bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal pH and propulsion: an explanation of diarrhoea in lactase deficiency and laxation by lactulose
Authors: Bennett Alan , Eley Kenneth G
Published: April 2011

Acidification of the lumen of guinea-pig isolated intestine increases peristaltic activity. A low colonic pH might therefore contribute directly to the diarrhoea induced by lactose in lactase-deficient subjects, and to the laxative effect of lactulose.
Influence of non-ionic surfactants on permeation of hydrocortisone, dexamethasone, testosterone and progesterone across cellulose acetate membrane
Authors: Barry B W , Eini D I D El
Published: April 2011

The lag-time method of diffusion has been used to investigate permeation of hydrocortisone, dexamethasone, testosterone and progesterone across cellulose acetate membranes between 10° and 40°. The process depended mainly on membrane-water partition coefficients of the steroids so that the least polar compound permeated the fastest. Permeation generally increased with increasing temperature and from the temperature dependance of the diffusion coefficient, energies of activation were derived. These varied from 2·4 kcal mol−1 for the least polar steroid, progesterone, to 7·4 kcal mol−1 for the most polar, hydrocortisone, n - C16 Polyoxyethylene surfactants when present below and above the cmc increased the steroids permeation rates. Varying the polyoxyethylene chain length (OE = 17–63) did not significantly affect permeation rates, suggesting that the enhancing effect of surfactants arises from their hydrophobic group.
The effect of cholinesterase inhibitors on the antimuscarinic effect of hemicholinium-3 (HC-3) in the rat
Authors: Hecker S E , Mitchelson F
Published: April 2011

The effect of hemicholinium-3 (HC-3) on responses of the rat isolated bladder and ileum to acetylcholine and carbachol was investigated in the absence and presence of a number of anticholinesterases. Responses of the bladder to acetylcholine were potentiated by DFP, edrophonium, BW284C51 and physostigmine but were unaffected by the specific butyrylcholinesterase inhibitor iso-OMPA. Responses to carbachol were not potentiated by the anticholinesterases. HC-3 (1·7 × 10−4m) inhibited responses to carbachol without affecting those to acetylcholine. In the presence of physostigmine or DFP responses to acetylcholine were inhibited by HC-3 but no such inhibition was observed in the presence of BW284C51, edrophonium or iso-OMPA or a combination of the latter two anticholinesterases. Responses to carbachol were also inhibited to a greater extent in the presence of DFP. In the ileum, responses to acetylcholine were increased in the presence of DFP, edrophonium and physostigmine but were unaffected by iso-OMPA. Responses to carbachol were not increased by any of the anticholinesterases. HC-3 (2·8 × 10−4 m) inhibited responses to both acetylcholine and carbachol in the ileum and the degree of inhibition was not significantly altered by the presence of any of the anticholinesterases used.

Although a weak anticholinesterase, HC-3 was also found to decrease the inhibitory action of physostigmine on the hydrolysis of acetylcholine by homogenates of rat ileum. A similar effect was noted with DFP but not with edrophonium.

The results obtained do not support a prejunctional action for HC-3 in antagonizing responses to carbachol. It is concluded that in addition to an inhibitory action on the postjunctional muscarinic receptor HC-3 may interfere with the anticholinesterase activity of some cholinesterase inhibitors such as physostigmine and DFP but not edrophonium.
Characterization of moisture interactions in some aqueous-based tablet film coating formulations
Authors: Okhamafe Augustine O , York Peter
Published: April 2011

Three methods—radiotracer, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)—have been employed to evaluate moisture interactions in aqueous-based hydroxypropyl methylcellulose films containing polyethylene glycol 400, polyethylene glycol 1000 or polyvinyl alcohol. The radiotracer employed was tritiated water. Using a proposed classification, the water present in the films was placed in three categories: tightly bound, moderately bound and free. The tightly bound water in hydroxypropyl methylcellulose and hydroxypropyl methylcellulose/polyvinyl alcohol films was related to the crystallinity of the films whilst tightly bound water was practically non-existent in the plasticized systems thus indicating the absence of crystallinity. Free (or freezable) water could not be detected in the films using DSC. The moisture content data obtained by TGA were considered to represent moderately bound water. The moderately bound water content of the film systems was in the rank order of the hydrophilicity of the polymer additives: polyethylene glycol 400 > polyethylene glycol 1000 > polyvinyl alcohol. This order was reversed for the calculated free water content.
The effect of proadifen on the metabolism of adinazolam
Authors: Sethy Vimala H , Francis Jonathan W , Day Jeffrey S
Published: April 2011

Binding affinities of adinazolam and its metabolite mono-N-demethyladinazolam, U-42352, to the brain tissue are not altered by the presence of proadifen (SKF-525A) in [3H]flunitrazepam ([3H]FNZ) binding assays in-vitro. Pre-treatment of mice with proadifen significantly blocked the ability of intravenously administered adinazolam to inhibit [3H]FNZ binding in the studies ex-vivo. The binding profile of [3H]FNZ to the brain tissue was not significantly different when animals were treated with U-42352 or proadifen with U-42352. These results suggest that proadifen may block the conversion of adinazolam to its active metabolite U-42352.
On the modulating effects of temperature, albumin, pH and calcium on the free fractions of phenobarbitone and phenytoin
Authors: Melten J W , Wittebrood A J , Wemer J , Faber D B
Published: April 2011

