarni S K
Published: April 2011

The hypothermic response of B-HT 920, a D2-dopamine agonist remained unaltered while that of apomorphine, a mixed D1-/D2-agonist was significantly reduced following chronic electroconvulsive shock (ECS) treatment. SKF 38393 (5 mg kg−1), a selective D1-agonist potentiated the hypothermic response of B-HT 920 in non-ECS-treated rats. The response of the combination was, however, attenuated following chronic ECS treatment. These observations suggested a reduction in Di-receptor density following chronic ECS treatment in rats.
Pharmacokinetics of Valproic Acid in Guinea-pigs with Biliary Abnormality
Authors: Yu Hsiu-Ying , Shen Yu-Zen
Published: April 2011

To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg−1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P < 0·05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P < 0·05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P < 0·05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2·0 ± 0·7 (s.e.m.) and 19·7 ±3·6 (s.e.m.) % of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.
Potentiation of gastric toxicity of ibuprofen by paracetamol in the rat
Authors: Bhattacharya Salil K , Goel R K , Bhattacharya Sujit K , Tandon R
Published: April 2011

A fixed dose combination of ibuprofen (400 mg) and paracetamol (325 mg) is by far the most extensively prescribed medicament for a variety of musculoskeletal disorders in India. Following clinical observations that this drug combination induces significant adverse effects, its gastric toxicity was investigated in rats. Ibuprofen (25 mg kg−1 p.o., twice daily × 5 days), paracetamol (20 mg kg−1 p.o, twice daily × 5 days), and a combination of the two, had no significant effect on free and total gastric acidity in pylorusligated rats. Ibuprofen induced visible gastric ulceration whereas paracetamol did not. However, the combination of these two drugs had an additive effect inducing severe gastric erosions, ulcerations and bleeding. The augmented toxicity of this drug combination appeared to be a consequence of attenuated gastric mucin activity and reduction in the gastric muco-protective barrier. This investigation indicates the likely hazard of an irrational fixed dose drug combination.
Improvement of Ocular Penetration of Amikacin Sulphate by Association to Poly(butylcyanoacrylate) Nanoparticles
Authors: Losa C , Calvo P , Castro E , Vila-Jato J L , Alonso M J
Published: April 2011

The main objective of this paper was to investigate the ability of polycyanoacrylate nanoparticles to improve the corneal penetration of hydrophilic drugs. Three different nanoparticle formulations were prepared by changing the nature of the stabilizer agent (Dextran 70000, Synperonic F 68 and sodium lauryl sulphate). The significant influence of the stabilizer type on the particle size, electrophoretic mobility and on the drug loading efficiency was proved. Moreover, the ocular disposition of amikacin was affected by its association to nanoparticles, displaying the most interesting results when Dextran 70000 was employed for preparation of nanoparticles. The increase of the amikacin concentration in cornea and aqueous humour was statistically significant for this nanoparticle formulation with respect to the other formulations and the control solution. The in-vitro release profiles obtained using a dialysis system were similar for all the nanoparticle formulations and for the control solution, indicating that drug molecules are desorbed from the nanoparticles quickly enough to maintain the equilibrium concentration in the dialysis system.
Assay of Pyrogens by Interleukin-6 Release from Monocytic Cell Lines
Authors: Taktak Y S , Selkirk S , Bristow A F , Carpenter A , Ball C , Rafferty B , Poole S
Published: April 2011

A novel in-vitro system has been developed for the detection and quantification of pyrogen in pharmaceutical products. The measured variable was evoked secretion of the pyrogenic cytokine interleukin-6 from MONO MAC 6 monocytic cells incubated with the product. The interleukin-6 was detected using a specific and sensitive ELISA developed for this purpose. The test system detected pyrogenic contamination in 3 batches of therapeutic human serum albumin which had caused adverse reactions in recipients. The contamination was not detected in conventional tests: the rabbit pyrogen test and the limulus amoebocyte lysate test.
Improvement of Absorption Rate of Indomethacin and Reduction of Stomach Irritation by Alginate Dispersions
Authors: Shiraishi Sumihiro , Imai Teruko , Iwaoka Daisuke , Otagiri Masaki
Published: April 2011

The dissolution rates of indomethacin from low molecular weight (mol. wt) alginate dispersions were significantly enhanced in comparison with that of indomethacin alone. The dispersion with lower mol. wt alginate exhibited more rapid dissolution rate than that of dispersion with higher mol. wt alginate. These enhanced dissolution rates of indomethacin by alginate may be due to the improvement of wettability and the decrease of crystallinity and crystal size. The absorption rate from alginate dispersions was enhanced in comparison with that from indomethacin alone, and enhanced only the rate of bioavailability in beagle dogs and volunteers. In addition, indomethacin-induced gastric lesions were reduced by dispersing indomethacin in alginate.
Studies to determine whether there is tolerance or cross-tolerance to the antisecretory effect of morphine and clonidine in the rat intestine
Authors: Margaritis Jamie , Coupar Ian M , Bentley Geoffrey A
Published: April 2011

