bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of cardiopulmonary resuscitation on plasma concentrations of nimodipine in the dog
Authors: Huyghens L P , Rosseel M T , Calle P A , Buylaert W A
Published: April 2011

The influence of cardiopulmonary resuscitation on the plasma concentrations of nimodipine in the anaesthetized dog has been examined. Nimodipine was given as a bolus injection followed by a maintenance infusion. When, during the maintenance infusion, the dogs were subjected to cardiac arrest followed by external cardiac massage combined with artificial ventilation (basic life support), a fast and almost threefold increase in the steady-state plasma concentrations of nimodipine was observed. When the maintenance infusion of nimodipine was stopped immediately before cardiac arrest and basic life support, the nimodipine concentrations decreased. These results indicate that during basic life support, there is a decreased transfer of infused nimodipine from plasma to the tissues. This is also supported by the fact that for antipyrine, a drug with a smaller volume of distribution than nimodipine, the increase in plasma concentrations when infused during cardiac arrest and basic life support, was much smaller. When nimodipine was started after restoration of the spontaneous circulation (advanced life support) in dogs that had been subjected to cardiac arrest and basic life support, the plasma concentrations were not significantly higher than in control dogs. It can be concluded that the fate of nimodipine is markedly altered during basic life support but not in the period following restoration of spontaneous circulation.
Effect of inflammation and proadifen on the disposition of antipyrine, lignocaine and propranolol in rat isolated perfused liver
Authors: Chindavijak B , Belpaire F M , Bogaert M G
Published: April 2011

The effect of inflammation, induced in rats by injection of turpentine oil, on drug disposition has been evaluated in rat isolated perfused livers. The drugs studied were a low extraction drug, antipyrine, and two high extraction drugs, lignocaine and propranolol. Turpentine significantly increased the half-life of antipyrine and of propranolol, but not that of lignocaine. Proadifen (SKF 525A) significantly increased the half-life of all three drugs. Turpentine decreased the clearance of antipyrine significantly by about 50% and that of propranolol non-significantly by about 20%, but did not affect the clearance of lignocaine. Proadifen significantly decreased the clearance of all three drugs, but this was most pronounced for antipyrine. In both turpentine- and proadifen-treated rats a significant increase in volume of distribution of propranolol was observed. The results show that, as with proadifen, turpentine-induced inflammation affects the hepatic clearance of antipyrine in the rat isolated perfused liver. With both high extraction drugs, the effect of inflammation on their clearance was low or absent, in contrast to the effect of proadifen. This suggests that a possible effect of inflammation on intrinsic clearance is not large enough to influence the hepatic clearance of the high extraction drugs.
Adenosine reduces agonist-induced production of inositol phosphates in rat aorta
Authors: Long C J , Stone T W
Published: April 2011

In rat aortic strips rendered permeable with digitonin, inositol trisphosphate induced an efflux of 45Ca from the tissue. This release was not affected by adenosine. In tissues not treated with digitonin the contents of inositol trisphosphate (IP3) and its metabolite inositol 1-phosphate (IP1***) were significantly enhanced by noradrenaline in the lithium-treated rat aorta. Adenosine was without effect on levels of IP1 or IP3 in tissues which had not been pretreated with noradrenaline, however, the noradrenaline-enhanced tissue content of IP1 was reduced by adenosine in a dose-dependent manner. The reduction in IP1 content by adenosine was enhanced by the uptake blocker dipyridamole (10 μM) and was blocked by the adenosine receptor antagonist 8-phenyltheophylline (10 μM). Adenosine may therefore lower production of inositol phosphates and thus reduce the stimulated release of calcium from intracellular stores. It is proposed that a reduction in phosphatidylinositol turnover may play a role in adenosine-mediated relaxation of blood vessels.
The effects of bromhexine hydrochloride and S-carboxymethyl-L-cysteine on guinea-pig uterine microflora
Authors: Malhi J S , Gard P R , Hanlon G W , Marriott C
Published: April 2011

This study used guinea-pigs as a mammalian model to investigate the effects of bromhexine hydrochloride and S-carboxymethyl-L-cysteine on the integrity of the cervical mucus plug. It was shown that under normal circumstances the uterus is sterile, but following drug administration microorganisms began to appear in the uterus with no significant effect on the vaginal microbial population. It therefore appears that these two mucolytic agents may reduce cervical mucus viscoelasticity. After the animals had been mated, microorganisms were isolated from the uterus even in the absence of drug treatment.
Proglumide, a cholecystokinin receptor antagonist, exacerbates alloxan-induced diabetes mellitus in Swiss mice
Authors: Parmar N S , Tariq M , Ageel A M
Published: April 2011

The effect of proglumide ((±)-4-benzamido-N,N-dipropylglutaramic acid), a gastrin and cholecystokinin receptor antagonist, has been studied on the fasting plasma glucose (FPG) and insulin levels in normal and alloxan-diabetic mice. In normal mice, proglumide, administered as a single oral dose or twice daily for five consecutive days, did not produce any alteration in those parameters. Injection of alloxan monohydrate (70 mg kg−1 i.v.) produced a significant decrease in plasma insulin and a significant elevation of FPG levels on the 5th day after its administration as evidence of diabetes mellitus. Proglumide sodium, given as a single acute dose on the 5th day of alloxan injection, or as a twice daily dose for 5 days immediately after alloxan injection, significantly exacerbated the hyperglycaemia and further decreased the plasma insulin levels thus worsening the diabetogenic effect of alloxan. These observations point to a possible involvement of cholecystokinin (CCK) in alloxan-induced diabetes and indicate a need for monitoring the levels of FPG in diabetic patients being treated with a high dose of proglumide or other CCK-antagonists.
Nitrates do not affect prostacyclin formation by rat arteries: this is unrelated to increased vascular prostacyclin formation with age
Authors: Bennett A , Melhuish P B , Stamford I F
Published: April 2011

