bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of 15-Hydroperoxyabietic Acid as a Contact Allergen in Portuguese Colophony
Authors: Karlberg Ann-Therése , Bohlinder Karin , Boman Anders , Hacksell Uli , Hermansson JÖrgen , Jacobsson Sven , Nilsson J Lars G
Published: April 2011

15-Hydroperoxyabietic acid (15-HPA) has been isolated from Portuguese colophony of the gum rosin type and identified as its methyl ester. The structure of the compound was elucidated using UV, IR, NMR and mass spectrometry. 15-HPA methyl ester was found to be an elicitor when tested in colophony-sensitized guinea-pigs. The sensitizing capacity was verified in the same species and 15-HPA methyl ester was considered to be a strong allergen. The eliciting potential was also verified in patients with known allergy to colophony. The Portuguese gum rosin investigated contained approximately 1% of 15-HPA. Based on its allergenicity and the amounts isolated, we conclude that 15-HPA is a main contact allergen in Portuguese gum rosin.
Evidence for a functional cholinergic deficit in human colonic tissue resected for constipation
Authors: Burleigh D E
Published: April 2011

There is evidence to suggest an abnormality of the colonic myenteric plexus in severe chronic constipation. The present study investigates whether this abnormality involves functional changes in the cholinergic innervation of human colon. Human taenia coli muscle strips (taenia), previously incubated with [3H]choline to radiolabel neuronal stores of acetylcholine, were subjected to electrical field stimulation (1 Hz or 10 Hz, 1 ms, 480 pulses at 200 mA). The stimulation evoked release of tritiated material, shown previously to accurately represent neural [3H] acetylcholine release, was depressed in tissue from constipated compared with non-constipated patients. Evoked release of tritiated material was reduced by storage of the taenia at 4 °C or by increasing the frequency of stimulation, but increased by stimulation during incubation with [3H]choline. The results indicate that reduced activity of cholinergic nerves may occur within the bowel wall of colon removed for severe chronic constipation.
Effects of zinc sulphate on gastric mucosal blood flow and gastric emptying of the rat
Authors: Lloris J M , Esplugues J V , Sarria B , Calvo M A , Marti-Cabrera M , Marti-Bonmati E , Esplugues J
Published: April 2011

Zinc sulphate (50 mg kg−1 p.o.) did not modify basal gastric mucosal blood flow, as measured by [3H]aniline clearance, but inhibited its reduction by noradrenaline (3.5 μg kg−1 min-1). Zinc sulphate also influenced gastric emptying of phenol red but its effects depended upon the dose; 30 mg kg−1 caused no variation whereas 80 mg kg−1 induced a significant delay. The nature of both actions is discussed and their implications in the development and prevention of gastric ulceration have been analysed.
Solubilization of Vitamin K1 by Bile Salts and Phosphatidylcholine-Bile Salts Mixed Micelles
Authors: Nagata Mariko , Yotsuyanagi Toshihisa , Ikeda Ken
Published: April 2011

The solubilization of vitamin K1 by bile salts (sodium deoxycholate, sodium cholate and their corresponding glycine conjugates) and phosphatidylcholine (egg)-bile salt mixed micelles has been investigated. The solubilization curves were not always linear with increasing bile salts, but the vitamin was appreciably solubilized in the region below their CMCs. In the bile salt solutions (20 mM, phosphate buffered saline, pH 7.5, ions strength 0.2), the solubilized vitamin ranged from 0.3 to 0.9 mM. With increasing phosphatidylcholine, the amount of vitamin solubilized was dramatically increased; at the molar ratio of 1:1 (both 20 mM), the amount of vitamin solubilized was about 25–30 times more than by the corresponding bile salts alone. There is a possibility that exogeneous phospholipid given orally as liposomal forms assists the solubilization of vitamin K1, in the intestine. This characteristic is suggested as being responsible, in part, for the enhanced recovery of blood coagulation after oral administration of liposomal vitamin K1 to warfarin-treated rabbits.
Age-dependent pulmonary first-pass elimination of propranolol in rats
Authors: Iwamoto Kikuo , Watanabe Jun , Aoyama Yoko
Published: April 2011

Plasma levels of propranolol after 2.5 mg kg−1 given i.v. and i.a. have been compared in 3- to 4-week-old rats to evaluate the effect of age on pulmonary first-pass elimination of the drug. In 5- to 52-week-old rats, the area under the plasma concentration-time curve (AUC) after an intra-arterial dose was always larger than that after the i.v. dose. The plasma elimination half-lives after both routes of administration were almost identical, but tended to increase with age between weeks 7 and 104. First-pass pulmonary clearance and extraction ratio tended to decrease with age between weeks 7 and 52.
Determination of rat cerebrospinal fluid concentrations of adenosine, inosine, hypoxanthine, xanthine and uric acid by high performance liquid chromatography
Authors: Walter Gary A , Phillis John W , O'Reagan Michael H
Published: April 2011

Isocratic reverse-phase high performance liquid chromatography techniques were developed to resolve and quantitate the purine nucleosides adenosine (Ado) and inosine (Ino) and their metabolites hypoxanthine (Hyp), xanthine (Xan), and uric acid (UA) in the cerebrospinal fluid of the rat. The moving phase composition for resolving hypoxanthine, xanthine and uric acid was a 0.22 M, pH 5.8 phosphate buffer. The moving phase composition for resolving adenosine and inosine was a 0.22 M, pH 6.8 phosphate buffer, 7% methanol (v/v) and 2.5 mM tetrabutylammonium phosphate. The observed cerebrospinal fluid concentrations in the rat were: Ado = 35 ± 9 nM (s.e.m.), Ino = 359 ± 85 nM, Hyp = 243 ± 77 nM, Xan = 1340 ± 423 nM and UA = 6130 ± 678 nM.
The emetic activity of centrally administered cisplatin in cats and its antagonism by zacopride
Authors: Smith William L , Callaham Esther M , Alphin Reevis S
Published: April 2011