Intra-arterial infusions (4 μg min−1) of prostaglandin E2 (PGE2) were used to stimulate intestinal fluid secretion in anaesthetized rats. Morphine (0·625–40 mg kg−1) produced a dose-dependent restoration of fluid transport from secretion to the normal rate of absorption. Pretreatment with up to eight doses of morphine (20 mg kg−1) did not induce tolerance, rather it enhanced the antisecretory effect of a subsequent acute dose of morphine. It seems probable that this was caused by the accumulation of morphine in the intestine. Clonidine (4–1000 μg kg−1, like morphine, produced a dose-dependent reversal of stimulated fluid secretion. Pretreatment with clonidine (4 × 0·25 mg kg−1) caused a shift of the clonidine antisecretory dose-response curve to the right, demonstrating tolerance. Pretreatment with clonidine also caused cross-tolerance to the antisecretory effect of morphine. The results suggest that there is a close relationship between opioid- and α2-adrenoceptors in controlling inhibition of intestinal fluid secretion.
Selective In-vitro Inhibition of Hepatic Oxidative Metabolism by Quinolones: 7-Ethoxyresorufin and Caffeine as Model Substrates
Authors: Valero Fernando , De La Torre Rafael , Segura Jordi
Published: April 2011

The in-vitro inhibition of several metabolic pathways has been studied in 3-methylcholanthrene-treated rats. The specificity of the 7-ethoxyresorufin O-de-ethylase reaction has been determined in the presence and absence of ciprofloxacin, enoxacin, norfloxacin, ofloxacin, nalidixic acid, oxolinic acid and pipemidic acid. For the caffeine N3-demethylation reaction, enoxacin and pipemidic acid were used. Enoxacin (IC50=105 μM, Ki = 65 μM) and pipemidic acid (IC50 = 115 μM, Ki=160 μM) significantly inhibited 7-ethoxyresorufin O-de-ethylase reaction and caffeine N3-demethylation (IC50 = 60 μM for enoxacin and IC50 = 185 μM for pipemidic acid) by a competitive mechanism. Other quinolones had lower or no (ofloxacin) inhibitory capacity. The order of inhibitory activity observed is in agreement with results obtained previously from in-vivo studies in man. No activity was detected towards ethylmorphine N-demethylation.
Regional Distribution of Imipramine, Desipramine and Specific [3H]Desipramine Binding Sites in the Rat Brain after Acute and Chronic Treatment with Imipramine
Authors: Daniel Wladyslawa , Danek Leokadia , Janczar Lucyna , Nocon Halina , Melzacka Miroslawa
Published: April 2011

Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment of rats with imipramine has been investigated. Both substances were distributed unevenly within rat brain after single and prolonged administration of imipramine. This was partly connected with the regional cerebral blood flow, lipid content in the regions and lipophilicity of the substances investigated. It was also found that the number of specific [3H]desipramine binding sites was different in the various brain areas, and that prolonged administration of imipramine led to a decrease of their number in some of those regions. No correlation was found between the regional cerebral distribution of desipramine and the regional density of specific [3H]desipramine binding sites.
The Effect of Immunization with Protein-sulphanilic Acid Conjugate on Sulphanilic Acid Disposition in the Rat
Authors: Yamamoto Akira , Kawaratani Toshitaka , Aisaka Ayumi , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

Rats were immunized with bovine γ-globulin-sulphanilic acid conjugate and the plasma concentration of sulphanilic acid examined after an intravenous injection of this drug. There was a significant increase in plasma half-life and AUC and a significant decrease in clearance of sulphanilic acid in the immunized rats compared with the control. In the immunized rats, binding of sulphanilic acid to macromolecules in serum, determined by ultrafiltration, decreased with increase of sulphanilic acid concentration. At low concentrations, there was a significant increase in % binding of the drug in the zerum of immunized rats compared with controls. There was also a significant reduction in urinary excretion of total drug in the immunized rats compared with controls. These findings suggest that sulphanilic acid-specific antibodies in the serum of immunized animals bind [14C]sulphanilic acid, giving rise to higher serum levels thereby making it unavailable for normal excretory processes.
Evaluation of in-vitro leishmanicidal activity of hydrazones of thiophene carboxaldehydes against promastigotes of Leishmania infantum and Leishmania tropica
Authors: Savornin B , Madadi N E , Delmas F , Gasquet M , Timon-David P , Vanelle P , Maldonado J
Published: April 2011