The question of whether vasodilator nitrates act by releasing prostacyclin is controversial. Since the ability of blood vessels to form prostacyclin changes with age, we have investigated whether this may explain the discrepancies in the literature. It does not, since isosorbide dinitrate or glyceryl trinitrate incubated with rat aorta or vena cava from male Wistar rats had little or no effect on the release of prostacyclin, measured as 6-keto-PGF1α. We confirm that the aorta produces substantially more prostacyclin than the vena cava. The arterial production of prostacyclin was greater in rats weighing 350-400 g than in those weighing 116-152 g, but the production by the veins was similar in both groups.
Spectrophotometric study of the photodecomposition kinetics of nifedipine
Authors: Majeed Ibraheem A , Murray Wallace J , Newton David W , Othman Sadeq , Al-turk Walid A
Published: April 2011

Nifedipine is a photosensitive compound. Irradiation for 4 h under a fluorescent lamp placed 30 cm from a solution of nifedipine in 95% ethanol leads to complete photo-oxidation as determined spectrophotometrically. The disappearance of the reduced form and appearance of the oxidized form is best described by zero-order kinetics at concentrations higher than 4 times 10−4 M. At lower concentrations pseudo-first order kinetics are followed. Monochromatic irradiation of nifedipine at wavelengths 400 to 700 nm in 25 nm increments showed no change in the absorbance at 280 nm, and, except for a hyperchromic effect at 237 nm, no other spectral changes were observed. Its photo-oxidation was dependent on the intensity of light and increased exponentially as solutions were irradiated progressively closer to a fluorescent light source. The pH studies showed that aqueous solutions of nifedipine photo-oxidized fastest at pH 2.
Guanethidine N-oxidation in human liver microsomes
Authors: McManus M E , Davies D S , Boobis A R , Grantham P H , Wirth P J
Published: April 2011

The capacity of human liver microsomes to N-oxidize guanethidine from 25 subjects has been assessed. Guanethidine N-oxidation was optimal at pH 8ṁ5 and proceeded at only 16% of the maximal rate at pH 7ṁ4. The mean rates of guanethidine N-oxidation at pH 8ṁ5 and 7ṁ4 were 2ṁ46 ± 0ṁ89 (mean ± s.d., n = 25) and 0ṁ38 ± 0ṁ22 (mean ± s.d., n = 22), respectively. Interindividual differences in the rate of guanethidine N-oxidation at pH 8ṁ5 and 7ṁ4 were 17- and 11-fold, respectively. The cytochrome P450 inhibitors, proadifen and 2,4-dichloro-6-phenylphenoxyethylamine (DPEA), at both pH 8ṁ5 and 7ṁ4 caused less than 20% reduction in the rate of guanethidine N-oxidation by human liver microsomes. These data indicate that guanethidine N-oxidation can be used as a measure of flavin-containing monooxygenase activity in human liver.
Tomoxetine and the stereoselectivity of drug action
Authors: Oberlender Robert , Nichols David E , Ramachandran P V , Srebnik Morris
Published: April 2011

The phenoxypropylamine derivative tomoxetine has been shown to inhibit noradrenaline (NA) uptake into synaptosomes from rat hypothalamus (Wong et al 1982). Differences in the potencies of the resolved optical isomers, (-)-tomoxetine (I) and (+)-tomoxetine were also noted, the (-)-isomer being more potent than the racemate or the (+)-isomer in-vitro and in-vivo.
Antinociceptive effects of (±)-, (+)- and (-)-nefopam in mice
Authors: Fasmer O B , Berge O-G , Jørgensen H A , Hole K
Published: April 2011

The antinociceptive activity of (±)-, (+)- and (-)-nefopam in mice has been examined using the hot-plate, formalin and tail-flick tests. Nefopam was administered by the intraperitoneal, intracerebroventricular (i.c.v.) and intrathecal (i.th.) routes. Intraperitoneal injection of (±)-nefopam (10–20 mg kg−1) had powerful analgesic effects in the hot-plate and formalin tests. In the tail-flick test it produced a weak, but significant elevation of the response latencies. In spinalized animals, however, the effect was abolished, indicating that nefopam prolonged the tail-flick latencies by activation of descending pain-modulating pathways. (±)-Nefopam (5–20 μg) elicited analgesia in the hot-plate test after i.c.v. or i.th. injection. These findings suggest that nefopam has both a spinal and a supraspinal site of action. (+)-Nefopam was significantly more potent than (-)-nefopam after both systemic and central administration.
Effects of nicorandil and verapamil, antianginal agents, on plasma digoxin concentrations in rats and dogs
Authors: Hinohara Y , Yamazaki T , Kuromaru O , Homma N , Sakai K
Published: April 2011