The effects of temperature, albumin, pH and Ca2+ on the binding of phenobarbitone and phenytoin to human serum albumin in buffer have been investigated using equilibrium dialysis. The free fractions of both anticonvulsants were much increased by raising the temperature. Lower free fractions were observed by increasing the albumin concentration from 5–8 g litre−1 and by raising pH from 6 to 9. No significant effect on the free fractions was observed by changing (at pH 7.4) the Ca2+ concentration from 0 to 5 mM. The observed differences in free fractions at 37 °C., as determined in phosphate, borate and Krebs-Ringer buffer at pH 7.4, indicate that great care is needed in the choice of dialysis fluid for dialysis of clinical samples.
The activity of non-steroidal anti-inflammatory drugs in the rat mesenteric vasculature
Authors: Stanton Bryan J , Coupar Ian M , Burcher Elizabeth
Published: April 2011

Rat isolated, perfused mesenteric blood vessels have been used to determine whether non-steroidal anti-inflammatory drugs (NSAIDs) display selectivity for inhibition of vasoconstrictor responses to noradrenaline compared with those to calcium. The rank order of potency of the NSAIDs for inhibition of responses to noradrenaline was: meclofenamate > flufenamate = diclofenac > indomethacin > fenbufen > phenylbutazone > ibuprofen > ketoprofen > naproxen > paracetamol (included as an inhibitor of cyclo-oxygenase). All NSAIDs show selectivity for noradrenaline (mean selectivity molar ratio = 0.19; s.e.m. 0.15–0.23) but there was a positive correlation (r = 0.98, P < 0.001) between inhibition of responses to noradrenaline and those to calcium. The depressant effect of meclofenamate and of fenbufen, the most potent and most selective in the series, respectively, on responses to noradrenaline, was completely reversed to control values by prostaglandin E2. The results support previous findings that inhibition of cyclo-oxygenase in rat mesenteric blood vessels leads to a loss of response to noradrenaline. Comparison of the present data for inhibition of responses to noradrenaline in the mesentery with published data indicates that the mesentery bears a greater similarity to other in-vitro rather than in-vivo models for screening NSAIDs.
Chronic subcutaneous treatment with acebutolol: haemodynamic effects and metabolism in spontaneously hypertensive rats
Authors: Heimburger M , Davy M , Midol-Monnet M , Beslot F , Cohen Y
Published: April 2011

Chronic administration of acebutolol (15 mg kg−1 s.c. three times a week for five weeks, then 30 mg kg−1 for three weeks) did not lower blood pressure in 17 and 33 weeks-old spontaneously hypertensive rats (SHR). At the end of this treatment, the plasma concentrations of acebutolol and diacetolol were measured by HPLC. After 24 h, acebutolol was absent from plasma while diacetolol was lower after chronic treatment than after acute administration. Twenty-four hours after the last injection of acebutolol, both isoprenaline-induced tachycardia and vasodilatation were reduced. The vasomotor agents, noradrenaline, bradykinin and angiotensin, exhibited the same activity in control and treated SHR. These findings suggest that the lack of antihypertensive effect of acebutolol in SHR may be the result of a decrease in diacetolol formation together with blockade of β2 vascular receptors.
ICI 180080, a novel selective thromboxane receptor antagonist: synthesis and relative activity
Authors: Brown George R , Foubister Alan J
Published: April 2011

The preparation of a novel potent thromboxane receptor antagonist ICI 180080, 5(Z)-7-[2,2-dimethyl-4-(2-hydroxyphenyl)-1, 3-dioxan-cis-5-yl] heptenoic acid, is described together with its methyl ether and methyl ester. Thromboxane antagonist pA2 data against U 46619 is presented for rabbit thoracic aorta in-vitro (ICI 180080, pA2 = 7.5). The relative antagonist pA2 values obtained are discussed in terms of the chemical structure of the molecules. The potent activity of ICI 180080 is attributed to a specific orientation of the phenolic oxygen, due to an intramolecular hydrogen bond.
Comparison of bioavailability in man of tamoxifen after oral and rectal administration
Authors: Tukker J J , Blankenstein M A , Nortier J W R
Published: April 2011

The bioavailability of tamoxifen from 40 mg suppositories was tested in six male volunteers and compared with that of tamoxifen (Nolvadex) tablets. Plasma concentrations of tamoxifen and its major metabolites, 4-hydroxytamoxifen and N-desmethyltamoxifen, were measured by extraction from plasma obtained at different times after administration, separated by HPLC, converted on-line to fluorescent phenanthrene derivatives and quantified with a fluorescence detector. The mean relative bioavailability from the suppositories was 28%; the addition of a surf active agent diminished the bioavailability to 13%. Simulation of repeated administration of 40 mg suppositories suggests a mean steady state plasma concentration for tamoxifen of approximately 70 ng ml−1, i.e. 30% of the steady state value after simulated oral administration. Rectal administration of tamoxifen leads to a lower bioavailability than that by oral administration and therefore cannot be recommended when used in equivalent doses.
The use of [3H]vasopressin for in-vivo studies of controlled delivery from an Accurel/collodion device in the Brattleboro rat
Authors: Kruisbrink J , Boer G J
Published: April 2011