The lack of leishmanicidal drugs has prompted the synthesis and testing of new hydrazones of thiophene carboxaldehydes against three Leishmania strains. The compounds were obtained by condensation of appropriate hydrazines with thiophene 2-carboxaldehyde (series 7), thiophene 3-carboxaldehyde (series 2), and 5-nitrothiophene-2-carboxaldehyde (series 3). Leishmanicidal activity was assessed against promastigotes of Leishmania strains, grown in-vitro in nutrient broth medium complemented with fresh rabbit blood. The minimal inhibitory concentrations were evaluated against pentamidine, as a reference drug. Several compounds exhibited significant leishmanicidal activity, the best being ten times more active than pentamidine.
New heteroaryl derivatives of fentanyl
Authors: Llama E F , Del Campo C , Capo M
Published: April 2011

The preparation of analogues of fentanyl with N-phenyl replaced with a heterocyclic aromatic ring, and with N-alkyl/arylalkyl N-acyl substituents is reported. Only those compounds carrying an N-phenylethyl substituent were active in the rat tail-withdrawal test. Fentanyl (1) is the prototype of the 4-anilido-piperidine class of opioid analgesics (Casy & Parfitt 1986). Several recent publications (Casy & Huckstep 1988; Bagley et al 1989) on this series have dealt with heterocyclic and aromatic modifications of the fentanyl molecule. Although the antinociceptive potency of most novel derivatives was greater than that of morphine, they had reduced activity when compared with fentanyl itself. To acquire further information on the structure-reactivity relationships of the series, new heteroaryl derivatives have been prepared and tested for antinociceptive activity.
Diuretic and saliuretic effects of 1,3-dipropyl-8-cyclopentylxanthine, a selective A1-adenosine receptor antagonist
Authors: Collis M G , Shaw G , Keddie J R
Published: April 2011

We have previously shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1-and A2-receptors, has a diuretic effect. In this study, the diuretic and adenosine antagonist effects of the A1-receptor selective compound 1,3-dipropyl-8-cyclopentylxanthine (CPX) have been examined in the conscious rat. CPX (0.1 and 0.3 mg kg−1 i.v.) significantly attenuated bradycardic but not hypotensive responses evoked by adenosine. In contrast, 8-PT (3 mg kg−1 i.v.) significantly antagonized both adenosine-induced bradycardia and hypotension. CPX (0.1 and 0.3 mg kg−1 i.v.) evoked a dose-related diuretic and saliuretic response in the conscious rat. These results indicate that the diuretic effects of adenosine antagonists are associated with blockade of the A1-receptor sub-type.
The Plasma Disposition and Renal Elimination of Digoxinspecific Fab Fragments and Digoxin in the Rabbit
Authors: Timsina M P , Hewick D S
Published: April 2011

Administering digoxin-specific antibody fragments (DSFab, 1·9 mg kg−1, i.v.) to rabbits 1 h after digoxin (15 μg kg−1 or 12·5 μCi kg−1, i.v.) produced a redistribution of digoxin associated with a 5-fold elevation in total plasma concentration and 36–86% reductions in elimination half-life, apparent volume of distribution at steady-state and total body clearance (CLT). Renal clearance (CLR) was also reduced (54%), but urinary digoxin excretion was increased by one-third (35% vs 25%). This apparent anomaly is due to the large rise in total plasma digoxin concentration with a consequent increase in the area under the plasma concentration curve (AUC). The AUC, which is the denominator term in calculating CLR (and CLT), was increased to a greater extent than urinary digoxin excretion (numerator term in calculating CLR) so that an overall reduction in CLR occurred. The initial presence of digoxin appeared to alter the distribution of DSFab, since their plasma concentrations were markedly higher when the antibody was given after the hapten. The digoxin also reduced (from 3 to 1%) the amount of detectable DSFab in the urine.
A Rapid Filtration Assay for the Glycine Binding Site on the NMDA Receptor in Rat Cortical Membranes using [3H]Dichlorokynurenic Acid
Authors: Canton Thierry , Doble Adam , Miquet Jean-Marie , Jimonet Patrick , Blanchard Jean-Charles
Published: April 2011

A filtration binding assay using [3H]dichlorokynurenic acid to label the glycine binding site on the N-methyl-d-aspartic acid receptor has been evaluated on rat cortical membranes. This ligand binds to a single population of binding sites following mass action kinetics with a Kd of 29 Nm and a capacity of 5·73 pmol (mg protein)−1. The pharmacological specificity of the binding site is identical to that previously reported for this binding site using [3H]glycine as a radioligand. Agonists showed lower affinity and antagonists higher affinity when [3H]dichlorokynurenic acid was used compared with [3H]glycine. The higher affinity of [3H]dichlorokynurenic acid compared with [3H]glycine make it the more suitable compound with which to label the glycine site.
Cardiovascular Effects of LAS 30538, a New Vascular Selective Ca2+-Channel Blocker
Authors: Cardelús I , Bou J , Llenas J , Berga P , Gristwood R W
Published: April 2011