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg−1) alone, or in combination with nicorandil (5 mg kg−1) or verapamil (25 mg kg−1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg−1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg−1) or verapamil (25 mg kg−1). In dogs, a loading dose of digoxin (50 μg kg−1) was given orally on day 1, then 25 μg kg−1 was administered for the following 6 days. On day 8, digoxin (50 μg kg−1) was given with nicorandil (5 mg kg−1) or verapamil (20 mg kg−1). In rats, the AUC0–24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.
Studies on the mechanisms of action of activated charcoal on theophylline pharmacokinetics
Authors: Mckinnon R S , Desmond P V , An P J Harm , Kamm M , Ghabrial H , Martin C J , Mashford M L
Published: April 2011

Oral administration of repeated doses of activated charcoal to volunteers and dogs significantly increased the systemic clearance of intravenously administered theophylline and decreased its elimination half-life. This effect is most likely to be due to theophylline entering the gut and being adsorbed onto the charcoal. The mechanism by which intravenously administered theophylline enters the gut has been examined. Its biliary excretion after intravenous administration to patients with T-tube biliary drainage accounted for 0ṁ28% of the dose and a similarly small biliary excretion was found in dogs. In the latter total biliary diversion had no effect on the clearance or half-life of theophylline after intravenous administration. In two dogs the theophylline content of jejunal aspirate was comparable with that of simultaneously withdrawn venous plasma samples. These results suggest that the presence of charcoal in the gut represents a sink adsorbing theophylline entering the lumen by diffusion across the intestinal wall, and by this mechanism it increases clearance of the drug even after intravenous administration.
Measurement ex-vivo of the inhibition of fatty acid biosynthesis by bezafibrate administration in different rat tissues
Authors: Ayala Antonio , Machado Alberto
Published: April 2011

The action of bezafibrate on fatty acid biosynthesis pathways has been examined in rat tissues. The drug abolished the induction of fatty acid synthesis that occurs on refeeding the animals with a high carbohydrate diet and by insulin administration in liver and adipose tissue. The rates of fatty acid biosynthesis in these tissues were estimated from the incorporation of 3H into lipids from 3H2O.
Gastric mucosal cytoprotection in the rat by cysteine
Authors: Salim Aws S
Published: April 2011

The free radical scavengers methyl-methionine sulphonium bromide and cysteine (5%) protected the rat gastric mucosa against ischaemic injury produced by reserpine (5 mg kg−1 i.p.). Pretreatment with 1 mL of 5% cysteine by gavage completely protected against injury rats with no ligation and 70% of rats with pyloric ligation after they had been given aspirin (200 mg kg−1 by gavage), a dose that produced gastric mucosal injury in 40% of rats with no ligation and 70% of rats with pyloric ligation after 4 h. Ethanol (1 mL of 40% solution by gavage) after 1 h produced gastric mucosal injury in all animals and pretreatment with 1 mL of 5% cysteine by gavage completely protected 80% of non-ligated and 70% of pyloric-ligated rats against this injury. This protection was not associated with any significant effect on H+ output. The data suggest that cysteine maintains gastric mucin by a mechanism independent of acid secretion.
Structural and conformational analogy between cholecystokinin and ergopeptines
Authors: Hughes Richard A , Andrews Peter R
Published: April 2011

The central nervous system (CNS) peptide cholecystokinin (CCK) and the ergopeptine alkaloids exhibit common pharmacology in the brain, particularly via catecholaminergic systems. We report here structural similarities between CCK and the ergot alkaloids, and the subsequent conformational analysis of the peptide undertaken to establish whether or not a three-dimensional relationship exists between the compounds. Two low-energy conformations of CCK that mimic the ergopeptine ergotamine are identified, one arising from an X-ray crystal structure and the other from a Dreiding model-based, computer-assisted search. The pharmacological, structural and conformational observations strongly support the hypothesis that CCK and the ergopeptines share common sites of action in the CNS.
Problems of haemoglobin freeze-drying: evidence that water removal is the key to iron oxidation
Authors: Labrude Pierre , Chaillot Bernard , Vigneron Claude
Published: April 2011

Formation of methaemoglobin during freeze-drying of oxyhaemoglobin raises the question of the cause and mechanism of the oxidation. Haemoglobin with or without lyoprotector (250 mM glucose or amino acid salt) has been subjected to freeze drying changes in either or both of two constraints—vacuum and rise in temperature. A rise in temperature from -40 to +10°C had no substantial denaturing effect on haemoglobin whether protected or not. Maintenance of a vacuum over frozen haemoglobin for 18 h often produced subtotal desiccation. Unprotected haemoglobin was partially oxidized (39% MetHb) whereas protected haemoglobin was not (<4% MetHb). Haemoglobin was also dried by rapid dehydration of thin films in a stream of air at room temperature (20 °C). The methaemoglobin content was then 43% whereas the amino acid salt or glucose limited it at 4 and 7%, respectively. Haemoglobin is oxidized, therefore, only because of the removal of water. Protectors, not specific in structure and action, probably work by holding or reinforcing the critical number of hydration layers around haemoglobin.
Comparative studies with the enantiomers of the glycol metabolite of propranolol and their effects on the cardiac β-adrenoceptor
Authors: Ogg G D , Neilson D G , Stevenson I H , Lyles G A
Published: April 2011

