bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood-brain-barrier Transport of Lipid Microspheres Containing Clinprost, a Prostaglandin I2 Analogue
Authors: Minagawa Toshiya , Sakanaka Kohji , Inaba Shin-Ichi , Sai Yoshimichi , Tamai Ikumi , Suwa Toshio , Tsuji Akira
Published: April 2011

Because the permeability of the blood-brain barrier to lipid microspheres (LMs) has not hitherto been demonstrated, blood-brain-barrier permeability to LM containing the prostaglandin I2 analogue clinprost has been evaluated for an in-vitro system of primary cultured monolayers of bovine brain capillary endothelial cells (BCECs), by a capillary depletion study in rats and by an in-situ brain perfusion study in normal and 4-vessel-occluded fore brain ischaemic rats.

Although energy-dependency was not observed in [3H]clinprost uptake by BCECs, in accordance with results for simple diffusional transport, uptake of [3H]clinprost contained in lipid microspheres (denoted [3H]clinprost(LM)) was significantly inhibited by the endocytosis inhibitor, dansylcadaverine. The transport of LM into BCECs by endocytosis was also confirmed by fluorescence microscopy and flow-cytometric analysis using LM labelled with a fluorescent probe, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI). The absolute uptake of DiI(LM) by BCECs, measured by HPLC, was, however, almost 1/10 that of [3H]clinprost(LM), results which suggest the superiority of simple diffusion of clinprost over endocytosis of its LM form in the uptake of clinprost(LM) by BCECs. In the capillary-depletion study with rat-brain-perfused [3H]clinprost(LM) from the internal carotid artery, the parenchyma apparent distribution volume was about 45 times larger than that of the capillary, showing that [3H]clinprost(LM) was transported through the blood-brain barrier into the brain. The permeability coefficients of [3H]clinprost and [3H]clinprost(LM) determined by in-situ brain perfusion in normal rats were considerably higher than those of the active metabolite [3H]isocarbacyclin and its LM form. In addition, the Blood-brain-barrier permeabilities to [3H]clinprost, [3H]isocarbacyclin and their LM forms in ischaemic rats were almost identical to those in normal rats.

It was concluded that clinprost(LM) was transported through the blood-brain barrier by endocytosis of LM, simple diffusion of clinprost released from LM, and transport of isocarbacyclin generated by hydrolysis of clinprost. The blood-brain-barrier permeability of clinprost(LM) is not reduced in ischaemic conditions, because the simple diffusion of clinprost released from LM contributed mainly to clinprost(LM) transport.
Comparison of Two Binding Equations for Prediction of the Concentration of Unbound Valproic Acid in the Serum of Adult Epileptic Polytherapy Patients
Authors: Kodama Yasuo , Kuranari Masae , Kodama Hirofumi , Zaizen Takako , Yukawa Eiji , Fujii Isao , Takeyama Masaharu
Published: April 2011

Because binding of valproic acid to plasma proteins affects the efficacy of the drug in the treatment of epilepsy (only the unbound fraction of the drug is effective) we have compared two methods which use different binding parameters to predict the in-vivo concentration of unbound valproic acid in serum.

The study was performed on 46 serum samples from 29 polytherapy adult patients with epilepsy. Mean prediction error, mean absolute prediction error and root mean squared error were calculated for each method; these values served as a measure of prediction bias and precision. The mean absolute prediction errors and root mean squared errors for the two methods were similar in magnitude (Method 1, mean absolute prediction error= 10.0 μM, root mean squared error= 15.0 μM; Method 2, mean absolute prediction error= 10.3 μM, root mean squared error= 13.5 μM). Method 2 had a general tendency to over-predict unbound valproic acid; both methods had a tendency to over-prediction for total concentrations above 500 μM. Method 1 had a tendency to under-prediction at total concentrations below 250 μM. Within the total concentration range of valproic acid investigated, Method 1 was superior to Method 2 for prediction of unbound serum valproic acid.

Our approach using Method 1 may be useful for prediction of unbound serum valproic acid concentration in patients with total valproic acid concentrations ranging from 250 to 500 μM; Method 2 may be useful for patients with total valproic acid below 500 μM. Our results suggest that there is wide and unpredictable variability in valproic acid binding to serum proteins among study populations.
Effects of Enzyme Inhibitors and Insulin Concentration on Transepithelial Transport of Insulin in Rats
Authors: Bai Jane P F , Chang L L
Published: April 2011

The objective of this study was to determine whether transepithelial transport of insulin can be improved by enzyme inhibitors and whether insulin concentration affects its ileal absorption.