Cisplatin administered by either the intravenous (i.v.) or intra-cerebroventricular (i.c.v.) route produced emesis in cats. The average time to onset of emesis was decreased significantly (4.0 min versus 100.6 min) when cisplatin was administered i.c.v. Zacopride administered either i.c.v. (0.02 mg) or i.v. (0.1 mg kg−1) completely blocked the emesis due to cisplatin given by either route. Their data show that cisplatin possesses a central emetic component and that this is blocked by zacopride.
The Dissolution Rate and Bioavailability of Hydrochlorothiazide in Pellet Formulations
Authors: Herman J , Remon J P , Lefebvre R , Bogaert M , Klinger G H , Schwartz J B
Published: April 2011

The influence of non-active ingredients in the manufacture of pellets on in-vitro dissolution rate and on bioavailability of hydrochlorothiazide has been studied. Pellets were formulated using either microcrystalline cellulose or microcrystalline cellulose-carboxymethylcellulose sodium blends as matrix, and hydrochlorothiazide as the active ingredient. In-vitro drug release from the different pellet formulations was retarded in comparison to a conventional tablet formulation and was dependent on the nature of the non-active ingredient and, for the microcrystalline cellulose-carboxymethylcellulose sodium blend, of the dissolution medium. In-vivo bioavailability of both pellet formulations was low compared with that of the conventional tablet and the plasma concentration-time profiles did not suggest slow release.
Evaluation of Reconstituted Sendai Virus Envelopes as Intra-articular Drug Vectors: Effects on Normal and Experimentally Arthritic Rabbit Knee Joints
Authors: Earl Rupert T , Hunneyball Ian M , Billett E Ellen , Mayer R John
Published: April 2011

Fusogenic vesicles reconstituted from the envelopes of Sendai virus particles were injected into rabbit knee joints (both normal and experimentally arthritic) to evaluate the in-vivo biocompatibility of these putative drug carriers. The reconstituted Sendai virus envelopes (RSVE) were > 80% retained within the arthritic knee joints after 24 h and studies with 125I- and fluoroscein-labelled RSVE both showed association of the vesicles with the synovia of arthritic and healthy joints. However, RSVE were found to cause inflammation after intra-articular injection, as judged by joint swelling and histological assessment, and these effects were exacerbated by successive administrations. RSVE-entrapped methotrexate, whether free or conjugated to human serum albumin, was ineffective in preventing the irritancy of RSVE or in reducing the chronic inflammation in joints affected by an experimentally induced arthritis.
Gastric emptying of large single unit dosage forms
Authors: Davis S S , Norring-Christensen F , Khosla R , Feely L C
Published: April 2011

The gastrointestinal transit of two single unit dosage forms has been followed in healthy subjects under different feeding conditions. Transit was affected by the size of the meal administered. When two tablets were given concurrently they often emptied from the stomach at or about the same time, but in a number of cases the two units were seen to empty at widely different times.
Dopamine-mediated behaviours produced in naive mice by bromocriptine plus SKF 38393
Authors: Jackson D M , Ross S B , Hashizume Mayko
Published: April 2011

The ability of bromocriptine and SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine) to produce some dopamine-mediated behaviours has been assessed in mice. Soon after injection, SKF38393 produced moderate increases in grooming and sniffing which were not very intense, while bromocriptine (with or without SKF38393) inhibited all grooming behaviour. Bromocriptine alone also depressed rearing and sniffing in the first hour and SKF38393 alone was without effect on rearing, but the combination produced a marked increase in the incidence of both rearing and sniffing, both of which behaviours appeared to be stereotyped. When bromocriptine-induced locomotor stimulation was peaking about 3 h after injection, as measured in automated activity cages in previous studies, there was an increase in sniffing and rearing, the incidence of which was unaffected by the addition of SKF38393, perhaps due to the shorter duration of action of SKF38393 than of bromocriptine. The data indicate that the D-1 agonist SKF38393 can qualitatively and quantitatively alter the behavioural spectrum produced by the D-2 agonist bromocriptine.
Study with Positron Emission Tomography of the Osmotic Opening of the Dog Blood-Brain Barrier for Quinidine and Morphine
Authors: Agon Philippe , Kaufman Jean-Marc , Goethals Patrick , van Haver Dirk , Bogaert Marc G
Published: April 2011

A canine model was used to evaluate the possibilities offered by positron emission tomography (PET) for the study of drug distribution in the brain during altered states of the blood-brain barrier (BBB). PET was used to monitor the changes in the distribution of [11C]quinidine and [11C]morphine resulting from BBB-disruption by intracarotid infusion of a hyperosmolar mannitol solution. Injection of Evans blue dye allowing post-mortem evaluation of the degree of BBB-opening was used as a reference method. Brain radioactivity concentrations observed after i.v. injection of either [11C]quinidine or [11C]morphine were markedly increased by intracarotid mannitol infusion, whereas they were not affected by saline infusion. For both drugs a close correlation was found between the radioactivity concentrations and the degree of Evans blue staining within the brain hemispheres and within smaller regions of interest corresponding to quadrants of a hemisphere. This parallelism between the findings for radioactivity concentrations and Evans blue staining suggests that PET allows the detection of in-vivo changes in brain distribution of drugs resulting from alterations of the BBB permeability.
Effects of BN 52063 and other agents inhibiting platelet-activating factor-induced contractile responses in rat portal vein
Authors: Hellegouarch A , Auguet M , Clostre F , Braquet P
Published: April 2011