Accurel polypropylene/collodion controlled drug-delivery devices containing 22 μg [3H]-vasopressin (VP) were implanted s.c. in VP-deficient Brattleboro rats. This caused a decrease in their urine production for at least 50 days, at which time the Accurel device was removed. Release of VP was followed by measurements of tritium radioactivity and by radioimmunoassay of VP in the urine. These parameters showed a constant pattern during the whole period. After re-implantation of the Accurel devices in another group of Brattleboro rats, release of VP continued to give the same level of urine production as during the last period of the first implantation. It is concluded that release of VP in-vivo is not influenced by encapsulation of the Accurel polymer by connective tissue, or that adaptation of the kidney adds to the maintenance of the urine production at this low level. In-vivo release rate is calculated to be about 1% of the original load each day. The in-vitro release in a flow cell system appeared to produce the same release rate which indicates that these data have a predictive value for the in-vivo situation.
Disposition of aprophen in rats
Authors: Aarbakke Jarle , Miura George A , Brown Nesbitt D , Gray Richard R , Gordon Richard K , Doctor B P , Chiang Peter K
Published: April 2011

The pharmacokinetics of [14C]aprophen and its distribution were determined after intravenous administration to rats. The drug was distributed rapidly with a t½ (α) of 4 min to highly perfused organs like the brain, kidney and adrenals. An elimination phase was apparent 10 min after injection with a t½ (β) of 23.5 min. The high plasma clearance of the drug was due both to a large volume of distribution and to a high metabolic rate. Aprophen could be hydrolysed to diphenylpropionic acid and diethylaminoethanol in-vivo and in-vitro. Diethylaminoethanol competed with [3H]QNB binding to muscarinic receptors of N4TG1 cells, whereas diphenylpropionic acid did not. The lower plasma concentrations and lower binding activity of diethylaminoethanol compared with aprophen indicate that unchanged aprophen is largely responsible for the in-vivo actions.
Tolerance to the anticonvulsant effect of clonazepam in mice: no concurrent change in plasma concentration
Authors: Haigh J R M , Feely M , Gent J P
Published: April 2011

Clonazepam was administered for 10 or more days on three different dose regimens (0.5, 0.25 and 0.08 mg kg−1 twice daily) to mice given pentetrazol by slow intravenous infusion. Plasma concentrations of clonazepam were assayed by high performance liquid chromatography. Tolerance developed to the anticonvulsant effect of clonazepam at all doses but was incomplete and could be overcome by increasing the dose. With the 0.5 and 0.25 mg kg−1 regimens there was no significant change in the drug plasma concentrations during development of tolerance; on the lowest dose, levels were below the limits of accurate detection. Anticonvulsant tolerance does not seem to be the result of a disturbance in clonazepam metabolism.
The effect of pentobarbitone anaesthesia and hypothermia on the hepatic clearance of indocyanine green and S(−)-acenocoumarol in the rat
Authors: Daemen M J A P , Thijssen H H W , Vervoort-Peters H T M , Smits J F M , Boudier H A J Struyker
Published: April 2011

The effect of pentobarbitone anaesthesia and the effect of hypothermia associated with the anaesthesia on the blood clearance of indocyanine green (ICG) and of S(−)-acenocoumarol (AC) was investigated in male Wistar rats using the constant rate infusion technique. During anaesthesia, body temperature was regulated by heat supply. At normothermia (rectal temperature of 37.5 °C), pentobarbitone anaesthesia decreased ICG clearance from 8.0 ± 1.7 ml min−1 (mean ± s.e.m., n = 3) in the conscious state to 4.3 ± 0.6 ml min−1 and AC clearance from 4.9 ± 0.4 ml min−1 to 3.4 ± 0.3 ml min−1. Hypothermia further reduced the clearances of the compounds to 0.9 ± 0.1 and 2.5 ± 0.2 ml min−1 for ICG and AC, respectively. The effect of hypothermia was reversible. The results show that pharmacokinetic constants obtained in the anaesthetized animal may differ greatly from those in the conscious one. If pharmacokinetic experiments are performed in the anaesthetized animal, body temperature should be controlled and a slight hyperthermia is most favourable. Our pharmacokinetic data on ICG seriously question the use of this drug to estimate liver blood flow in the rat.
The use of ordered mixtures for improving the dissolution rate of low solubility compounds&
Authors: Nyström C , Westerberg M
Published: April 2011

The dissolution rate of micronized griseofulvin has been investigated, both for the agglomerated raw material and the material formulated as an ordered mixture, by means of the USP XX paddle method. During the experiments, which were performed at sink condition and constant temperature, the effects of adding a surfactant and of agitation were tested. The ordered mixture with sodium chloride gave a fast dissolution rate, practically independent of the test parameters. Micronized griseofulvin alone gave dissolution profiles that were improved by adding polysorbate 80 and by increased agitation, but the dissolution rates obtained were much lower than those for the ordered mixture. It was concluded that the rate limiting step in the dissolution of griseofulvin as the raw material is the penetration of the dissolution medium into the agglomerates. With an ordered mixture, these agglomerates were deaggregated during the mixing process, producing a system in which the entire external surface area of the primary particles was exposed to the dissolution medium. This conclusion was supported by calculation of the contact surface areas taking part in the dissolution process for the systems tested. The procedure developed in this study could be applied to preformulation work where a cohesive, low solubility drug of hydrophobic nature is to be formulated.
Role of efficacy in the assessment of the actions of α-adrenoceptor agonists in rat aorta with endothelium
Authors: Malta E , Schini V , Miller R C
Published: April 2011

Concentration-effect curves to phenylephrine are shifted to the right in the presence of endothelium in rat aorta while responses to clonidine are practically abolished. Analysis of the concentration-effect curves showed that the effect of endothelium could possibly be explained by a reduction in relative intrinsic efficacy of the two agonists by between 3.5- and 6-fold. Published observations on the modulatory effects of agonist-induced contractions by endothelium in the rat aorta tend to support this explanation. It is further concluded that this reduction in efficacy could be related to the basal release of an endothelium-derived substance and that changes in tissue contractility in the presence of endothelium cannot necessarily be taken as evidence for a stimulated liberation of endothelium-derived products by agonists.
Presynaptic actions of piribedil on the cardiovascular system of the pithed rat
Authors: Moron A , Cuffi L , Vila E , Badia A
Published: April 2011