Ussing chambers and radioimmunoassay were used to study insulin transport across the rat ileum, and circular dichroic spectra were used to determine whether insulin aggregated at high concentrations. Inhibitors that inhibit insulin-degrading enzyme, including N-ethylmaleimide, 1,10-phenanthroline and N-chloromercuribenzoate, dramatically improved insulin transport across the ileum. At 100 nm, the ileal permeability of immunoreactive insulin was 10-6 cm s−1 in the presence of inhibitors, and was negligible when inhibitors were not used. Ammonium chloride, a lysosomotropic agent that increases intralysosomal pH, and aprotinin, a proteasome inhibitor, did not increase transport of insulin to a detectable extent. Insulin permeability decreased as its concentration increased from 100 nm to 83.3 μM, and at 83.3 μM insulin aggregated.

It is concluded that insulin transport is improved by enzyme inhibitors, but is impaired by insulin aggregation at high concentrations.
Active Secretion of Drugs from the Small Intestinal Epithelium in Rats by P-Glycoprotein Functioning as an Absorption Barrier
Authors: Terao Toshimitsu , Hisanaga Etsuko , Sai Yoshimichi , Tamai Ikumi , Tsuji Akira
Published: April 2011

Because the significance of P-glycoprotein in the in-vivo secretion of β-blockers in intestinal epithelial cells is unclear, the secretory mechanism for β-blockers and other drugs has been evaluated.

Uptake of the β-blockers acebutolol, celiprolol, nadolol and timolol, and the antiarrhythmic agent, quinidine by the multidrug-resistant leukaemic cell line variant K562/ADM was significantly lower than that by drug-sensitive K562 cells, suggesting that these β-blockers are transported by P-glycoprotein out of cells. The reduced uptake of acebutolol by the drug-resistant K562/ADM cells was reversed by treating the cells with anti-P-glycoprotein monoclonal antibody, MRK16, whereas no such alteration in uptake was observed for drug-sensitive K562 cells. Acebutolol uptake by K562/ADM cells was, moreover, markedly enhanced, in a concentration-dependent manner, in the presence of the specific P-glycoprotein inhibitors, MS-209 and cyclosporin. Caco-2 cells were used for evaluation of the role of P-glycoprotein in intestinal permeability to drugs in-vitro. Basolateral-to-apical transport of acebutolol was twice that in the reverse direction. A similar polarized flux was also observed in the transport of vinblastine, but not in that of acetamide or mannitol. When in-vivo intestinal absorption was evaluated by the rat jejunal loop method, with simultaneous intravenous administration of a P-glycoprotein inhibitor, cyclosporin, intestinal absorption of both acebutolol and vinblastine increased 2.6- and 2.2-fold, respectively, but no such enhancement was observed in the absorption of acetamide. The effect of cyclosporin on the intestinal absorption of several drugs was further examined, and the extent of the contribution of P-glycoprotein as an absorption barrier to those drugs was evaluated. ATP depletion by occlusion of the superior mesenteric artery resulted in a clear increase in epithelial permeability to vinblastine, but not to 3-O-methylglucose or acetamide, indicating that vinblastine is secreted by ATP-dependent P-glycoprotein into the lumen.

These findings demonstrate that P-glycoprotein plays a role as an absorption barrier by transporting several drugs from intestinal cells into the lumen.
Force-time Curves of a Rotary Tablet Press. Interpretation of the Compressibility of a Modified Starch Containing Various Amounts of Moisture
Authors: Leitritz M , Krumme M , Schmidt P C
Published: April 2011

On a rotary tablet press, the force-time curves are segmented into three phases: the compression phase, the dwell phase during which both stress and strain are variable for plastically deforming materials and the decompression phase. The following seven parameters were investigated: the compression area (A1) and the compression slope (Slc) describing the initial phase, the area ratio (AR) and the peak offset time (toff) characterizing the dwell time, the decompression area (A4) and the decompression slope (Sld) describing the terminal phase and the total area under the force-time curve (Atot). AR, toff, Slc and A1 (the last with limitations) are used for phase-specific allocation of the occurrence of plastic flow, which is found to be a function of compression force and moisture content. Tablet strength, tablet porosity and in-die bulk porosity provide additional information for comprehensive interpretation.

The values of A4 for the four starch batches are not significantly different. Sld provides somewhat better information about the elastic compact recovery. In general, however, the short decompression phase seems to be inappropriate for characterization by force-time curve parameters, because it is difficult to separate machine recovery from that of the tablet.