The two enantiomers ((R)- and (S)-) of propranolol glycol, a metabolite of propranolol, have been synthesized, and their effects upon the β-adrenoceptor studied by two methods. The ability of these compounds to antagonize the inotropic actions of isoprenaline was examined on spontaneously beating rat atrial preparations. Also, the effects of these enantiomers upon the binding of [3H]dihydroalprenolol to β-receptors in rat cardiac ventricular membranes was studied. Experiments with the atria indicated that the (S)-glycol was a reversible competitive antagonist of isoprenaline with a potency approximately one thousand times lower than that of (±)-propranolol. In contrast, the (R)-glycol appeared to act as an irreversible antagonist, producing complex dose-response curves. The effects of these compounds to cause displacement of alprenolol binding were consistent with the organ bath data. The interaction of the (S)-glycol with the β-receptor binding site was reversible (Ki of 27ṁ6 ± 4ṁ2 μM) but less potent than that of (±)-propranolol (Ki of 0ṁ99 ± 0ṁ07 nM). On the other hand, pretreatment of ventricular membranes with the (R)-glycol, followed by extensive washing techniques, resulted in alprenolol binding which did not regain control values, providing further evidence for an irreversible effect upon the β-receptor. The possible significance of these pharmacological actions of the two enantiomers is discussed in terms of the in-vivo metabolic pathways for propranolol.
Dose-related inhibition of the drug-metabolizing enzymes of rat liver by the pyrrolizidine alkaloid, monocrotaline
Authors: Dalvi R R
Published: April 2011

Adult, male Sprague-Dawley rats were given 0, 10, 20, 40 or 80 mg kg−1 of monocrotaline intraperitoneally and the following toxicity parameters determined 24 h post treatment. Compared with the control none of the doses caused significant change in either the relative liver weight or the hepatic microsomal protein concentration. Microsomal cytochrome P450 content and activities of benzphetamine N-demethylase and aniline hydroxylase did not differ from the control at 10 or 20 mg kg−1 dosage. But, there was a significant loss of cytochrome P450 at 40 and 80 mg kg-1 dosages and decrease in the activity of the two enzymes only at the highest dose. Similarly, the highest dose caused a marked elevation of serum sorbitol dehydrogenase and glutamic pyruvic transaminase activity suggestive of severe liver damage.
Diazepam and desmethyldiazepam differ in their affinities and efficacies at ‘central’ and ‘peripheral’ benzodiazepine receptors
Authors: Gobbi M , Barone D , Mennini T , Garattini S
Published: April 2011

The in-vitro binding characteristics of three different ligands ([3H]Ro 15–1788, [3H]Ro 5–4864 and [3H]flunitrazepam) and the structural requirements for binding to ‘central’ and ‘peripheral’ benzodiazepine receptors have been evaluated in rat cerebral cortex, cerebellum and adrenal glands. [3H]Ro 15–1788 binding was detectable only in the brain. Clonazepam was the most potent inhibitor followed by diazepam and desmethyldiazepam, which showed the same affinity, and by premazepam; Ro 5–4864 did not show appreciable affinity. The same pattern was seen for [3H] flunitrazepam binding in brain areas while in adrenal gland the inhibition pattern was exactly superimposable on that with [3H]Ro 5–4864 in all the areas considered (Ro 5–4864 > diazepam > desmethyldiazepam > clonazepam > premazepam). These data confirm and extend previous reports. A methyl group in position 1 enhances the affinity for peripheral benzodiazepine binding sites which are labelled in the adrenal gland by [3H]Ro 5–4864 and [3H]flunitrazepam; in brain areas, [3H]flunitrazepam, like [3H]Ro 15–1788, selectively labels central binding sites. Methylation in position 1 did not change the affinity for these sites. Desmethyldiazepam is less active than diazepam as an anticonvulsant and in other tests. In-vivo experiments were therefore carried out to assess the ‘intrinsic activity’ of desmethyldiazepam: it appeared that this compound acts as a partial agonist at central benzodiazepine receptors.
Relationship between progesterone suppression and pregnancy in rats
Authors: Carnathan Gilbert W , Metcalf Linda E , Cochrane Robert L , Nutting E F , Black D L
Published: April 2011

Four luteolytic agents were administered to groups of pregnant rats to examine the quantitative relationship between serum progesterone levels and the maintenance of pregnancy. Each agent inhibited progesterone in a dose-dependent manner, however only three, azastene, thiosemicarbazone and dihydrotestosterone, adversely affected pregnancy. A statistical analysis of the data suggests that, regardless of the mechanism of action of a particular luteolytic agent, a treatment-induced depression of serum progesterone to concentrations less than 45% of that of the controls on day 11 of pregnancy is incompatible with pregnancy maintenance.
Ca2+ channel-blocking effect of the yohimbine derivatives, 14β-benzoyloxyyohimbine and 14β-p-nitrobenzoyloxyyohimbine
Authors: Watanabe K , Yano S , Horiuchi H , Yamanaka E , Aimi N , Sakai S
Published: April 2011

Yohimbine possesses a relatively selective α2-adrenoceptor antagonistic effect and a weak Ca2+ channel blocking activity, so two derivatives, 14β-benzoyloxyyohimbine and 14β-p-nitrobenzoyloxyyohimbine were compared with yohimbine using those parameters. The two derivatives blocked Ca2+-induced contraction of the rat perfused mesenteric vascular bed at 3 times 10−6 M, and developed dose-dependent shifts of the dose-response curve to the right in concentrations from 3 times 10−6 to 10−5M. Yohimbine showed a weak Ca2+ channel-blocking effect only at a concentration of 10−5M. On the other hand, both derivatives at 3 times 10−6 M did not affect the dose-response curve to noradrenaline-induced vasoconstriction. Furthermore, at 10−8 M they had no effect on the dose-response curve to clonidine-induced inhibition of the twitch response of the rat isolated vas deferens evoked by electric stimulation, whereas yohimbine significantly attenuated clonidine-induced inhibition. These results indicate that introduction of bulky substituents into the 14-position of yohimbine intensely potentiated the Ca2+ channel-blocking effects and reduced α-adrenoceptor antagonistic effects compared with those of yohimbine, and suggest that chemical modifications of yohimbine may lead to structurally new types of Ca2+ channel-blockers.
Common ion effect on solubility and dissolution rate of the sodium salt of an organic acid
Authors: Serajuddin Abu T M , Sheen Pai-Chang , Augustine Matthew A
Published: April 2011