Platelet-activating factor (PAF-acether) is a potent agonist (EC50: 3.2 × I0−8 M) of isolated rat portal vein. BN 52063 (composed of BN 52020, BN 52021 and BN 52022; molar ratio 2:2:1) specifically inhibits PAF-acether (10−7 M) induced tone (IC50: 3.9 × 10−5 M). Salbutamol (IC50: 3.1 × 10−7 M), forskolin (IC50:3.1 × 10−6M) and theophylline (IC50: 2.25 × 10−4M) are also effective in inhibiting PAF-acether-induced contractile responses and all excepting forskolin, show a certain specificity in this action. The basal myogenic activity of the rat portal vein is dose-dependently decreased by salbutamol (IC50: 1.2 × 10−7M), forskolin (IC50: 2.6 × 10−4M) and theophylline (IC50: 2.3 × 10−4 M) whereas BN 52063 has no effect. The data suggest that rat portal veins possess specific PAF-acether receptors sensitive to BN 52063 and that PAF-acether effects could be inhibited by compounds which can bypass these putative receptors and modulate cAMP levels.
Circadian phase-dependent pharmacokinetics and acute toxicity of mepivacaine
Authors: Bruguerolle Bernard , Prat Marin
Published: April 2011

The aim of this study was to investigate the possible influence of the time of administration on mepivacaine acute toxicity and kinetics in mice. Four different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on: = 0600–1800 h) were injected at one of the following times: 1000, 1600, 1900, 2200, 0100 and 0400 h with one of four doses of mepivacaine at each time point to establish the acute toxicity (LD50). To assess chronokinetics, a single 60 mg kg−1 i.p. dose of mepivacaine was given to adult male NMRI mice at four fixed times: 1000, 1600, 2200 and 0400 h. Mepivacaine plasma concentrations were determined by GLC. Our data showed significant 24 h variations in the following parameters: Highest tmax value = 0.366 ± 0.073 h at 1000 h (P < 0005, amplitude, maximum-minimum/mean × 100, = 184%), highest Cmax/tmax ratio = 177.17 ± 9.49 at 2200 h (P < 0005, amplitude = 192%), highest Vd = 0.842 ± 0.23 L kg−1 at 2200 h (P < 0005, amplitude = 158%) and highest β phase elimination half-life = 5.408 ± 1.36 h at 2200 h (P < 0.025, amplitude = 145%). Cmax (amplitude = 15%), AUCox (amplitude = 24%) and clearance (amplitude = 23%) were not significantly time-dependent. These data demonstrate a temporal pattern of mepivacaine kinetics similar to those reported previously for bupivacaine. The temporal changes in mepivacaine-induced acute toxicity may result in part from its chronokinetic changes.
Oesophageal transit of small tablets
Authors: Robertson Charles S , Hardy John G
Published: April 2011

Oesophageal transit has been studied in six asymptomatic subjects aged 29–80 years. Using gamma scintigraphy, the transit of a liquid and five small tablets was monitored in each subject. All the subjects exhibited normal liquid swallowing, with 50% oesophageal clearance times of less than 5 s. In three subjects all the tablets passed through the oesophagus within 6 s, but transit was prolonged in 60% of the swallows in the other subjects. Tablet hold up occurred more frequently in the elderly. An additional drink of water cleared all lodged tablets into the stomach. To minimize possible mucosal irritation, the taking of even small tablets should be followed by an additional drink of water.
The Sorption of Isosorbide Dinitrate to Intravenous Delivery Systems
Authors: de Muynck C , Remon J P , Colardyn F
Published: April 2011

The sorption of isosorbide dinitrate from 0.9% sodium chloride and 10% glucose solutions, by intravenous delivery systems has been investigated under simulated infusion conditions. Isosorbide dinitrate was stable in both 0.9% sodium chloride and 10% glucose solutions. Intravenous fluid containers, burettes, a syringe, infusion sets and end-line filters were evaluated. Glass containers, methacrylate butadiene styrene burettes and polybutadiene giving sets did not sorb isosorbide dinitrate. Neither did polypropylene syringes when a 10% glucose solution was used. The sorption of isosorbide dinitrate to end-line filters was unimportant but there was a significant loss to the PVC tubing used to connect the filter housing to the catheter.
Structure-Activity Studies of Fentanyl
Authors: Casy A F , Huckstep M R
Published: April 2011

The preparation of analogues of fentanyl with para substituents in the anilino aromatic ring, anilino nitrogen separated from phenyl by methylene or bimethylene, and phenacyl replacing propionyl as the N-acyl substituent is reported. Although all para substituents examined depressed antinociceptive potency in rats, most analogues of this kind were more effective than morphine and the p-F, I, and Me derivatives were only a few-fold less active than fentanyl. Separation of anilino nitrogen from phenyl lowered potency with N-phenethyl analogues retaining reasonable levels of activity (> morphine). All the phenacyl analogues were of low potency or inactive. Diagnostic details of the mass spectra of analogues likely to be encountered as ‘designer drugs’ are appended.
Dihydroergotoxine-induced Bradycardia in Rats
Authors: Roquebert Jacques , Grenié Bruno
Published: April 2011

Dihydroergotoxine (0.01–0.3 mg kg−1 i.v.) decreased heart rate in pentobarbitone-anaesthetized rats. The bradycardia was reduced but not blocked by pre-treatment with guanethidine, yohimbine, propranolol or pithing. It was not prevented by bivagotomy, atropine, sulpiride or haloperidol. Dihydroergotoxine failed to affect, either the bradycardia produced by electrical stimulation of the vagus, or the cardioacceleration induced by i.v. isoprenaline. The increase in heart rate elicited in pithed rats by electrical stimulation of the spinal cord was reduced by dihydroergotoxine; this effect being inhibited by yohimbine but not by sulpiride. In conclusion, the main mechanism by which dihydroergotoxine (i.v.) induces bradycardia in the rat involves stimulation of α2-adrenoceptors located predominantly at the cardiac sympathetic nerve endings.
The stability of morphine in isobaric and hyperbaric solutions in a drug delivery system
Authors: Caute B , Monsarrat B , Lazorthes Y , Cros J , Bastide R
Published: April 2011