Porosity above the porosity limit of the material was found to be a prerequisite for plastic flow within the compact. When the porosity limit is reached, further densification remains elastic and leads to a reduced compact strength during expansion. The area ratio, as a robust in-process control parameter for plastically flowing formulations, is suggested as a means of preventing this effect.
Synthesis, Physical Properties, Toxicological Studies and Bioavailability of L-Pyroglutamic and L-Glutamic Acid Esters of Paracetamol as Potentially Useful Prodrugs
Authors: Bousquet E , Marrazzo A , Puglisi G , Spadaro A , Tirendi S
Published: April 2011

Paracetamol ester prodrugs with L-pyroglutamic and L-glutamic acid, biosynthetic precursors of glutathione, have been synthesized to reduce paracetamol hepatotoxicity and improve bioavailability.

The toxicological studies of paracetamol esters show that only L-5-oxo-pyrrolidine-2-paracetamol carboxylate reduces toxicity after administration of an overdose. The glutathione hepatic values in mice obtained by intraperitoneal injection of the ester are superimposable on controls and the oral LD50 was found to be greater than 2000 mg kg−1 and the intraperitoneal LD50 was 1900 mg kg−1.

These results taken together with hydrolysis and bioavailability data show that ester is a potential candidate as a prodrug of paracetamol.
The Disposition of Morphine and Morphine-3-glucuronide in the Isolated Perfused Rat Liver: Effects of Altered Perfusate Flow Rate
Authors: O'Brien Josephine A , Nation Roger L , Evans Allan M
Published: April 2011

The rat single-pass isolated perfused liver preparation was used to study the effects of altered perfusate flow rate on the hepatic disposition of morphine and its polar metabolite morphine-3-glucuronide (M3G). Using a balanced, cross-over design, livers of female Sprague-Dawley rats (n = 6) were perfused at 15 and 30 mL min−1 with erythrocyte- and protein-free perfusion medium containing a constant concentration of morphine (2.7 μM). After reaching steady-state, inflow and outflow perfusate and bile samples were collected and morphine and M3G were measured by HPLC.

Doubling of perfusate flow rate was associated with a significant increase (P < 0.05) in the availability of morphine (mean ±s.d. of 0.19± 0.06 at 15 mL min−1 and 0.29 ± 0.08 at 30 mL min−1). The magnitude of the change in morphine availability was consistent with the predictions of the well-stirred model of hepatic elimination.

The fate of hepatically generated M3G was assessed by the biliary extraction ratio of M3G; alterations in perfusate flow rate had no significant effect on this ratio (mean ± s.d. of 0.49 ± 0.14 at a perfusate flow rate of 15 mL min−1 and 0.47 ± 0.22 at 30 mL min−1).

A physiologically-based mathematical model, in which the vascular and intracellular spaces of the liver were represented by two well-mixed compartments, was utilized to derive an equation for the biliary extraction ratio of M3G. According to the model, the value of this extraction ratio will become insensitive to changes in perfusate flow rate when the permeability for M3G of the membrane separating the intracellular and vascular compartments is low compared with perfusate flow rate. Hence, the experimental results are consistent with the concept that the hepatic sinusoidal membrane represents a diffusional barrier to M3G.
A High-performance Liquid-chromatographic Microanalytical Procedure for the Rapid Estimation of Piracetam in Plasma or Cerebrospinal Fluid
Authors: Doheny M H , O'Connell M T , Patsalos P N
Published: April 2011

Presently available GC and HPLC methods for analysis of piracetam, require large samples and suffer from interference.

A micro scale, isocratic high-performance liquid-chromatographic method is described for the determination of piracetam in plasma (25 μL) or cerebrospinal fluid (10 μL) using ultraviolet absorbance at 215 nm. The limit of quantitation is 4 μg mL−1 and the within-batch and between-batch coefficients of variation are less than 10%. No interference from other commonly prescribed antimyoclonic or antiepileptic drugs was observed and thus the method can be used to monitor piracetam in patients on polytherapy antimyoclonic or antiepileptic drug regimens.

Because of the sensitivity and rapidity of the method it is suitable for pharmacokinetic and mechanistic studies and for analysis of paediatric samples.
Uptake Mechanism of Trientine by Rat Intestinal Brush-border Membrane Vesicles
Authors: Tanabe Ryou , Kobayashi Michiya , Sugawara Mitsuru , Iseki Ken , Miyazaki Katsumi
Published: April 2011

The uptake characteristics of trientine by rat intestinal brush-border membrane vesicles were studied.