The solubility and the dissolution rate of the sodium salt of an acidic drug (REV 3164; 7-chloro-5-propyl-1H,4H-[1,2,4]triazolo[4,3-a]quinoxaline-1,4-dione) decreased by the effect of common ion present in aqueous media. The solubility of the sodium salt of REV 3164 in a buffered medium was much lower than that in an unbuffered medium. Also, the presence of NaCl decreased its solubility in water. The apparent solubility product (K'sp ***of the salt, however, did not remain constant when the concentration of NaCl was changed. A decrease in K'sp value with the increase in NaCl concentration was observed; for example, the K'sp values at 0 and 1 M NaCl were 7ṁ84 times 10−4 and 3ṁ94 times 10−4 M2, respectively. Even when corrected for the effect of ionic strength, the solubility product decreased. This decrease in the solubility product in the presence of NaCl indicated a decrease in the degree of self-association (increase in activity coefficient) of the drug in aqueous media.
Cyclosporin: measurement of fraction unbound in plasma
Authors: Legg Brian , Rowland Malcolm
Published: April 2011

A reproducible ultracentrifugation method has been developed for the measurement of the fraction of cyclosporin (CyA) unbound in plasma. The sample is centrifuged to remove any particulate matter, ultracentrifuged in polyallomer tubes and then frozen in liquid nitrogen. Appropriate sections are then cut from the tube for determination of the concentration of radioactivity and calculation of fraction drug unbound. Using this method, the fraction unbound has been measured in plasma from renal transplant patients receiving CyA and found to range between 0ṁ04 to 0ṁ122. The binding is temperature-dependent and principally hydrophobic.
Effect of nadolol, a β-adrenoceptor blocking agent, on myocardial metabolism in the dog ischaemic heart
Authors: Ichihara K , ABIKO Y
Published: April 2011

The effect of nadolol at a dose of 1 mg kg−1, i.v. on the ischaemic myocardial metabolism has been examined in the dog. Ischaemia was induced by ligating the left anterior descending coronary artery for 3 min, and nadolol was injected 5 min before ligation. Ischaemia caused myocardial metabolic changes; it decreased energy charge potential and inhibited glycolytic flux through phosphofructokinase reaction. Pretreatment with nadolol lessened the decrease in energy charge potential and the inhibition of glycolytic flux being caused by ischaemia. Nadolol may have a beneficial effect on the ischaemic myocardium.
Effects of diclofenac sodium and disodium ethylenediaminetetraacetate on electrical parameters of the mucosal membrane and their relation to the permeability enhancing effects in the rat jejunum
Authors: Yamashita Shinji , Saitoh Hidetaka , Nakanishi Kunio , Masada Mikio , Nadai Tanekazu , Kimura Toshikiro
Published: April 2011

The effects of diclofenac sodium and disodium ethylenediaminetetraacetate (EDTA) on electrical parameters of rat jejunal membrane were investigated, together with measurement of the mucosal-to-serosal flux of sulphanilic acid or L-phenylalanine. Both adjuvants increased the flux rate of sulphanilic acid to a similar extent when added to the mucosal solution at 10 mM, but there were apparent differences in their effects on the electrical parameters. The addition of EDTA induced the gradual reduction in the membrane resistance (Rm) by 6–8 ohm cm−2, while the effect of diclofenac on Rm was complicated and concentration-dependent. The short circuit current (Isc) was reduced rapidly to the level of 30–40 μA cm−2 by the addition of diclofenac, but was less affected by EDTA. The flux rate of L-phenylalanine was decreased extensively by diclofenac or the 10 mM concentration of EDTA, suggesting an inhibition of carrier-mediated transport systems in the membrane. Together with our preceding communication (Yamashita et al 1985, J. Pharm. Pharmacol. 37: 512–513), it became obvious that the sites of action of diclofenac and EDTA were different, the former directly interacting with the epithelial cell to alter the permeability and functions of the cell membane, while the primary effect of EDTA could be at the intercellular junctions.
L-Dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease
Authors: Cooper D R , Marrel C , Van De Waterbeemd H , Testa B , Jenner P , Marsden C D
Published: April 2011

Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.
The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and β2-adrenoceptors in the dog
Authors: Smith George W , Hall Janet C , Farmer John B , Simpson Wilfrid T
Published: April 2011