Intrathecal preparations of morphine for use in intractable pain must contain no preservatives. They are generally formulated in saline (isobaric) or dextrose (hyperbaric) which raises questions of stability. The behaviour of morphine in hyperbaric and isobaric solutions stored in a reservoir for implantation has been examined and the effect of temperature and the time of contact of morphine with the different components of the reservoir as well as the sterilization procedure have been investigated. The best stability was observed with a hyperbaric solution in which there was 15 to 20 times less pseudomorphine than in the isobaric solution, which was found to contain 1% pseudomorphine after 1 month of storage at 37 °C in the reservoir. Similar solutions stored in ampoules did not degrade.
Effects of Phosphatidylcholine on the Topical Bioavailability of Corticosteroids Assessed by the Human Skin Blanching Assay
Authors: Jacobs M , Martin G P , Marriott C
Published: April 2011

A non-occluded multiple application skin blanching assay has been used to determine the effect of applied phosphatidylcholine (PC) on the bioavailability of corticosteroids. One forearm of each often volunteers was treated twice daily for one week with PC presented as a liposomal suspension in Sørensen’s (pH 5.0) phosphate buffer (2.5 mg PC/0.5 mL) while the other arm was treated with 0.5 mL of phosphate buffer. For the following two weeks this treatment regimen was continued but in addition, each of four corticosteroid formulations (containing (i) hydrocortisone 0.1%, (ii) clobetasone butyrate 0.05%, (iii) betamethasone 0.1 % and (iv) clobetasol propionate, 0.05%) was applied to sites on both arms. 5 ± 1 mg of each cream was applied twice daily to the sites on day 1, then once daily for a further four days; after two days of no application, the protocol was repeated. Estimation of pallor was usually made four times daily. At the end of the second week of corticosteroid application the blanching response to all four formulations on the PC treated arms was significantly higher than on the buffer treated arm. Tachyphylaxis to the applied corticosteroids was markedly less apparent on the lipid-treated arms. It is proposed that the applied phospholipid either supplements the lipid content of the skin or provides a thin film in intimate epidermal contact. Such a film may promote hydration of the stratum corneum and also provide an environment into which corticosteroids initially partition before a subsequent, more controlled, release to the underlying tissue.
β2-Adrenoceptor influences on the α1- and α2-mediated vasoconstriction induced by phenylpropanolamine and its two component enantiomers in the pithed rat
Authors: Moya-Huff Fernando A , Maher Timothy J
Published: April 2011

Phenylpropanolamine (PPA, (±)-norephedrine) is commonly found in appetite suppressants and nasal decongestants. Within the cardiovascular system of the pithed rat, the drug and its two component enantiomers ((−)- and (+)-norephedrine) are largely direct-acting agonists. The interaction between simultaneous α1-, α2- and β2-adrenoceptor mediated effects of the drug and its two enantiomers have been examined using the cardiovascular system of the pithed rat. On all adrenoceptors tested the potency was (−)- > (±)-, > (+)-norphedrine. The α1- and α2-mediated pressor responses of each were enhanced in the presence of the β2-adrenoceptor antagonist, ICI 118,551, and diminished in the presence of the selective β2-adrenoceptor agonist salbutamol. It is concluded that each form of the drug possesses the intrinsic ability to interact with the α1-, α2- and β2-adrenoceptors in the system used and that the interaction with those adrenoceptors determines the net increase in diastolic blood pressure that follows the intravenous administration of the compounds. These findings have a bearing on the recent controversy regarding the use of β-blocking agents in the treatment of overdosage of the drug.
Senna still causes laxation in rats maintained on a diet deficient in essential fatty acids
Authors: Mascolo N , Meli R , Autore G , Capasso F
Published: April 2011

The laxative effect of senna has been investigated in normal and essential fatty acid deficient (EFAD) rats. Oral administration of senna pod extract (7-5-90 mg kg−1) produced a dose-dependent increase in the number of soft faeces excreted by normal rats. Senna 30 mg kg−1 also reversed net absorption of water and increased the prostaglandin (PG) production in the colonic lumen of normal rats by about four times. Oral administration of senna pod extract to rats, maintained on a fat-free diet for 30–90 days, produced diarrhoea and reversed net absorption of water as in normal rats. However, a fat-free diet reduced the PG production drastically in the colonic lumen both in senna-free rats and in senna-treated rats. In EFAD rats carrageenan oedema, but not dextran oedema, was also drastically reduced. Since PG mediation is not present in EFAD rats we conclude that the PG are not essential for laxation induced by senna and that water secretion and PG production in the rat intestinal lumen are unrelated.
Effect of Meptazinol on Evoked Responses in Rat Vas Deferens
Authors: Charlton J , Hughes I E
Published: April 2011