The influence of piribedil on cardiovascular sympathetic responses has been studied in the pithed rat. Piribedil (0.3–1 mg kg−1) inhibited the increases of diastolic blood pressure induced by spinal cord electrical stimulation at the level Th5-L4. This effect was reversed by sulpiride (0.3 mg kg−1) but not by yohimbine (0.3 mg kg−1). The cardiovascular responses induced by noradrenaline were unaffected by piribedil (0.3–1 mg kg−1). However piribedil (0.3–1 mg kg−1) did not modify the heart rate increase induced by spinal cord electrical stimulation at the C7-Th1 level. These results suggest that piribedil inhibits the vascular sympathetic transmission in the pithed rat via stimulation of presynaptic dopamine receptors.
Potentiation of dermorphin-induced antinociception by peptidase inhibitors
Authors: Sakurada Shinobu , Watanabe Hiromi , Sakurada Tsukasa , Andoh Ryuichiro , Kisara Kensuke , Sasaki Yusuke , Suzuki Kenji
Published: April 2011

We have investigated the effect of amastatin, an aminopeptidase inhibitor, and captopril, an angiotensin converting enzyme inhibitor, on the antinociceptive activity induced by intracerebroventricular administration of dermorphin, a heptapeptide. In addition, the potency of dermorphin was compared with that of one of its metabolites, N-terminal tetrapeptide (Tyr-D-Ala-Phe-Gly), by using the tail pressure test. The antinociceptive activity induced by dermorphin was not potentiated by simultaneous administration of amastatin or captopril. However, there was potentiation when dermorphin was combined with both peptidase inhibitors. Moreover, the N-terminal tetrapeptide was 84 times less potent than its parent heptapeptide when administered intracerebroventricularly. The results suggest that the cleavage of Tyr1-D-Ala2 and Gly4-Tyr5 bonds by brain endopeptidase modulates dermorphin-induced antinociceptive activity.
Liver function in patients on long-term paracetamol (co-proxamol) analgesia
Authors: Hutchinson D R , Schilds A F , Parke D V
Published: April 2011

Eleven patients on long term co-proxamol therapy for pain, in general practice, showed no abnormalities of liver or renal function, as assessed by serum prealbumin concentrations and blood enzyme and electrolyte activities. This indicates that although the preparation is hepatotoxic when taken acutely in overdose, in chronic therapeutic dosage it appears to be free from this hazard.
Tissue atenolol levels following chronic β-adrenoceptor blockade using oral atenolol in dogs
Authors: Davies M K , McAinsh J
Published: April 2011

Tissue atenolol concentrations are high following chronic continuous β-adrenoceptor blockade in dogs. Furthermore, significant concentrations of this poorly lipid soluble drug are found within the central nervous system after chronic dosing. It is suggested that all β-adrenoceptor blocking agents may enter the central nervous system in significant and sufficient quantities to account for a central antihypertensive action of this group of compounds. Sequestration of β-adrenoceptor agents in the CNS or other tissues may account for other clinically observed effects including adaptive effects.
A comparison of the effects of fentanyl and alfentanil on the sleeping times of the intravenous induction agents
Authors: Dingwall A E , Pleuvry B J
Published: April 2011

The effect of increasing doses of fentanyl and alfentanil administered before four intravenous induction agents (thiopentone, methohexitone, Althesin and etomidate) on the sleeping time were studied in mice. A biphasic pattern of sleeping time was noted with the more rapidly metabolized and eliminated compounds. Possible explanations are discussed.
In-vitro biotransformation of antipyrine, lignocaine and propranolol in the liver of rats with turpentine-induced inflammation
Authors: Chindavijak B , Belpaire F M , Bogaert M G
Published: April 2011

In rats with inflammation induced by turpentine injection, changes in drug disposition occur in-vivo and in the perfused isolated liver. Therefore the biotransformation of a low extraction drug, antipyrine, and of two high extraction drugs, lignocaine and propranolol, has been evaluated in the 9000g supernatant fraction of the liver of turpentine-treated rats. Aminopyrine N-demethylase activity and cytochrome P450 content were also measured. Turpentine treatment significantly reduced the in-vitro breakdown of the three drugs; aminopyrine N-demethylase activity and cytochrome P450 content were also decreased. Similar results were found in the proadifen-treated rats, except that in those, the cytochrome P450 content was slightly increased. The changes in drug disposition seen after turpentine-induced inflammation, could therefore be due in part to a change in hepatic enzymatic activity.
Enhancement of jejunal and colonic absorption of fosfomycin by promoters in the rat
Authors: Ishizawa Takayuki , Hayashi Masahiro , Awazu Shoji
Published: April 2011