A new compound, 1-[2-(2,6-dimethylphenoxy)ethyl]-α,α-bis-(p-fluorphenyl)-4-piperidine methanol (LAS 30538), was found to have potent vasodilator effects. Its vasorelaxant activity was demonstrated in rat perfused hindlimbs contracted with 80 Mm K+, having an IC50 value of 40 Nm. In conscious spontaneously hypertensive rats, LAS 30538 administered orally, caused dose-dependent sustained falls in systolic blood pressure with an ED30 value of 11 mg kg−1. In pithed rats, LAS 30538, strongly inhibited vasoconstriction induced by the α2-adrenoceptor agonist B-HT 933 and the calcium agonist compound Bay K8644 with ED50 values of 4 mg kg−1 p.o. and 1·3 mg kg−1 i.v., respectively. Results from electrophysiological studies carried out using guinea-pig papillary muscles partially depolarized by 22 Mm K+ are consistent with LAS 30538 acting as a Ca2+-channel blocker. When compared with verapamil, in guinea-pig and rabbit isolated heart preparations, LAS 30538 caused less cardiodepression and bradycardia. The results suggest that LAS 30538 may have some advantages over other Ca2+-channel blockers such as verapamil in causing less myocardial depression for a given level of vasodilatation.
Effects of selective histamine receptor antagonists on skin responses to intradermal bradykinin in healthy volunteers
Authors: Li Kam Wa Tin C , Cooke Ernest D , Turner Paul
Published: April 2011

The effects of chlorpheniramine and cimetidine on the cutaneous responses to intradermal injections of bradykinin were investigated in a randomized, double-blind, placebo-controlled, cross-over study. Chlorpheniramine significantly attenuated the increase in cutaneous blood flow and erythema induced by bradykinin but not the weal response. Cimetidine was without influence on these parameters and the effects of the combined therapy of chlorpheniramine and cimetidine were not significantly different from those due to chlorpheniramine alone. These results suggest that the cutaneous vasodilator effect of bradykinin is in part due to histamine release acting on histamine H1-receptors.
Gastric anti-ulcer activity of silymarin, a lipoxygenase inhibitor, in rats
Authors: De La Lastra C Alarcon , Martin M J , Marhuenda E
Published: April 2011

Oral treatment with silymarin was found to be effective in the prevention of gastric ulceration induced by cold-restraint stress, in rats. Statistically significant ulcer index values with respect to the control group, were observed. In 6 h pyloric-ligated animals silymarin showed a significant reduction in the number and severity of the ulcers; however, it did not alter the gastric secretion volume or acidity although histamine concentration was significantly decreased. In absolute ethanol-induced ulcers, treatment with silymarin 1 or 2 h before the anti-ulcerogenic agent, did not prevent the formation of gastric lesions. Furthermore, the hexosamine content was decreased significantly, but the total protein output was enhanced, showing similar values to those with the standard drug, carbenoxolone. These results suggest that the anti-ulcerogenic effect of silymarin could be related to its inhibitory mechanism of enzymatic peroxidation by the lipoxygenase pathway, avoiding leukotriene synthesis.
Safety Aspects of Non-ionic Surfactant Vesicles: A Toxicity Study Related to the Physicochemical Characteristics of Non-ionic Surfactants
Authors: Hofland H E J , Bouwstra J A , Verhoef J C , Buckton G , Chowdry B Z , Ponec M , Junginger H E
Published: April 2011

Two different toxicity models were used to assess the relationship between the physicochemical properties of non-ionic surfactant vesicles (NSVs), and the safety of these vesicles for topical drug administration. The vesicles used in this study consisted of polyoxyethylene alkyl ethers (CnEOm) in which the number of C atoms (n) varied between 12 and 18 and the number of oxyethylene units (m) between 3 and 7. The physicochemical properties of the vesicles are described in terms of hydrophilic-lipophilic balance (HLB) values, and critical micelle concentrations (CMC), and the rigidity of the bilayers as determined by the gel-liquid transition temperatures and the cholesterol content of the bilayers. The first toxicity model, comprising the measurement of the ciliary beat frequency, is a tool to assess the safety of intranasally applied formulations. Studies using this ciliotoxicity model revealed that by increasing the length of the alkyl chain of the surfactant, a decrease in toxicity was observed. The opposite correlation was found if the length of the polyoxyethylene headgroup was increased. Furthermore, it was observed that gel-state vesicles produce less of an effect on the ciliary beat frequency than liquid state vesicles. The second toxicity model, comprising the determination of cell proliferation of human keratinocytes, is a method to assess skin irritancy. In contrast to the ciliotoxicity model the length of the polyoxyethylene headgroup and of the alkyl chains did not seem to have an effect on the safety of the vesicles. However, the bond by which the headgroup is linked to the alkyl chain, showed a very strong effect on the toxicity of the surfactant: oleyl-EO5 ester vesicles were found to have an effect on the cell proliferation, which was one-sixteenth that of the oleyl-EO5 ether vesicles. The cholesterol content did not appear to have an effect on the proliferation of the keratinocytes. Neither the HLB nor the CMC values appeared to have an effect on the safety of the NSV formulations as observed in both toxicity models.
Roles of PMN Leucocytes, Platelets and Some Mediators in Rat Hind-paw Oedema Induced by Two Phospholipase A2 Enzymes From Trimeresurus mucrosquamatus Venom
Authors: Wang Jih-Pyang , Teng Che-Ming
Published: April 2011