The uptake characteristics of trientine were similar to those of the physiological polyamines with respect to the excessive accumulation in vesicles, the pH dependency, the temperature dependency and the ineffectiveness of K+ diffusion potential (inside negative). The initial uptake of trientine was saturable with a Km value of 1.13 mM, which was larger than that of spermine and spermidine. Furthermore, the uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Spermine competitively inhibited the uptake of trientine with a Ki value of 18.6 μM, and it was close to the Km value for spermine (30.4 μM).

These data suggested that the uptake of trientine was similar to that of spermine and spermidine in rat small intestinal brush-border membrane vesicles, and these polyamines seem to inhibit the absorption of trientine from the gastrointestinal tract.
Selective Cyclodextrin Inhibition of Alfaxolone-induced Ataxia
Authors: Koetzner Lee , Riggs Raine L , Mastropaolo John , Deutsch Stephen I
Published: April 2011

The effect of the use of a number of popular solubility treatments was examined on alfaxolone- and diazepam-induced ataxia.

The effects of diazepam were not significantly altered by solution in cyclodextrin, Alkamuls EL-620 or a mixture of propylene glycol and ethanol. The effects of alfaxolone were not altered by solution in Alkamuls EL-620, but were significantly lessened by solution in cyclodextrin. In a dose-response experiment, the ED50 of alfaxolone increased from 15.3 mg kg−1 (in Alkamuls EL-620) to 25.6 mg kg−1 (in hydroxypropyl-β-cyclodextrin).

The results suggest that although cyclodextrins are popular and effective solubilizers, their use must be considered carefully in the context of the experiments in which they are to be used.
Evaluation of the Relaxant Activity of some United Arab Emirates Plants on Intestinal Smooth Muscle
Authors: Tanira M O M , Ali B H , Bashir A K , Wasfi I A , Chandranath I
Published: April 2011

Although medicinal plants are used as antispasmodic agents in folk medicine there have been no scientific studies of the phytochemical composition and usefulness of these plants for such treatment. Extracts of 23 plants used in the traditional medicine of the United Arab Emirates were tested for their effects on intestinal smooth muscle activity.

Most of the plants tested caused stimulation followed by inhibition of the motility of the rabbit jejunum and guinea-pig ileum. The inhibitory effect of plants that had EC50 values < 1 mg was confirmed in-vivo using the gastrointestinal transit time test. These plants were phytochemically screened for their secondary constituents. The effect of Rhazya stricta was investigated, particularly in relation to acetylcholine effect.

The results indicated the potential of some of the plants, especially Rhazya stricta, as a source of antispasmodic agents.
Animal Pharmacokinetics and Interspecies Scaling from Animals to Man of Lamifiban, a New Platelet Aggregation Inhibitor
Authors: Lave Thierry , Saner Alphonse , Coassolo Philippe , Brandt R , Schmitt-Hoffmann Anne H , Chou Ruby C
Published: April 2011

Relating pharmacokinetic information obtained in animal species to man (interspecies scaling) can play an important role in enabling understanding of the differences and similarities between species, and helping to predict the kinetic profile of a new compound in man.

Interspecies scaling techniques have been applied to lamifiban (Ro 44–9883), a new selective and potent nonpeptidic inhibitor of human glycoprotein IIb-IIIa intended for use in clinical treatment of, for example, acute coronary syndrome. The pharmacokinetic profile of lamifiban in man was predicted from animal data (in rats, dogs and cynomolgus monkeys) by using allometric scaling and concentration-time transformations. These extrapolations for lamifiban were performed prospectively, to help design the first pharmacokinetic studies in man. The approach based on equivalent time was preferred for our prospective predictions, in view of the high values found for the allometric exponents. Using allometric scaling, clearance (CL), half-life(t1/2) and volume of distribution (Vd) were overestimated by approximately two-to fourfold. Compared with allometric scaling, the transformation based on equivalent time improved the prediction for all human pharmacokinetic parameters. For t1/2 and CL, the observed values for man were within the range predicted from the various animal species.

Of the individual animal species, the cynomolgus monkey gave the most reliable predictions of these two parameters, as well as accurately predicting the Vd value.
Adrenomedullin is Inactivated in the Lungs of Neonatal Piglets
Authors: Sabates Braulio , Granger Tommie , Choe Ella , Pigott John , Lippton Howard , Hyman Albert , Flint Lewis , Ferrara John
Published: April 2011

Adrenomedullin, a novel 52 amino acid peptide normally present in adult human plasma, has been shown to induce systemic hypotension in the adult rat, pig and cat, and in the new-born piglet. Little is known about the site(s) of adrenomedullin inactivation in adults or neonates.