A means of enhancing absorption of the antibiotic, fosfomycin, has been investigated using promoters in rat jejunum and colon. Polyoxyethylene lauryl ether (BL-9EX), saponin, the sodium salts of fatty acids and mixed micelles were effective at 1% in increasing fosfomycin absorption. Of the sodium salts of saturated medium-chain fatty acids examined, the strength of this effect was in the order caprate > laurate > caprylate. Mixed micelles, consisting of fusogenic lipids and sodium taurocholate, enhanced fosfomycin absorption independently of the degree of unsaturation of the lipids; their effectiveness far exceeded that of sodium taurocholate alone. The action of these promoters was more evident in the colon than in the jejunum, except for the sodium salts of bile acids and disodium ethylenediaminetetraacetate (EDTA-2Na). The effects of glycocholate and taurocholate were essentially the same at both absorption sites, but that of EDTA-2Na was much greater in the jejunum than the colon. Improved fosfomycin absorption was observed at more than 0ṁ5% sodium caprate concentrations in both the jejunum and colon. BL-9EX was effective at 0ṁ1% in the jejunum or at 0ṁ05% in the colon. The effectiveness at these low concentrations demonstrates the practicality of promoters for improving fosfomycin absorption with only minor membrane damage, especially in the colon.
Nasal administration of desmopressin by spray and drops
Authors: Harris A S , Hedner P , Vilhardt H
Published: April 2011

A solution of desmopressin was administered intranasally as a spray using a metered dose pump, or as drops using a single dose pipette or rhinyle catheter. Volunteers, and patients with diabetes insipidus, were given an intranasal dose of 20 μg desmopressin by each method. The antidiuretic activity was measured by determination of urine osmolality and diuresis. Each delivery system was equally effective in producing a rapid onset of activity, a highly reproducible magnitude of effect and duration of the antidiuretic effect which lasted for more than 8 h. The pipette and spray pump offer a choice of single dose administration without preservative, or for chronic use, well-controlled, reproducible dosing, respectively.
The effect of hydroxocobalamin on the nitroprusside-induced relaxation of rat aortic preparations
Authors: Hewick D S , Butler A R , Davidson A
Published: April 2011

Hydroxocobalamin (HOCb) when mixed with sodium nitroprusside (SNP) in a 10:1 or 1:1 molar ratio had no significant effect on the relaxation of noradrenaline-pre-contracted rat aortic rings. However, the addition of HOCb did prolong the time taken for the relaxant response to occur. The time taken for a 0ṁ34 μM SNP dose to exert 50% of its relaxant effect was increased by about 120 and 35% with 10:1 and 1:1 HOCb/SNP molar ratio mixtures, respectively. A 0ṁ5:1 HOCb/SNP molar ratio mixture caused no prolongation. In incubations with [14C]SNP, it was found that mixing with equimolar, or greater, amounts of HOCb, reduced aortic tissue uptake of radioactivity. The results support the hypothesis that both SNP alone and SNP/HOCb complexes breakdown extracellularly to release the same amount of active species, but that in the case of the complexes the active agent is released at a slower rate.
Cross-tolerance development to the prolongation of pentobarbitone-induced sleep by Δ8-tetrahydrocannabinol and 11-hydroxy-Δ8-tetrahydrocannabinol in mice
Authors: Watanabe K , Narimatsu S , Yamamoto I , Yoshimura H
Published: April 2011

Repeated administration (5 mg kg−1 day−1 i.v.) of Δ8-tetrahydrocannabinol and its active metabolite, 11-hydroxy-Δ8-tetrahydrocannabinol caused tolerance to develop to their prolonging effect on pentobarbitone-induced sleep in mice. Reciprocal cross-tolerance also developed after seven daily doses of these cannabinoids. The magnitude of the tolerance developed by the metabolite was greater than that by Δ8-tetrahydrocannabinol. The results suggest that 11-hydroxy-Δ8-tetrahydrocannabinol plays an important role both in the sleep-prolonging effect of Δ8-tetrahydrocannabinol and its tolerance development.
Extraordinary postmortem stability of kappa opioid receptors in guinea-pig brain
Authors: Ori Carlo , Su Tsung-Ping , Weissman Arthur D , London Edythe D
Published: April 2011

Postmortem delay can be an important variable in biochemical studies on autopsy tissue. We subjected guineapig brains to gradual cooling, simulating temperature conditions of human postmortem brains, in order to assess the sensitivity of kappa receptors to postmortem degradation. Kappa receptor specific binding was defined as the (-)-[3H]ethylketocyclazocine bound in the presence of 100 nM D-ala2-D-leu5-enkephalin and 30 nM morphine. Postmortem delays of up to 16 h did not alter the affinity or density of kappa binding sites. The remarkable stability of kappa receptors may greatly facilitate the study of this opioid receptor subtype in human brain.
The characterization of the mechanical properties of microcrystalline cellulose: a fracture mechanics approach
Authors: Mashadi Ali B , Newton J M
Published: April 2011

The mechanical properties of compressed beam specimens of microcrystalline cellulose (Avicel pH 101) have been assessed in terms of the tensile strength (σt), Young's modulus (E) and the following fracture mechanics parameters: the critical stress intensity factor (KIC), the critical strain energy release rate (GIC) and the fracture toughness (R). Increase in the compaction pressure used to form the beams resulted in compacts with higher values of tensile strength, Young's modulus, KIC, GIC and R, indicating that the compacts became less brittle as their porosity decreased. Extrapolation of the values of σt, E, KIC, GIC and R to provide values at zero porosity indicated that the material had values of 30 Nm m−2, 0ṁ0103 GPa, 1ṁ21 MN m−3/2, 1ṁ98 times 102 Nm−1 and 2ṁ19 times 103 Nm−1, respectively. These provide a range of values whereby a fuller characterization of the mechanical properties of pharmaceutical materials can be made.
Biochemical and pharmacological tests for the prediction of ability of monoamine uptake blockers to inhibit the uptake of noradrenaline in-vivo: the effects of desipramine, maprotiline, femoxetine and citalopram
Authors: Pawłowski Leszek , Nowak Gabriel
Published: April 2011