Two phospholipase A2 (PLA2) enzymes, TMVPLA2 I and TMVPLA2 II, isolated from Trimerusurus mucrosquamatus venom induced rat hind-paw oedema. Recovered myeloperoxidase activity increased within 1 h and was greatly elevated in the rat paw 3–6 h after subplantar injection of these venom PLA2 enzymes. Methotrexate pretreatment significantly reduced not only the peripheral leucocyte count but also venom PLA2-induced paw oedema. In rat isolated PMN leucocyte suspension, venom PLA2 induced superoxide radical formation. Paw swelling caused by TMVPLA2 I or TMVPLA2 II was only slightly or not, respectively, reduced in the rats pretreated with anti-platelet plasma, which reduced peripheral blood platelet count by >96%, suggesting platelets are not involved. In isolated platelet preparation, TMVPLA2 I induced platelet activation in a concentration-dependent manner, while TMVPLA2 II had no effect. Pretreatment with diphenhydramine/methysergide greatly suppressed the oedematous responses caused by the two venom PLA2 enzymes; the residual responses were significantly further depressed by aspirin. The oedematous responses caused by the enzymes were also suppressed by FPL 55712, BW 755C, dexamethasone, superoxide dismutase/catalase, isoprenaline and terbutaline. However, BN 52021 and L 652731, both platelet aggregating factor antagonists, were not effective on these responses. Thus, in addition to histamine and 5-hydroxytryptamine release by the mast cells in PLA2-induced paw oedema (Wang & Teng 1990), the results of this study indicate minor, but significant, roles for neutrophils and inflammatory mediators including prostaglandins, leukotrienes and superoxide radicals.
Effects of Platelet Activating Factor on Contractions and Ca Influx Induced by Noradrenaline and Potassium in Rat Rubbed and Intact Aorta. Comparison with Its Hypotensive Effect in Anaesthetized Normotensive Rats
Authors: Orallo Francisco , Verde Ignacio , Loza Ma Isabel , Alzueta Alejandro F , Campos Manuel , Freire-Garabal Manuel
Published: April 2011

In order to clarify the mechanism of hypotensive activity of platelet activating factor (PAF), the effects of this drug on blood pressure in anaesthetized normotensive rats, on KCl- and noradrenaline-induced 45Ca uptake and contractile responses in rat aorta rings with and without endothelium were studied. PAF (3 μg kg−1, i.v.) showed long-lasting hypotensive effects in anaesthetized normotensive rats accompanied by a significant increase in heart rate. PAF (0·1–10 μm) did not relax the contractions induced by noradrenaline (10 μm) or K+ (60 Mm) in rubbed or intact rat aorta. PAF did not affect the basal uptake of 45Ca2+ nor that induced by the two vasoconstrictor agents. In experiments in a calcium free medium, PAF (10 μm) had no effect on the noradrenaline- (10 μm) induced contractions. These results suggest that the hypotensive activity of PAF in normotensive anaesthetized rats is not due to a direct effect on rubbed and intact rat aorta rings (acting within the cell or blocking Ca2+ influx through l-type transmembrane calcium channels).
Bupivacaine kinetic changes during the oestrous cycle in rats
Authors: Bruguerolle Bernard
Published: April 2011

After a single 20 mg kg−1 i.p. dose during pro-oestrus, oestrus or dioestrus, bupivacaine kinetics in rats were not significantly different except for Cmax which was significantly higher during dioestrus.
Use of prostaglandin E1 (lipo-PGEi) to treat Raynaud's phenomenon associated with connective tissue disease: thermographic and subjective assessment
Authors: Katoh Kyoshi , Kawai Takako , Narita Masahiro , Uemura Junta , Tani Kenji , Okubo Takao
Published: April 2011

Four patients with connective tissue disease who had been suffering from severe Raynaud's phenomenon were treated with an intravenous infusion of prostaglandin E1 (PGE1) and its effectiveness was assessed by thermography and a questionnaire approach. PGE1 in a lipid microsphere formulation (lipo-PGE1) produced a significantly greater increase in lesional skin temperature compared with treatment with PGE1 clathrated in α-cyclodextrin 12 months previously in the same group of patients. These results were supported by the subjective assessment obtained from the patients by questionnaire.
Anti-inflammatory activity of oleanolic acid in rats and mice
Authors: Singh G B , Singh Surjeet , Bani S , Gupta B D , Banerjee S K
Published: April 2011