The receptor pharmacology of the cardiovascular effects of dopexamine hydrochloride in the anaesthetized dog (given by i.v. infusion of 3 times 10−9-10−7 mol kg−1 min−1) has been analysed by the use of selective receptor antagonists and of ganglionic blockade. The increases in cardiac output, contractility, and rate were antagonized by the β2-adrenoceptor antagonist, ICI 118551. Renal blood flow rose secondary to reduction in renal vascular resistance and this was antagonized by SCH 23390, a highly selective DA1-receptor antagonist. Peripheral vasodilation and reduction of blood pressure were mediated by a combination of DA1 and DA2-receptor and β2-adrenoceptor stimulation. In a separate group of dogs, the cardiac stimulant effects of dopexamine HCl were partially reflex and were reduced by ganglion block, revealing responses due to stimulation of cardiac β2-adrenoceptors. Thus the β2-adrenoceptor agonist action of dopexamine HCl is not only partly responsible for afterload reduction but also leads to direct cardiac stimulation. From its cardiovascular profile, dopexamine HCl is likely to be of use in acute treatment of heart failure.
Determination of the apparent failure viscosity of tablets
Authors: Patel C I , Staniforth J N
Published: April 2011

Quantitative differences in the plasticity of several direct compression excipients were found to be distinguishable using normalized work of failure determinations. New parameters were developed to characterize the importance of changes in strain rate application during a diametral crushing test. Failure viscosity was found to have a similar sensitivity to normalized work of failure measurements and was also able to distinguish small changes in plastic behaviour. In cases where it is not possible to measure tablet deformation during tablet crushing, failure viscosity determinations could provide an alternative method for characterizing differences in deformation behaviour.
Unloaded polyisobutylcyanoacrylate nanoparticles: efficiency against bloodstream trypanosomes
Authors: Lherm C , Couvreur P , Loiseau P , Bories C , Gayral P
Published: April 2011

The potential use of polyisobutylcyanoacrylate nanoparticles in antiparasitic chemotherapy is described. The nanoparticles on their own proved to have trypanocidal activity against Trypanosoma brucei brucei in-vitro but not against Trichomonas vaginalis or Entamoeba histolytica. The trypanocidal activity was partly confirmed in-vivo with T. brucei-infected mice.
Non-specific prolongation of the effects of general depressants by pyrazole and 4-methylpyrazole
Authors: Taberner P V , Unwin J W
Published: April 2011

The liver alcohol dehydrogenase inhibitors, pyrazole and 4-methylpyrazole, have been tested for their ability to prolong drug-induced sleep times in mice. Both drugs (at 1 mmol kg−1 i.p.) prolonged the duration of loss of righting reflex following chloral hydrate, pentobarbitone, barbitone, temazepam and halothane, but not diethyl ether. This suggests that the effects of these pyrazoles are not specific to the inhibition of liver alcohol dehydrogenase.
Inhibitory role of D-1 dopamine receptors for the jerks induced by B-HT 920 in rats
Authors: Grabowska-Andén M , Andén N-E
Published: April 2011

Jerks of the head and upper trunk produced by the dopamine agonist B-HT 920 in reserpine-treated rats were abolished by the D-1 dopamine receptor agonist SKF 38393. The combined treatment with SKF 38393 and B-HT 920 instead resulted in stereotypies and locomotion. B-HT 920 also caused jerks when given after the D-1 receptor antagonist SCH 23390 to rats not pretreated with reserpine. The results indicate that B-HT 920 induces jerks by stimulation of postsynaptic D-2-like dopamine receptors provided that the D-1 receptors are not activated.
Persistent depletion of striatal dopamine and its metabolites in mice by TMMP, an analogue of MPTP
Authors: Fuller Ray W , Hemrick-Luecke Susan K
Published: April 2011

TMMP (1-methyl-4-[methylpyrrol-2-yl]-1,2,3,6-tetrahydropyridine) mimicked MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in causing persistent depletion of striatal dopamine and its metabolites one week after the last of four daily subcutaneous injections in mice. MMPP (1-methyl-4-[1-methylpyrrol-2-yl]-4-piperidinol) produced no depletion of dopamine or its metabolites under these conditions. None of the three compounds affected dopamine or its metabolites when administered orally. TMMP was even more rapidly oxidized by type B monoamine oxidase in-vitro than was MPTP, but MMPP was a very poor substrate for the enzyme. The lack of neurotoxicity of MMPP toward nigrostriatal dopamine neurons when it was given orally or subcutaneously to mice contrasts with previously reported results in monkeys, in which case MMPP was reported to be neurotoxic.
Some factors affecting the release of imipramine from gel-precipitated aluminium hydroxide spheres
Authors: Ramsey M P , Newton J M , Shaw G G , Sammon D C , Lane E S
Published: April 2011

Changing the pH of the dissolution medium has been found to affect the release of imipramine from gel-precipitated aluminium hydroxide spheres. Release from unwashed, unheated spheres into solutions of pH 1·2 was controlled by dissolution of the gel matrix, whereas that into solutions of pH 3 and pH 5 appeared to be under diffusion control. The liberation of drug from unwashed, heated spheres into the media of higher pH exhibited more complex kinetics. Washed spheres failed to release significant amounts of imipramine into the solutions of pH 3 and 5. Changing the ionic strength of the media had little effect on drug release. These phenomena have been explained with reference to model theories of the precipitation and ageing of aluminum hydroxide gels and their pH-solubility profiles.
A highly sensitive HPLC method for the assay of propantheline used to measure its uptake by rat intestinal brush border membrane vesicles
Authors: Saitoh Hiroshi , Kobayashi Yukari , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