The ability of desipramine and maprotiline (NA uptake inhibitors), as well as citalopram and femoxetine (5-HT uptake inhibitors) to protect mice against brain NA depletion induced by H 77/77 (4-α-dimethyl-m-tyramine), has been compared with their ability to counteract reserpine (2ṁ5 mg kg−1)- or apomorphine (16 mg kg−1)-induced hypothermia and to potentiate TRH (40 mg kg−1)-induced hyperthermia in mice. While both NA uptake inhibitors antagonized the action of H 77/77, maprotiline being weaker than desipramine, femoxetine and citalopram were inactive. However, in contrast to citalopram, femoxetine was active in the other tests, being about twice as weak as maprotiline, which itself was several times weaker than desipramine in those tests. On the basis of the results obtained it is concluded that functional in-vivo tests for NA uptake inhibitors are more sensitive than the H 77/77 biochemical test; moreover, femoxetine, which in in-vitro studies is less selective than citalopram, may inhibit the uptake of NA in-vivo.
Muscarinic receptor density is reduced in diabetic rat atria, an effect prevented by the aldose reductase inhibitor, Statil
Authors: Kofo-Abayomi A , Lucas P D
Published: April 2011

Binding assays using [3H]quinuclidinyl benzilate (QNB) as a muscarinic receptor ligand were carried out on atrial tissue from 6 control and 11 six-week streptozocin-diabetic rats. Five of the latter had received the aldose reductase inhibitor, Statil (25 mg kg−1 day−1 orally). Dissociation constants for specific (atropine displaceable QNB) binding were not changed either by diabetes or Statil treatment. Muscarinic receptor numbers, as estimated by Bmax values, were, however, significantly depressed in tissues from the untreated diabetic group, compared with tissues from either the controls or the Statil-treated diabetic group. These results may explain the reduced sensitivity to muscarinic agonists previously observed in atria from similarly diabetic rats and indicate the involvement of the sorbitol pathway in the change. Possible mechanisms are discussed.
Lymphoid tissue responses to a novel perfluorochemical emulsion in rats
Authors: Bollands A D , Lowe K C , Sharma S K , Davis S S
Published: April 2011

The effects of a novel perfluorochemical emulsion on rat lymphoid tissues and antibody production against sheep red blood cells (SRBC) have been studied. The responses were compared with those following injection of identical doses of the proprietary emulsion, Fluosol-DA 20% (F-DA). Liver weight was increased up to 15% at 8 days following intravenous (i.v.) or intraperitoneal (i.p.) injection of the novel emulsion but was unaffected by F-DA injection. Spleen weight also increased by a maximum of 20% in response to i.p. injection of the novel emulsion but this was less than increases of up to 44% which occurred in F-DA-injected rats. Thymus weight decreased (P < 0ṁ05) following i.p. injection of the novel emulsion whereas mesenteric lymph node (MLN) weight remained unchanged. However, MLN weight was increased in response to i.v. injected F-DA, while thymus weight showed a small increase following i.p. F-DA injection. Mean plasma antibody titres to SRBC were significantly (P < 0ṁ01) increased at 7 days after immunization in rats pretreated with i.p. injections of either the novel emulsion or F-DA; titres in animals pretreated with i.v. injections of either emulsion were similar to control.
Surface area and crystallinity of Form A of chloramphenicol palmitic and stearic esters: which one is the limiting factor in the enzymatic hydrolysis?
Authors: Forni F , Iannuccelli V , Cameroni R
Published: April 2011

Chloramphenicol stearic and palmitic esters in the polymorphic Form A, when ground for 85 h showed an in-vitro enzymatic hydrolysis rate constant (Khydr), the value of which was the same as that of a commercial Form B. The increase in the rate of the enzymatic hydrolysis was not related to the specific surface area as shown by the fact that the micronized Form A, having a higher specific surface area value than ground Form A, showed the same Khydr as the unground Form A. The Khydr value of the ground Form A could be the result of an increase in the crystalline disorder brought about by the grinding process.
An alteration in the liver microsomal membrane of the rat following paracetamol overdose
Authors: Araya Hiroshi , Horie Toshiharu , Hayashi Masahiro , Awazu Shoji
Published: April 2011

Fluorescence polarization of dansyl chloride covalently labelled microsomal membranes revealed an alteration in rat liver microsomal membranes following as a consequence of a paracetamol overdose. This suggests that dansyl chloride would be a useful probe in the study of the effects of paracetamol on microsomal membranes.
Comparative studies of cardiodepressant drugs on contraction dynamics and electrophysiological parameters of cardiac tissues at pH 7ṁ4 and 9
Authors: Schlieper P , Tawfik H
Published: April 2011

The effects of propranolol, amethocaine (tetracaine), lignocaine (lidocaine), procaine and benzocaine on force of contraction and action potential parameters of guinea-pig left atria and papillary muscles have been investigated at pH 7ṁ4 and 9. All the drugs decreased the force of contraction of both preparations. Their biological activities correlated with their lipid/buffer partition coefficients and with their ability to change the surface potential of liposomes. The sequence of activities is as follows: propranolol > amethocaine > lignocaine > benzocaine > procaine. Uncharged benzocaine had no effect on the liposome surface charge. Biological and physicochemical effects obtained at pH 9 were higher than those observed at pH 7ṁ4. Action potential amplitude and Vmax were decreased by all the drugs except benzocaine. At pH 9, the action potential duration was generally shortened, except by amethocaine and procaine; both caused a prolongation of the action potential at 90% repolarization.
Probenecid inhibition of the renal excretion of dyphylline in chicken, rat and man
Authors: Acara M , JR E A Carr , Terry E N
Published: April 2011