Responses of rat isolated vas deferens to electrical stimulation through field electrodes (400 mA, 1 ms duration, single shocks at 5 min intervals) were potentiated by meptazinol (10 to 300 μM) in whole tissues and also in the separated prostatic and epididymal portions. The effect was fast in onset, reproducible and easily reversed by washing. Prazosin (0·1 μM) practically abolished the response of the epididymal portion to electrical stimulation while the response of the prostatic portion was only slightly reduced (<20%). In the presence of prazosin, meptazinol still produced potentiation of the response of the prostatic portion. Nifedipine (2 μM) practically abolished the response of the prostatic portion to electrical stimulation while the response of the epididymal portion was only slightly reduced (<20%). In the presence of nifedipine, meptazinol no longer produced potentiation of the response of the epididymal portion. Exogenous ATP (5 μM to 1 mM) and phenylephrine (1 to 50 μm) produced a contractile response which was potentiated in the presence of meptazinol (100 μM) but in the presence of meptazinol (100 μM) and nifedipine (5 mM) together, potentiation of phenylephrine no longer occurred. It is suggested that potentiation by meptazinol of electrically induced responses in this tissue is due to a direct action on the smooth muscle.
Suppression of pentobarbitone-induced hyperactivity by past experience in mice
Authors: Sansone Mario , Pavone Flaminia , Battaglia Mario , Vetulani Jerzy
Published: April 2011

Locomotor activity of CD-1 mice, tested in an unfamiliar environment (toggle-floor box), was increased either by a subhypnotic dose (20 mg kg−1) of pentobarbitone or after recovery from pentobarbitone-induced (50 mg kg−1) anaesthesia. On the contrary, when mice were tested 6 h after a single exposure to the apparatus, pentobarbitone in either case failed to produce hyperactivity. The results demonstrate that mice recovering from barbiturate anaesthesia maintain susceptibility to the exteroceptive stimuli provided by a novel environment and knowledge of the environment acquired during past experience.
Factors in snake venoms that increase capillary permeability
Authors: Miller Roger A , Tu Anthony T
Published: April 2011

Capillary permeability increasing (CPI) activity is a phenomenon of the microvasculature caused by many agents such as snake venoms, histamine, 5-hydroxytryptamine (5-HT), prostaglandins and leukotrienes. Since no systematic study has been done to determine what components of snake venom cause CPI activity, a CPI factor from Naja naja atra (Taiwan cobra) venom was isolated using intravenous injections of Evan’s blue dye as the indicator of increased permeability and the factor’s properties were extensively studied. Cardiotoxin from Naja naja kaouthia (Thailand cobra) and Mojave toxin from Crotalus scutulatus scutulatus (Mojave rattlesnake) venoms demonstrated CPI activity. Postsynaptic neurotoxins from an elapid and a hydrophid and myotoxin a from Crotalus viridis viridis (prairie rattlesnake) showed no CPI activity at the dose studied. The purified CPI active component from Naja naja atra venom was found to have cardiotoxic activity. Therefore, Elapidae cardiotoxins are CPI active factors. However, CPI activity is not due to cardiotoxins alone as the presynaptic neurotoxin, Mojave toxin, also showed CPI activity. Selective inhibitors were used to indicate possible mechanisms of action on the capillaries by Naja naja atra venom and Crotalus scutulatus scutulatus venom. The histamine H1-receptor blockers diphenhydramine, promethazine, and cyproheptadine were effective against both venoms in preventing increased capillary permeability. These results suggested that histamine release activity is the most likely mechanism resulting in CPI activity from these venoms.
The systemic availability of buprenorphine administered by nasal spray
Authors: Eriksen Jørgen , Jensen Niels-Henrik , Kamp-Jensen Michael , Bjarnø Helle , Friis Poul , Brewster David
Published: April 2011

The kinetics and systemic bioavailability of intranasally administered buprenorphine have been investigated in 9 healthy volunteers in an intranasal/intravenous cross-over study. Each subject received a nominal 0·3 mg dose of buprenorphine intranasally followed one week later by a matched dose intravenously. For the intranasal administration mean tmax and mean Cmax were 30·6 min and 1·77 ng mL−1, respectively. Mean intranasal bioavailability was 48·2 ± 8·3% (mean ± s.e.m.) of the intravenous value. Intranasal administration may represent a valuable new delivery route for buprenorphine.
Decreased 5-hydroxytryptamine turnover in striatum and other brain regions after administration of 5-methoxy-3-(di-n-propylamino)-chroman to rats
Authors: Fuller Ray W , Perry Kenneth W , Ward John S
Published: April 2011

5-Methoxy-3-(di-n-propylamino)chroman (5-MeO-DPAC) caused a dose-dependent decrease in the accumulation of 5-hydroxytryptophan after decarboxylase inhibition in rat striatum, hippocampus and frontal cortex. The decreased 5-hydroxytryptamine (5-HT) turnover may have resulted from activation of 5-HT receptors on cell bodies of 5-HT neurons that project to the striatum and other brain regions, since 5-MeO-DPAC had earlier been reported to lack affinity for striatal binding sites.
[3H]Acetylcholine Release from the Guinea-pig Distal Colon: Comparison with Ileal [3H]Acetylcholine Release and Effect of Adrenoceptor Stimulation
Authors: Marcoli Manuela , De Ponti Fabrizio , Lecchini Sergio , Crema Antonio , Frigo Gian Mario
Published: April 2011

To study cholinergic function in the guinea-pig colon, resting and electrically evoked 3H release after preincubation with [3H] choline has been compared in colonic and ileal myenteric plexus preparations. Fractional spontaneous colonic 3H release was significantly higher than ileal 3H release, while the reverse was true for electrically evoked 3H outflow. Electrically evoked 3H outflow in the colon was linearly related to stimulation frequency (0·2–3 Hz range) and current intensity (300–600 mA range), while 3H outflow per pulse was inversely related to stimulation frequency. Electrically evoked 3H outflow was prevented in Ca2+-free solution, indicating that it probably mirrored neuronal exocytotic [3H]acetylcholine release. Both noradrenaline and clonidine concentration-dependently inhibited electrically evoked 3H outflow, Clonidine being more potent but less efficacious than noradrenaline. For both noradrenaline and Clonidine, the potency and efficacy for inhibition of 3H outflow were close to the values previously reported for the inhibition of electrically evoked endogenous acetylcholine output from colonic preparations. In conclusion, these data indicate that 3H release after incubation with [3H]choline is a valid alternative to measurement of endogenous acetylcholine output to study colonic cholinergic neuronal function in the guinea-pig.
Anaesthetic Concentrations of Enflurane and Methoxyflurane in Rat Brain In-vivo and In-vitro
Authors: Bazil Carl W , Minneman Kenneth P
Published: April 2011