Oleanolic acid displayed anti-inflammatory activity in carrageenan and dextran-induced oedema in rats. It elicited marked anti-arthritic action in adjuvant-induced polyarthritis in rats and mice and in formaldehyde-induced arthritis in rats. Oleanolic acid checked the inflammation-induced increased serum transaminase levels. It reduced exudate volume and inhibited leucocyte infiltration in carrageenan-induced pleurisy in rats. It is devoid of any analgesic, antipyretic or ulcerogenic action. Oleanolic acid did not affect the parturition time in pregnant rats or castor oil-induced diarrhoea in rats. Oral LD50 was found to be greater than 2 g kg−1 in mice and rats.
Estimation of Elastic Recovery, Work of Decompression and Young's Modulus Using a Rotary Tablet Press
Authors: Dwivedi S K , Oates R J , Mitchell A G
Published: April 2011

Capping and lamination occur when the bonds within a tablet cannot withstand the elastic recovery during decompression. To estimate tablet recovery, it is necessary to subtract the machine recovery from the total recovery during decompression. A direct relationship between the force and machine deformation is applied in a novel fashion to calculate in-die tablet recovery on a Manesty Betapress and to estimate the Young's modulus, E, of various solids from the recovery data. The E values of about twenty-five pharmaceutical solids were found to be in reasonable agreement with literature values. This procedure allows in-process analysis of tablet recovery and gives E without the use of specialized equipment.
A Comparison of Glycine, Sarcosine, N,N-Dimethylglycine, Glycinebetaine and N-Modified Betaines as Liposome Cryoprotectants
Authors: Lloyd Andrew W , Baker James A , Smith Geoffrey , Olliff Cedric J , Rutt Ken J
Published: April 2011

Glycinebetaine has previously been shown to be effective at reducing leakage from liposomes which are frozen then thawed. This study involved the preparation of a series of N-modified betaines and the comparison of their cryoprotective activities with those of glycine, sarcosine, N,N-dimethylglycine and glycinebetaine. All the compounds investigated, with the exception of (dimethyloctylammonio)acetate, reduced the degree of leakage, after freezing and thawing, with additive concentrations up to 0·6 m. Reducing the degree of N-terminal methylation of glycinebetaine appeared to increase the leakage from liposomes at additive concentrations between 0·2 and 0·6 m. (Dimethylethylammonio)acetate, (dimethyl-isopropylammonio)acetate and (N,N,N',N'-tetramethylethylenediammonio)-N,N'-diacetate appeared to be no more effective than glycinebetaine, whereas improved protection was afforded by (triethylammonio)acetate and (diethylmethylammonio)acetate at most concentrations. This study demonstrates that the cryoprotective activity of glycinebetaine may be improved with modifications to the N-terminal.
Effects of lithium and haloperidol on human sperm motility in-vitro
Authors: Shen Meng-Ru , Yang Rei-Cheng , Chen Shun-Sheng
Published: April 2011

Two psychotropic drugs, lithium and haloperidol, were evaluated for their in-vitro effects on sperm motility using a transmembrane migration method. Sperm motility was measured either immediately after semen had been mixed with the drug or after a 2 h incubation period at 37°C. Lithium inhibited human sperm motility in a dose-dependent manner with an EC50 of 10 Mm when the semen-lithium mixture had been incubated. Sperm motility was increased to 127% of control when semen had been incubated with 0027 μm haloperidol; this concentration was within the therapeutic range.
Tetrandrine and Isotetrandrine, Two Bisbenzyltetrahydroisoquinoline Alkaloids from Menispermaceae, with Rat Uterine Smooth Muscle Relaxant Activity
Authors: D'Ocón Pilar , BláZquez M Amparo , Bermejo Almudena , Anselmi Elsa
Published: April 2011

The effects of two bisbenzyltetrahydroisoquinoline alkaloids, 1S, 1′S tetrandrine and its isomer 1R, 1′S isotetrandrine, were investigated in rat isolated uterus in order to identify the mechanism of relaxant action and to study the influence of the absolute configuration on the activity of these alkaloids. Both inhibited the uterine contraction induced by high K+, acetylcholine and oxytocin. In Ca2+-free medium, isotetrandrine relaxed the sustained contraction induced by oxytocin but tetrandrine did not. The relaxant effects of the alkaloids may be due to blockade of calcium influx through specific channels. Tetrandrine and isotetrandrine modify the calcium channel in a nonreversible manner whilst only isotetrandrine acts intracellularly. Tetrandrine shows a more specific relaxant activity as a calcium entry blocker.
Design, Synthesis and Biological Activity of a Series of Torasemide Derivatives, Potent Blockers of the Na+ 2Cl− K+ Co-transporter: In-vitro Study
Authors: Masereel B , Lohrmann E , Schynts M , Pirotte B , Greger R , Delarg J
Published: April 2011