The effect of probenecid on the renal excretion of dyphylline was studied in chicken, rat and man. Dyphylline was found to be actively excreted when measured by the Sperber preparation in hens, the isolated perfused kidney of the rat and clearance studies in man. In each study probenecid significantly decreased dyphylline excretion demonstrating that dyphylline occupied the renal organic anion transport system. This same drug interaction, at the level of the renal excretory system, in these three species occurred at comparable concentrations of dyphylline and probenecid.
Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties
Authors: Okamoto Hirokazu , Ohyabu Makiko , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

The effects of four new percutaneous absorption enhancers containing an azacyclo ring and terpene chain (l-geranylazacycloheptan-2-one (GAH), 1-farnesylazacycloheptan-2-one (FAH), 1-geranylazacyclopentan-2,***5-dione (GAPD), and 1-farnesylazacyclopentan-2-one (FAP)) and 1-dodecylazacycloheptan-2-one (Azone) on the percutaneous penetration of mitomycin C (MMC) through hairless mouse and rat skin in-vitro has been investigated. GAH, FAH, FAP and Azone enhanced MMC penetration by 20 to 60 times that of the control (ethanol). During the early part of the experiments, when the sink condition was maintained, FAH was the most effective for hairless mouse skin, whereas Azone showed the highest effect in the rat skin. The enhancing effect of GAPD was only about half that of the other enhancers, suggesting the importance of the polar group of the ring moiety in these compounds. The penetration of MMC through rat skin was also increased by pretreatment with these compounds, suggesting that the enhancers had a direct effect on the skin.
A high molecular weight form of pancreatic polypeptide was present in USP insulin and is absent in a more recent insulin preparation
Authors: Bauman William A , Meryn Siegfried
Published: April 2011

The concentrations and molecular forms of pancreatic polypeptide (PP) and glucagon were determined in USP XX and single-peak insulin preparations. In USP insulin the concentration of PP was 7 ng mg−1 insulin; on gel chromatography the PP immunoreactivity fractionated into two peaks of about equal size. One of the PP peaks was in the region of 4200 dalton PP, and the other PP peak eluted earlier in the region of a 7000-10***000 dalton peptide. The concentration of PP in single-peak insulin was 0ṁ8 ng mg−1 insulin; the immunoreactivity eluted in a single peak in the region of [125I]PP. The concentration of glucagon in each preparation was 55 ng mg−1 insulin. On gel chromatography the immunoreactive glucagon in each insulin preparation eluted in the region of [125I]glucagon.
The sorption of nitroglycerin by infusion sets
Authors: De Rudder D , Remon J P , Neyt E N
Published: April 2011

The sorption of nitroglycerin, from 5% glucose solution, by infusion sets was investigated under simulated perfusion conditions. Several burettes, sets and catheters were evaluated. The stability of the drug in the presence of glucose was also determined. High density polyethylene and glass proved satisfactory for its perfusion in solutions. A method for the evaluation of its uptake under simulated perfusion conditions is described.
Capsaicin-sensitive mechanisms and experimentally induced duodenal ulcers in rats
Authors: Maggi Carlo Alberto , Evangelista Stefano , Abelli Luigi , Somma Vincenzo , Meli Alberto
Published: April 2011

The incidence and degree of cysteamine- or dulcerozine-induced duodenal ulcers are increased by systemic capsaicin desensitization (50 mg kg−1 s.c. 4 days before) in adult rats. Acute administration of capsaicin, but not neurokinins or CGRP, produced a small but distinct plasma extravasation (Evans blue leakage) in the rat proximal duodenum which was absent in capsaicin-pretreated rats. These findings indicate the existence of a capsaicin-sensitive ‘duodenal defence mechanism’ in rats.
Inhibition of basal and insulin-stimulated gastric acid secretion by phenoxybenzamine or phentolamine
Authors: Salim Aws S
Published: April 2011

The present study in the rat was undertaken to investigate the possible involvement of α- and β-adrenoceptors in mediating gastric acid secretion in response to insulin-hypoglycaemia. Phenoxybenzamine, 15 mg kg−1, depressed the basal acid secretion to a level similar to that associated with vagotomy; phentolamine, 15 mg kg−1, had a similar effect. Insulin (1 unit kg−1) significantly stimulated gastric acid secretion. Vagotomy or phenoxybenzamine or phentolamine, 15 mg kg−1 prevented this action. The β-adrenoceptor blocking drug, propranolol, 5–15 mg kg−1, had no significant effect on the basal acid secretion or its stimulation by insulin. The similarity in action between vagotomy and large doses of phenoxybenzamine and phentolamine suggests that, in the rat, vagal α-adrenoceptor stimulation is involved in the mechanisms of basal and insulin-stimulated gastric acid secretion.
Mean residence time for drugs subject to reversible metabolism
Authors: Aarons Leon
Published: April 2011

Conventional methods based on moment analysis lead to biased estimates of the mean residence time for drugs subject to reversible metabolism. A stochastic approach is described which enables unbiased estimation of the mean residence time.
Anti-inflammatory activity of a polysaccharidic fraction of Echinacea angustifolia
Authors: Tubaro A , Tragni E , Del Negro P , Galli C L , Loggia R Della
Published: April 2011