A simple, sensitive, high-performance liquid chromatographic method for propantheline has been developed. Propantheline was quantitatively hydrolysed into xanthene-9-carboxylic acid in neutral or alkaline medium and the hydrolysate assayed by reversed phase high-performance liquid chromatography. This method measured to 2 pmol per injection and was used to investigate the uptake of the drug by rat intestinal brush border membrane vesicles. Propantheline was highly bound to the membrane and this binding was inhibited to varying extents by several quaternary ammonium compounds. Mepenzolate and methylbenactyzium inhibited it significantly, and neostigmine, butylscopolamine and N-methylnicotinamide inhibited it moderately. Choline, acetylcholine and thiamine had no effect.
In-vivo studies of amphotericin B liposomes derived from proliposomes: effect of formulation on toxicity and tissue disposition of the drug in mice
Authors: Payne Nicholas I , Cosgrove Raymond F , Green A Peter , Liu Lin
Published: April 2011

The repeat dose toxicity of various liposomal formulations containing amphotericin B has been determined in mice. In general, small liposomes (e.g. 100–150 nm) were found to be more toxic than their larger counterparts (e.g. about 2000 nm). However, the repeat dose toxicity of small liposomes could be diminished substantially by the inclusion of sterol (i.e. ergosterol) into the liposomal membranes. Tissue accumulation studies of amphotericin B after repeat dosing may be a useful adjunct to formulation development.
The antagonistic effect of morphine on rhein-stimulated fluid, electrolyte and glucose movements in guinea-pig perfused colon
Authors: Verhaeren E H C , Geeraerts V C J , Lemli J
Published: April 2011

Rhein (1,8-dihydroxy-3-carboxyanthraquinone), in a concentration of 6 × 10−4 M, inhibits water absorption from the colon and causes a net transfer of fluid and electrolyte into the intestinal lumen. Morphine (4 × 10−4 M) counteracted the water and electrolyte secretion. Prior perfusion with morphine protected the large intestine from the laxative effect of a rhein perfusion. Differences in absorption rate of 99mTc-EDTA, a poorly absorbable marker, were found, as morphine caused nearly all radioactive compound to be retained in the colon, while rhein significantly facilitated the transfer of marker from colon through mucosal barrier to blood. The route followed by the 99mTc-EDTA complex was not the same as that followed by water, suggesting that 99mTc-EDTA travels by a paracellular route. Morphine counteracted the inhibition of Na+ absorption caused by rhein and antagonized the massive loss of K+ incurred by the presence of rhein in the colon. Cl− absorption is reversed to secretion in the presence of rhein while normal values were restored by morphine. Neither the HCO−3 content nor the pH were affected by either drug. Active absorption of glucose was completely blocked in the presence of rhein; the block could be antagonized by morphine.
Locomotor activity and contracture of isolated ileum precipitated by naloxone following treatment of guinea-pigs with a single dose of morphine
Authors: Chahl Loris A , Thornton Cynthia A
Published: April 2011

Guinea-pigs treated with a single dose of morphine, 15 mg kg−1 s.c., exhibited an increase in locomotor activity 2 h later on injection of naloxone, 4 mg kg−1 i.p. At the same time, contracture of ileal preparations isolated from morphine-treated guinea-pigs occurred on addition of naloxone 1 μM. Contracture of the ileum was inhibited by the tachykinin antagonist, spantide, and was therefore presumably mediated by a substance P-like agent. This study has established a useful model for the parallel investigation of central and enteric nervous system mechanisms of opiate dependence.
The topical anti-inflammatory effects of a topical preparation of meclofenamic acid on carrageenan-induced footpad swelling in mice
Authors: Schrier Denis J , Moniot Susan , Gluckman Melvyn I , Gilbertsen Richard B
Published: April 2011

A topical preparation of meclofenamic acid (Meclomen) was tested for anti-inflammatory activity in a murine model of carrageenan footpad oedema. The preparation significantly inhibited swelling when applied to the carrageenan-injected paw. Maximum inhibition was observed 4–5 h after carrageenan injection. The topical effects could not be attributed to systemic absorption because the preparation was more inhibitory when applied topically to the carrageenan-injected paw than to a distant site or orally.
Effects of microiontophoretic pentobarbitone on conditioned inhibitions mediated by GABA-A receptors in the cuneate nucleus of the rat in-vivo
Authors: Andres-Trelles F , Orviz P
Published: April 2011

We have studied the effects of microiontophoretic sodium pentobarbitone on the conditioned inhibition of the negative potential (N-wave) evoked in the cuneate nucleus of the rat by electrical stimulation (5 V, 0.2 ms, 0.5 Hz) of the ipsilateral forepaw. Five- or seven-barelled micropipettes were used, the tip being placed at a depth of 600–900 μm below the dorsal surface of the medulla oblongata. The conditioned inhibition was elicited by a previous identical stimulus. When the interval between the stimuli is shorter than about 40 ms (short duration) the inhibition is thought to be mediated by γ-aminobutyric acid (GABA), acting on GABA-A receptors. When it is longer (long duration conditioned inhibition) GABA-A receptors are not thought to be involved. Microiontophoretic sodium pentobarbitone potentiated both short (15 ms) and long (45 ms) duration conditioned inhibitions. The effect was current-dependent and appeared whether or not the first N-wave was depressed. Microiontophoretic application of (-)- bicuculline methiodide (a GABA-A antagonist) reduced the potentiation by pentobarbitone up to the basal inhibition when the interval between the stimuli was 45 ms or longer and to a greater extent when it was 30 ms or shorter. It seems likely that pentobarbitone prolongs the GABA-ergic mechanism which produces the short duration inhibiton, making it visible with long stimulus intervals, superimposed upon the normal long duration conditioned inhibition which is not potentiated by local pentobarbitone.
Evidence for spare α1-adrenoceptors for the accumulation of inositol phosphates in smooth muscle
Authors: Fox Anthony W , Friedman Paul A
Published: April 2011