Pharmacomodulation of the torasemide molecule, a loop diuretic inhibiting Na+ 2Cl− K+ co-transport in the thick ascending limb of the loop of Henlé has been performed in order to obtain new long-acting diuretics. The aim of this study was to decrease the metabolism of the drug and to slow down its rate of excretion by increasing its hydrophobicity. The present study describes the synthesis and the inhibitory potency of new torasemide derivatives in the bioassay system of the cortical thick ascending limb of rabbit. A correlation between the lipophilicity (log P') of these substances and their activity as inhibitors of the Na+ Cl− K+ co-transporter was observed. The present design led to compounds more active than torasemide. Structure-activity relationships permit us to propose an interaction model between torasemide derivatives and the Na+ 2Cl− K+ co-transport system of the cortical thick ascending limb.
Induction of propranolol metabolism in the Hep G2 human hepatoma cell line
Authors: Steiner Alain , Walle U Kristina , Walle Thomas
Published: April 2011

Metabolism of propranolol by the human hepatoma cell line Hep G2 was studied. Although metabolism qualitatively was similar to that in-vivo, the P450-mediated N-desisopropylation clearly predominated. Pretreatment of cells with 3-methylcholanth-rene increased the activity of this pathway 14-fold, whereas phenobarbitone had no effect. This is similar to the pathway-selective inductive response observed for cigarette smoking in-vivo. As in-vivo, secondary metabolism of N-desisopropylpropranolol was extensive. This could, however, be completely blocked by 0·1 μm clorgyline, a potent MAO type A inhibitor. As in human liver microsomes, the stereochemistry of propranolol metabolism demonstrated a preference for the R(+)-enantiomer. These observations emphasize the usefulness of the Hep G2 cell line as a model of man.
Metabolic Activation of Sennoside C in Mice: Synergistic Action of Anthrones
Authors: Yamauchi Kazuko , Shinano Kayoko , Nakajima Kazuko , Yagi Teruyo , Kuwano Shigeaki
Published: April 2011

Sennosides A and C directly injected into the caecum of mice showed equal purgative activity. Intracaecal administration reduced time to onset of diarrhoea induced by sennoside C from about 3 h after oral administration to about 24 min. At 2·3 h after oral administration of sennoside C., nearly equimolar amounts of aloe-emodin anthrone and rhein anthrone were detected in the large intestine of mice. The purgative effect of oral sennoside C could be reduced by pretreating mice with chloramphenicol. This was observed as a decreased formation of total anthrones in the large intestine. Both anthrones and an equimolar mixture of both anthrones directly injected into the caecum exerted a purgative effect, although the activity was lower for aloe-emodin anthrone. The intracaecal ED50 values were 54·5 (24·1–89·6), 11·4 (5·0–15·7) and 11·2 (6·1–14·6) μmol kg−1 for aloe-emodin anthrone, rhein anthrone and an equimolar mixture of both anthrones, respectively. We concluded that aloe-emodin anthrone and rhein anthrone, formed mainly by intraluminal bacterial action, are the true active metabolites of sennoside C in mice and that both anthrones synergistically exert their purgative effects on mice.
The Effects of Labetalol and Dilevalol on Isolated Cardiovascular Preparations of the Guinea-pig and Rat
Authors: Doggrell Sheila A
Published: April 2011

Differing effects of labetalol and dilevalol on cardiovascular preparations have been reported. I have studied the effects of labetalol and dilevalol on the contractile responses of the rat and guinea-pig left atria and rat portal vein. On the guinea-pig left atria low concentrations of labetalol (≥ 10−8  m) and of dilevalol (≥ 10−7  m) inhibited to a small extent the responses to electrical cardiac stimulation, which is indicative of membrane stabilizing activity. Labetalol (≥ 3× 10−8  m) and dilevalol (≥ 10−8  m) caused surmountable antagonism of the isoprenaline responses of the atria and the pA2 values were 8·60 and 8·98 at the β1-adrenoceptors of the rat left atria and 7·90 and 8·31, respectively, on the guinea-pig left atria which has functional β1 and β2-adrenoceptors. Labetalol and dilevalol (both at ≥ 10−7  m) attenuated the spontaneous contractile activity of the rat portal vein and the attenuation to labetalol at 10−6  m was abolished by ICI 118,551 which illustrates that the labetalol-induced attenuation is β2-adrenoceptor mediated. The isoprenaline attenuation responses of the portal vein were inhibited by labetalol and dilevalol (both at ≥ 10−7  m) and the pA2 value for the labetalol at β2-adrenoceptors was 7·59. It is concluded that labetalol and dilevalol are β1-adrenoceptor selective antagonists.
Simultaneous Determination of Bufadienolides in the Traditional Chinese Medicine Preparation, Liu-Shen-Wan, by Liquid Chromatography
Authors: Hong Z , Chan K , Yeung H W
Published: April 2011