We measured concentrations of enflurane and methoxyflurane in brains of anaesthetized rats and established conditions for reproducing these concentrations in brain tissue in-vitro. Despite a 12-fold difference in inspired potency, brain concentrations resulting in anaesthesia were similar for both compounds. However, substantially lower concentrations in the equilibrating gas were necessary to achieve similar tissue concentrations in-vitro, probably because anaesthetic-induced respiratory depression or changes in cardiac output causes incomplete equilibration in-vivo. These studies provide direct evidence that brain concentrations associated with anaesthesia are similar for anaesthetics with different inspired potencies. They also suggest that lower concentrations in the equilibrating gas should be used in-vitro to reproduce clinically relevant tissue concentrations that are necessary to cause anaesthesia in-vivo.
Correlation Between Hydrophobicity of N-Alkylxanthine Derivatives and their Biological Activities on Guinea-pig Isolated Tracheal Smooth Muscle
Authors: Miyamoto K , Takagi K , Sakai R , Wakusawa S , Koshiura R , Nadai M , Apichartpichean R , Hasegawa T
Published: April 2011

Cyclic (c) AMP phosphodiesterase (PDE) inhibitory activities of N-alkylxanthine derivatives (3-methyl-, 3-ethyl-, 3-propyl-, 3-butyl-, 1,3-dimethyl-, 1-methyl-3-ethyl-, 1-methyl-3-propyl-and 1-methyl-3-butyl xanthines) and their relaxant effects on carbachol-induced contraction and on resting tone guinea-pig isolated tracheal smooth muscle have been investigated. The PDE inhibition constant (Ki) and the concentration producing 50% tracheal smooth muscle relaxation in-vitro (EC50) were determined. Significant correlations between the -log Ki values and the -log EC50 values on the carbachol-induced contraction or on the resting tone were found (r = 0·902 and 0·892). The apparent partition coefficient (P) between n-octanol and pH 7·4 phosphate-buffered saline (PBS) was measured as an index of hydrophobicity of the xanthine derivatives. There were significant correlations between log P and both -log EC50 values and between the log P and -log Ki values. These findings suggest that the cAMP PDE inhibitory activity of N-alkylxanthine derivatives contributes to the mechanism of bronchodilatory action, and that an increase in hydrophobicity of the xanthine molecule enhances the biological activity.
In-vitro Characterization of Blood-brain Barrier Permeability to Delta Sleep-inducing Peptide
Authors: Raeissi Shamsi , Audus Kenneth L
Published: April 2011

The diffusion of delta sleep-inducing peptide (DSIP) across the blood-brain barrier (BBB) has been investigated with an in-vitro model comprised of primary cultures of brain micro vessel endothelial cell (BMEC) monolayers. The BMEC monolayers were mounted in a side-by-side diffusion apparatus and the transendothelial flux of DSIP analysed by HPLC with UV detection at 280 nm. The transendothelial flux of the peptide was linear with time and increasing concentrations of DSIP (non-saturable), but was not altered by reduced temperature. The apparent permeability coefficient for DSIP penetration of BMEC monolayers was in a range similar to water-soluble substances (e.g. fluorescein, fluorescein isothiocyanate dextrans) that penetrate the blood-brain barrier to a limited degree based on molecular weight. DSIP flux across the BMEC monolayers was also found to be bidirectional, insensitive to metabolic inhibitors, and not altered by high concentrations of tryptophan. Little degradation (apparent t 1/2 about 10 h) of DSIP to major metabolites, tryptophan (trp) and des-trp DSIP, occurred over the time of the diffusion experiments. The results of these studies support and confirm observations in-vivo indicating that intact DSIP crosses the BBB by simple transmembrane diffusion.
Excretion of proguanil in human saliva
Authors: Onyeji C O , Ogunbona F A , Dixon P A F
Published: April 2011

After a single oral administration of a 300 mg dose of proguanil to six volunteers, the presence of the drug in saliva was established by chromatographic and spectrophotometric methods. The tmax and elimination half-life of proguanil derived from salivary levels were 4·0 ± 1·26 h and 15·1 ± 1·8 h, respectively. These results are in agreement with values previously reported for the drug using plasma level data. The mean saliva: plasma proguanil concentration ratio was 0·41 ± 0·17 and this was not time dependent. There was a correlation (r = 0·82) between the saliva and simultaneous plasma proguanil concentration. The results suggest that proguanil is passively secreted into saliva and that saliva levels may be useful in the determination of pharmacokinetic parameters and the therapeutic monitoring of the drug.
Physicochemical Characterization of Methotrexate—Bovine Serum Albumin Conjugates
Authors: Halbert Gavin W , Florence Alexander T
Published: April 2011

Physicochemical parameters have been determined for a series of methotrexate-bovine serum albumin conjugates produced using a water-soluble carbodiimide. Drug coupling produces a heterogeneous product consisting of mixtures of albumin and albumin polymers with varying quantities of covalently bound drug. Due to this heterogeneity, the measurement of absolute physicochemical values was not possible but two factors producing change were evident. The water soluble carbodiimide is responsible for major changes by producing polymers that dominate the properties of the conjugates. The changes induced by the covalently attached drug are less dramatic but still appreciable. The results emphasize that both the attached drug and the method of coupling are significant factors in altering the physicochemical properties of proteinaceous drug carriers.
On the Mechanism Involved in the Ability of Meptazinol to Potentiate the Effects of Sympathetic Nerve Stimulation
Authors: El-Mas M , Goodall J , Hughes I E
Published: April 2011