The anti-inflammatory activity of a polysaccharidic fraction (EPF) obtained from Echinacea angustifolia roots has been examined using the carrageenan paw oedema and the croton oil ear test. EPF (0ṁ5 mg kg−1 i.v.) almost inhibited the carrageenan-induced oedema over 8 h and furthermore, EPF, topically applied, inhibited mouse ear oedema induced by croton oil. EPF also reduced the leukocytic infiltration of the croton oil dermatitis, evaluated both as peroxidase activity and histologically. After topical application EPF appears to be slightly inferior in potency to indomethacin. The results suggest that the anti-inflammatory activity of E. angustifolia resides in its polysaccharidic content.
The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat
Authors: Fisher A N , Brown K , Davis S S , Parr G D , Smith D A
Published: April 2011

The nasal absorption of a range of water-soluble compounds with different molecular weights, 4-oxo-4H-1-benzopyran-2-carboxylic acid (mol. wt 190), p-aminohippuric acid (mol. wt 194), inulin (mol. wt 5200) and dextran (mol. wt 70 000), has been investigated in the male Wistar rat. Compounds were instilled into the nasal cavities of anaesthetized animals and, for comparison, similar doses were administered intravenously. Serial samples of bile and urine were collected for up to 6 h. Nasal absorption, estimated by comparison of the extent of excretion in bile and urine following intranasal and intravenous administration, was 100% for 4-oxo-4H-1-benzopyran-2-carboxylic acid (1 mg kg−1), 75% for p-aminohippuric acid (1 mg kg−1), 15% for inulin (0ṁ1 mg kg−1) and 2ṁ8% for dextran (0ṁ25 mg kg−1). The log molecular weight gave a good linear correlation with the log per cent intranasally absorbed (correlation coefficient of -0ṁ996). From the molecular weight relationship, these data infer aqueous channel mechanisms for the nasal absorption of water-soluble compounds.
Evidence for tryptaminergic and noradrenergic involvement in the antisecretory action of morphine in the rat jejunum
Authors: Coupar Ian M , Taylor David A
Published: April 2011

Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) effect of morphine in the intestine is mediated by a direct action of morphine on enteric nerves. Rats were pretreated with 6-hydroxydopamine (6-OHDA) or p-chlorophenylalanine (PCPA) to deplete intestinal stores of noradrenaline and 5-hydroxytryptamine (5-HT). Intraperitoneal injection of 6-OHDA (3 doses at 50 mg kg−1) caused a selective reduction in the level of noradrenaline in the jejunum to 7ṁ3% of control. Intraperitoneal injection of PCPA (200 mg kg−1) selectively reduced the jejunal level of 5-HT to 30ṁ5% of control. Groups of rats that had been treated as described above were anaesthetized and then injected intravenously with saline or with blocking doses of either atropine (0ṁ25 mg kg−1), hexamethonium (20 mg kg−1), ketanserin (30 μg kg−1), methysergide (30 μg kg−1), phentolamine (2 mg kg−1) or propranolol (1 mg kg−1). Following perfusion of the lumen of the jejunum, the rate of glucose absorption was measured to assess the integrity of the mucosa. Glucose absorption was unaltered in animals pretreated with hexamethonium and propranolol but there was a small enhancement in animals pretreated with atropine, PCPA, methysergide, 6-OHDA and phentolamine. The rate of net water absorption from the lumen of the jejunum and the rate of fluid secretion into the lumen following intra-arterial infusion of vasoactive intestinal peptide (VIP, 0ṁ8 μg min−1) were unaltered by any of the drug treatments. Intravenous injection of morphine (10 mg kg−1) did not alter the levels of noradrenaline or 5-HT in the whole jejunum. However, this dose of morphine did cause a 63ṁ5% decrease in the VIP-induced change in water transport. This antisecretory effect of morphine was unaltered in animals pretreated with atropine, hexamethonium and propranolol. In contrast, methysergide, ketanserin and 6-OHDA abolished the antisecretory effect of morphine. PCPA and phentolamine produced a partial inhibition of morphine's antisecretory effect. It is concluded that morphine produces its antisecretory effect in the jejunum by activation of noradrenergic and tryptaminergic systems.
The potentiation of phorbol ester-induced aggregation of human platelets by the prostaglandin endoperoxide analogue, U46619
Authors: Edwards Mary C , Williamson Elizabeth M , Evans Fred J
Published: April 2011

It was not possible to desensitize human blood platelets to 12-deoxyphorbol-phenylacetate (DOPP) stimulation in a manner analogous with that to platelet aggregating factor (PAF), prostaglandin-endoperoxide analogue (U46619) or adenosine diphosphate (ADP). Platelets previously desensitized to U46619, when challenged with DOPP and ADP, showed an increased aggregation and release of 5-HT. Sub-threshold aggregating doses of U46619 also caused a potentiation of the platelet response and release reaction to DOPP. The concentration of U46619 used to pretreat platelets affected the extent of potentiation of platelet stimulation induced by DOPP. The degree of potentiation was also affected by the time interval between addition of U46619 and DOPP. U46619 did not potentiate the aggregating effects of PAF, or ionophore A23187. The stimulus potentiation of DOPP by U46619 was abolished by prostacyclin (PGI2) and an antibody to U46619, but was unaffected by indomethacin and CP/CPK.
A new method for measuring the free fraction of cyclosporin in plasma by equilibrium dialysis
Authors: Henricsson S
Published: April 2011

The free fraction of cyclosporin in plasma has been measured by equilibrium dialysis in steel chambers. Equilibration time was 16 h. The intra-assay coefficient of variation was 7%. The free fraction remained constant in plasma samples frozen for up to 6 months, and was independent of the total concentration within the therapeutic range.