The bufadienolide compounds (bufalin, cinobufagin and resibufogenin), major constituents of Chansu in Liu-Shen-Wan (LSW), were determined by reverse phase high performance liquid chromotography. The procedure involves a preliminary extraction of the bufadienolides from LSW with chloroform using ultrasonication and subsequent evaporation to dryness of the chloroform extract. The residue of the chloroform extract was dissolved in methanol and separated on a Merck LiChrosorb RP-18 column. Methanol: water (74:26) was used as mobile phase. The compounds were satisfactorily separated with good chromatographic peaks. Good coefficients of correlation (r > 0·999) were obtained from the calibration of peak areas with concentrations for the 3 bufadienolides. Results of analysis showed that there were differences between the contents of bufadienolides in 11 LSW samples of different origin available to the public in Hong Kong where at present there is no legal control over the sale of traditional Chinese medicines. The variability of quantities of bufadienolides in Chansu may be a hazard to the public.
A Semi-empirical Study of some Clavulanic Acid Derivatives in Relation to their Activity as β-Lactamase Inhibitors
Authors: Fernández Berta , Ríos Miguel A
Published: April 2011

Clavulanic acid and some of its derivatives are inhibitors of β-lactamases and hence enhance the activity of antibiotics such as cephaloridine, amoxycillin and ampicillin against β-lactamase-producing bacteria. Several empirical structure-activity relationships have been proposed for these compounds; bearing these findings in mind, we have carried out a semi-empirical structural study on clavulanic acid and twelve of its derivatives lacking the carboxyl group. We relate our results to the available activity data, focusing on features such as planarity at the N atom, charge distribution and the orientation of the substituents, all of which are related to the activity of these systems.
The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size
Authors: González-Martin Guillermo , Ponce Graciela , Inostroza Verónica , González Mario , Paulos Claudio , Guevara Alfredo
Published: April 2011

The disposition of nifurtimox was studied in the rat isolated perfused liver using a recirculating system. The drug was administered as a bolus (5·0, 15·0 or 30·0 μg mL−1), and its disappearance was monitored by analysing perfusate samples. In all experiments perfusate disappearance was monoexponential, and no significant difference was found between the three doses for the elimination constant (0·016, 0·011 and 0·012 min−1, respectively), half-life (46·6, 65·8 and 66·8 min, respectively), extraction rate (0·128, 0·091 and 0·099, respectively) and distribution volume (41·1, 47·3 and 30·7 mL g−1, respectively). At 30 μg mL−1 the hepatic clearance was lower than the other concentrations of nifurtimox (0·66, 0·51 and 0·34 mL min−1 g−1, respectively). Relatively little parent drug was recovered from the liver at the end of the perfusions. In summary, nifurtimox is cleared slowly from the rat isolated perfused liver, is poorly extracted by hepatocyte cells and is completely metabolized from 2 to 4 h after perfusion.
The Urinary Excretion of Tryptophan and Tryptophan Metabolites in the Chronic Ethanol-fed Rat
Authors: Bonner Adrian B , Brien Sarah , Preedy Victor R
Published: April 2011

An investigation was made into the hypothesis that chronic ethanol ingestion disturbs the metabolism of tryptophan which is reflected by alterations in the urinary excretion of the metabolites 5-hydroxyindoleacetic acid (5-HIAA), anthranillic acid (AA) and indoleacetic acid (IAA). In particular, we investigated whether experimental chronic alcoholism is associated with a decrease in the tryptophan metabolite ratios as suggested in the literature. Male Wistar rats were chronically fed a nutritionally-complete liquid diet in which ethanol comprised 35% of total calories: controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. At 6 weeks, 24 h urine samples were collected for the analysis of tryptophan, 5-HIAA, AA and IAA by HPLC. During ethanol-feeding there were reductions in the daily urinary excretion (i.e. μmol/24 h) of tryptophan (–57%, P = 0·026) and concomitant increases in 5-HIAA excretion (62%, P = 0·057). Expression of data in terms of lean tissue mass (i.e. urinary creatinine) revealed identical conclusions. An analysis was performed on the molar ratios of these urinary analytes. The tryptophan: total metabolite ratio was significantly decreased (by −53%), but the AA: total metabolite ratio was not significantly altered (P = 0·102). The ratios 5-HIAA/AA and 5-HIAA/IAA were slightly increased, but they did not attain statistical significance (P > 0·351). It was concluded that chronic ethanol feeding is associated with significant changes in the urinary excretion of tryptophan and its related metabolites. Many of the above changes were contrary to previous clinical data and this may be due to dietary and nutritional deficiencies or to alterations in the diurnal pattern of 5-hydroxytryptamine and tryptophan metabolism.