Mouse isolated vas deferens responded to field stimulation (0.1 Hz) with twitch responses which were abolished by ag-methyleneadenosine 5′-triphosphate (0.5 p μM) and were potentiated 2 to 3 fold by meptazinol(5–300 p μM). Exogenous adenosine 5′-triphosphate (4–30 p μM) also caused a twitch response but was unaffected by meptazinol(30 p μM) as was the response to phenylephrine. The effect of meptazinol on the electrically-induced twitch was reproducible, fast in onset, easily reversed by washing and was still seen in the presence of prazosin (1 p μM), yohimbine (1 p μM), propranolol(O.1 p μM), atropine (0.1 p μM), physostigmine (1 p μM), cocaine (1 p μM) or desmethylimipramine (0.3 p μM) indicating that the mechanism involved does not depend on adrenoceptors, cholinergic mechanisms or blockade of uptake,. Mouse isolated atria responded to stimulation (1, 2 or 5 Hz) of their sympathetic nerves via transmural electrodes with chronotropic responses which were abolished by atenolol(5 and 50 p μM) but were unaffected by ag-methyleneadenosine 5′-triphosphate (0.5 p μM). Meptazinol (100 p μM) failed to potentiate the responses. It is suggested that meptazinol potentiates the effects of the non-adrenergic non-cholinergic transmitter thought to be involved in the response of the mouse vas deferens to electrical stimulation.
The Effect of Hydrotropic Agents on the Heat Coagulation of Bovine Serum Albumin
Authors: Saleh A M , Florence A T , Whateley T L , El-Khordagui L K
Published: April 2011

The effect of two hydrotropic solubilizers on the heat coagulation of bovine serum albumin (BSA) has been investigated. Photon correlation spectroscopy indicated possible unfolding of BSA molecules in solutions of sodium benzoate and sodium salicylate at 25°C. The effect of these hydrotropes on the heat coagulation of BSA was concentration-dependent. Relatively low concentrations stabilized the protein structure as indicated by the increase in the transition temperature (Tm) and induced gelation at temperatures and BSA concentrations lower than those required in the absence of hydrotropes. Higher concentrations of the hydrotropes considerably reduced Tm and inhibited gelation of BSA, the effect of sodium salicylate being more pronounced, as was the lower aggregation rate of BSA. The behaviour of these hydrotropes as protein denaturants differs from that of neutral electrolytes but is similar to that of concentrated solutions of urea.
Comparative Effects of Azapropazone on Cellular Events at Inflamed Sites. Influence on Joint Pathology in Arthritic Rats, Leucocyte Superoxide and Eicosanoid Production, Platelet Aggregation, Synthesis of Cartilage Proteoglycans, Synovial Production and Actions of Interleukin-1 in Cartilage Resorption Correlated with Drug Uptake into Cartilage In-vitro
Authors: Rainsford K D , Davies Alison , Mundy Linda , Ginsburg I
Published: April 2011

Azapropazone (APZ) has been compared with standard NSAIDs in title systems to establish aspects of its mode of action on cellular events at inflamed sites. APZ (150 mg kg−1 day−1) given for 10–13 days exhibited a reduction in joint pathology in established adjuvant arthritis in rats comparable with that of indomethacin (2 mg kg−1 day−1) and clobuzarit (20 mg kg−1 day−1). APZ was shown to be a potent inhibitor of the production of leucocyte superoxide and synovial interleukin-1 (IL-1)-like activity and stimulated articular cartilage proteoglycan synthesis, but was ineffective as an inhibitor of platelet aggregation or IL-1 induced cartilage degradation in-vitro. These in-vitro effects may have relevance to the mode of action of this weak inhibitor of prostaglandin synthesis.
Conformational Analysis of 9-Substituted Adenines in Relation to Their Microsomal N1-Oxidation
Authors: Lam Siu Ping , Barlow David John , Gorrod John William
Published: April 2011

Metabolic TV-oxidation of adenine, 9-methyladenine, 9-benzyladenine, 9-benzhydryladenine and 9-trityladenine has been investigated using hepatic microsomes from hamster, guinea-pig, rabbit, mouse, rat, and dog. N1-Oxide formation occurs with 9-benzyladenine and 9-benzhydryladenine using liver preparations of all species examined, although to different extents. The N-oxidase activity was found, amongst rodents, in the order hamster > mouse > rabbit > rat > guinea-pig. Microsomal preparations from dog liver contained a small quantity of P-450 and yet produced a relatively large amount of the N-oxides, possibly indicating that other cytochromes in addition to P-450 may be involved in the TV-oxidation of these compounds. The most favourable conformations of these 9-substituted analogues have been established using computer graphics modelling and 1H NMR techniques. Results obtained confirmed the importance of the stereochemical properties of these compounds in relation to N1-oxidation. These observations substantiate and extend our previous findings on the electronic, lipophilic, and stereochemical factors affecting the TV-oxidation of adenine derivatives.
Kinetics and Mechanism of the Facile Cyclization of Histidyl-prolineamide to Cyclo (His-Pro) in Aqueous Solution and the Competitive Influence of Human Plasma
Authors: Møss Judi , Bundgaard Hans
Published: April 2011