The accumulation of inositol phosphates (IP) in smooth muscle from rat vas deferens and caudal artery was maximally increased 3- to 4-fold in response to exposure of the tissues to 100 μM noradrenaline. Clonidine (up to 3 mM) was a partial agonist. Pretreatment of the tissues with the irreversible α-adrenoceptor antagonist phenoxybenzamine (0.3–10 μM) shifted the noradrenaline concentration-response curve to the right before depressing the maximum. The maximum of the clonidine concentration-response curve was depressed without significant change in the EC50 by the same treatment. These data, which are most easily interpreted as demonstrating the presence of a receptor reserve for IP accumulation, are discussed.
Effect of 711389-S, a New Antiarrhythmic Agent, on Myocardial Energy Metabolism in Guinea-Pigs and Rats
Authors: Iwaki K , Ishii M , Shinosaki T , Ueda M , Yonetani Y
Published: April 2011

The effect of 711389-S, a new antiarrhythmic agent, on myocardial energy metabolism was investigated using anaesthetized guinea-pigs and rats. 711389-S elevated the adenylate energy charge and phosphorylation potential in normal guinea-pig myocardium. Large doses also increased the myocardial lactate content with ECG abnormalities. The close relationship between rate-pressure product and the myocardial energy state under 711389-S treatments showed the suppression of energy consumption due to a decrease of work output. In guinea-pigs with arrhythmic myocardia induced by intravenous infusion of ouabain, 711389-S prevented the loss of high-energy phosphate compounds and the acceleration of anaerobic glycolysis concomitant with the effective antiarrhythmic property. In ischaemic myocardium produced by ligation of the coronary artery in rats, 711389-S suppressed the decreases of creatine phosphate, NAD+ and adenylate energy charge. Moreover, this agent effectively blocked the incidence of ventricular arrhythmias at an early stage following the ligation. In all of these actions, 711389-S was more effective than disopyramide, which is in the same class of antiarrhythmics. 711389-S was concluded to be a favourable antiarrhythmic agent offering beneficial action against arrhythmic and ischaemic metabolic changes in the myocardium.
Inhibition of Glucose-induced Insulin Secretion by Calcium Channel Blocking Drugs In-vitro but not In-vivo in the Rat
Authors: Semple Colin G , Smith Maureen , Furman Brian L
Published: April 2011

The organic calcium channel blocking drugs darodipine, nicardipine, diltiazem and verapamil inhibited glucose-induced (8.3 mmol L−1) insulin secretion by rat isolated islets in a concentration-dependent manner. The IC50 values (μmol L−1) for nicardipine, diltiazem and verapamil were 0.0025, 1.94 and 3.6, respectively. There were no significant differences between the potencies of any one drug when compared at two different glucose concentrations (27.8 and 8.3 mmol L−1). Isolated islets were also responsive to the calcium channel activating drugs BAY K 8644 and CGP 28392, which enhanced glucose-induced insulin secretion and prevented the inhibitory effect of verapamil. BAY K 8644 was more potent than CGP 28392. In the anaesthetized rat, neither verapamil (1 mg kg−1 i.v. 10 min before glucose) nor nicardipine (0.2 mg kg−1 i.v.) modified the glucose or insulin response to intravenous glucose whilst producing marked cardiovascular effects. The plasma concentrations of nicardipine (3.9 × 10.8 M at 10 min post injection) were similar to those producing effects in-vitro whereas the plasma concentrations of verapamil (5 × 10−7 M) were lower. It thus appears that the islet B cell calcium channel is less sensitive to calcium channel blocking drugs in-vivo than in-vitro. Moreover, in-vivo, the cardiovascular system is more sensitive to these drugs than are the islet B cells, although the potencies of the calcium channel blocking drug in isolated islets are similar to those reported for cardiac muscle and vascular smooth muscle in-vitro.
Distribution of 7-hydroxymethotrexate in human blood
Authors: Slørdal Lars , Sager Georg , Huseby Nils-Erik , Aarbakke Jarle
Published: April 2011

We have examined the in-vitro distribution of 7-hydroxymethotrexate (7-OH-MTX), a cytotoxic metabolite of methotrexate (MTX), in human blood, and its protein binding in serum. The distribution of 7-OH-MTX (10−6 M) in fresh samples of whole blood was studied at 37 °C and pH 7.51 ± 0.05 (mean ± s.d.), and its protein binding was assessed by equilibrium dialysis of serum against Krebs Ringer phosphate buffer at 37 °C and pH 7.41 ± 0.07 (mean ± s.d.). 7-OH-MTX had a mean cell/plasma concentration ratio of 0.03 (range 0–0.27, n = 18). It was extensively bound in human serum, with a bound fraction of 90.4 ± 3.3% (mean ± s.d.) in healthy volunteers (n = 11), and significantly lower, 82.3 ± 4.0% (mean ± s.d.), in hypoalbuminaemic surgical patients (n = 7). The binding of 7-OH-MTX was correlated with serum albumin (HSA) concentrations (r = 0.72, P < 0.0007, n = 18). Blood distribution data support the contention that 7-OH-MTX has a small volume of distribution, and HSA appears to be mainly responsible for the high degree of its protein binding in serum.