A crucial point in the biosynthesis of cyclo (His-Pro), an endogenous and biologically active cyclic dipeptide, is the spontaneous cyclization of its precursor L-histidyl-L-prolineamide (His-ProNH2). In this study the kinetics and mechanism of the cyclization process has been investigated. His-ProNH2 was found to be converted quantitatively to cyclo(His-Pro) in aqueous solution at pH 2–10 and 37°C, the rate of cyclization being maximal at pH 6–7. Buffer substances such as phosphate (pH 6–7.4) were found to catalyse the cyclization. The bell-shaped pH-rate profile observed was accounted for by assuming spontaneous and specific acid- and base-catalysed reactions of the His-ProNH2 species in which the imidazole group is protonated and the primary amino group unprotonated. The much more rapid rate of cyclization of His-ProNH2 (t 1/2 of 140 min at pH 6–7 and 37°C) relative to other proline-containing di- and tripeptides studied was suggested to be due to an intramolecular general acid catalytic effect by the protonated imidazole group. In the presence of human plasma enzymatic hydrolysis of His-ProNH2 competed with the cyclization and predominated greatly at 80% plasma concentration.
Relaxant Effects of α-Adrenoceptor Agonists in the Rat Isolated Gastric Fundus
Authors: Kelly J , Macdonald A
Published: April 2011

In rat gastric fundus preparations with tone raised by the addition of barium chloride or carbachol, and in the presence of propranolol (2 μM) to prevent β-adrenoceptor mediated effects, the adrenoceptor agonists noradrenaline, adrenaline, α-methylnoradrenaline, isoprenaline, cirazoline and phenylephrine all caused concentration-related relaxant responses. Relaxations to the catecholamines were poorly antagonized by prazosin (0.01-1 μM) resulting in the slopes of Schild plots being less than unity, low pA2 values for prazosin against the catecholamines and a clear relaxant effect of the catecholamines even in the presence of 1 μM prazosin. The prazosin-resistant relaxations were unaffected by higher concentrations of prazosin (2 μM) and propranolol (30 μM) or by further additions of idazoxan (1 μM) or haloperidol (30 μM). The relaxations were not due to a non-specific effect of the catechol nucleus since neither dihydroxyphenylethylene glycol (DOPEG) nor dihydroxyphenylacetic acid (DOPAC) produced relaxant effects at concentrations upto 300 μM. In contrast to the results with the catecholamines, prazosin was a potent antagonist of the relaxant effect of cirazoline and phenylephrine, although the antagonism was difficult to quantify due to a lowering of the slope of the concentration response curves to cirazoline and phenylephrine with the higher concentrations of prazosin (0.1 and 1.0 μM). In conclusion postjunctional relaxatory effects of catecholamines in the rat gastric fundus are mediated partly via α1-adrenoceptors and partly via an atypical adrenoceptor.
Failure of σ-receptor ligands to reduce the excitatory actions of N-methyl-DL-aspartate on rat spinal neurons in-vivo
Authors: Church John , Lodge David
Published: April 2011

Haloperidol and (+)-3-PPP, compounds with known affinity for the σ-receptor, have been examined for their ability to reduce the excitatory actions of N-methyl-DL-aspartate (NMDLA), quisqualate and kainate on rat spinal neurons in-vivo. The actions of (-)-3-PPP were also tested. Haloperidol was injected intravenously whereas the 3-PPP enantiomers were administered by microelectrophoresis. Haloperidol had little effect on excitations evoked by NMDLA, quisqualate or kainate whereas both (+)- and (-)-3-PPP usually enhanced, non-selectively, responses to all three excitatory amino acid analogues. The results support suggestions that phencyclidine (PCP)-like compounds with affinity for both PCP and σ-receptors reduce neuronal excitations mediated by the N-methyl-D-aspartate (NMDA) receptor via a selective effect at the PCP site.
Effects of Intra-accumbens Administration of Dopamine Agonists on Stress-induced Behavioural Deficit
Authors: Plaźnik Adam , Stefański Roman , Pucilowski Olgierd , Kostowski Wojciech
Published: April 2011

The effect of post-footshock injections of (+)-amphetamine, the selective D2-receptor agonist quinpirole (LY 171555), and the D2-receptor antagonist metoclopramide, into the nucleus accumbens, on the formation of the open field deficit, has been studied in rats. Microinjections of (+)-amphetamine (10 μg) stimulated rat locomotor activity tested 5 min later, while quinpirole (10 μg) significantly inhibited animal motility in the test. The open field behaviour was not changed 24 h after injection of either drug. Amphetamine applied immediately after inescapable footshock did not modify stress-induced locomotor depression, when the rats' behaviour was examined 24 h later. On the other hand, post-shock injections of quinpirole significantly attenuated the long-term effects of the stressor, in the open field. Metoclopramide (10 μg) inhibited rat locomotor activity 5 min, but not 24 h, after local injection. Administration of a solution containing both quinpirole (10 μg) and metoclopramide (1 μg) decreased motor activity of unstressed rats to a smaller degree than did quinpirole (10 μg) alone. Post-footshock injection of metoclopramide did not affect stress-induced hypomotility. It is concluded that the present data support the hypothesis that local depletion of brain dopaminergic stores causes some behavioural effects of stressors.
Reproducible Withdrawal Contractions of Isolated Guinea-pig Ileum after Brief Morphine Exposure: Effects of Clonidine and Nifedipine
Authors: Valeri P , Martinelli B , Morrone L A , Severini C
Published: April 2011

Guinea-pig ileum stored for 30 min in Krebs solution and then mounted in Tyrode solution gave reproducible contracture responses to naloxone after brief exposure to morphine. The preparation lasted for several hours and a variety of pharmacological tests could be made. Clonidine, an α2-adrenoceptor agonist, and nifedipine, a calcium channel antagonist, both known to interfere with tolerance and physical dependence, inhibited naloxone withdrawal contractures in a dose related way. Their action seemed to be receptor-mediated since yohimbine and Bay k 8644, respectively, reversed their inhibitory effect.