Groups of five 0–2-day old and 2-week old anaesthetized piglets were prepared to enable continuous monitoring of cardiac output, mean systemic arterial pressure, mean pulmonary artery pressure, mean systemic vascular resistance and mean pulmonary vascular resistance. In both age groups, injections of human adreno-medullin1–52 into the left atrium produced significant (P < 0.05) reductions in mean systemic arterial pressure and mean pulmonary artery pressure. Although injections of similar doses of human adrenomedullin1–52 into the right atrium produced significant (P < 0.05) decreases in mean pulmonary artery pressure, there were no appreciable alterations in mean systemic arterial pressure in either age group.

These results suggest that the systemic vasodilator properties of human adrenomedullin1–52 are reduced upon first pass through the pulmonary circulation in 2-week old piglets, a phenomenon that is present at birth.
Twenty-eight-day Double-blind Safety Study of an HFA-134a Inhalation Aerosol System in Healthy Subjects
Authors: Harrison Lester I , Donnell David , Simmons Jean L , Ekholm Bruce P , Cooper Katherine M , Wyld Peter J
Published: April 2011

A 28-day double-blind parallel group study has been conducted to compare the safety and tolerability of HFA-134a, a chlorofluorocarbon-free propellant in a pressurized metered-dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C).

Sixteen subjects were randomly assigned to receive one of the two MDIs, either four inhalations four times per day for 14 days or eight inhalations four times a day for 14 days, and were then crossed over to the alternative exposure regime with the same propellant for the next 14-day period. No clinically significant changes occurred in blood pressure, heart rate, electrocardiograms, pulmonary function (FEV1, FVC, FEF25–75%), haematology or serum chemistry. One subject in the MDI A group had elevated eosinophil counts throughout the study; there were no other remarkable clinical laboratory data. Fifty six adverse events were related to the study propellants; 34 of these occurred in the MDI C group and 22 in the MDI A group. For each adverse event no statistically significant differences were detected between propellant systems or between exposure levels. The most frequent adverse event was headache, which was reported by four subjects with each propellant system. Blood samples for HFA-134a in the MDI A group were collected on day 28 to measure systemic absorption. Blood levels of HFA-134a were detected in all subjects given this propellant within 1 min post-exposure, and these levels decreased to one-tenth of the original value by 18 min after the start of exposure.

The safety and tolerability of an HFA-134a chlorofluorocarbon-free system was demonstrated over 28 days of exposure in healthy subjects. These negative results are clinically important because they indicate it will be safe to proceed with the study of this chlorofluorocarbon-free system in asthmatic patients.
Pharmacodynamics of ZM 241385, a Potent A2a Adenosine Receptor Antagonist, after Enteric Administration in Rat, Cat and Dog
Authors: Poucher S M , Keddie J R , Brooks R , Shaw G R , Mckillop D
Published: April 2011

4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes.

In conscious spontaneously hypertensive rats, ZM 241385 (1–10 mg kg−1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg−1 min−1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg−1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6–10 mg kg−1, i.v.) by 94% after 10 mg kg−1 (p.o.) and by up to 74% after 0.3 mg kg−1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg−1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1–10 mg kg−1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg−1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg−1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog.

In conclusion, ZM 241385 is a potent, selective A2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A2a receptors in the action of adenosine in-vivo.
Dexamethasone Reduced Clonidine-induced Hypoactivity in Mice
Authors: Capasso A , Di Giannuario A , Loizzo A , Pieretti S , Sorrentino L
Published: April 2011

Reduced clonidine anti-nociception in mice given low doses of dexamethasone has encouraged us to investigate the effects of dexamethasone pretreatment on locomotor hypoactivity, another example of clonidine-induced behaviour in mice.

Dexamethasone administered intraperitoneally (0.1, 1.0, 10 mg kg−1) 30 min before clonidine reduced clonidine-induced locomotor hypoactivity in the activity cage to an extent which was dose-dependent. Dexamethasone administered centrally (10 ng/mouse) 30 min before clonidine was also able to reduce clonidine-induced locomotor hypoactivity. Cycloheximide administered at a dose of 10 mg kg−1 2 h before clonidine did not change the effects of clonidine but was able to prevent the effects of dexamethasone on clonidine-induced hypoactivity. The glucocorticoid receptor antagonist RU38486 administered centrally at the dose of 1 ng/mouse did not change the effects of clonidine, whereas it was able to block the effects of dexamethasone on clonidine-induced locomotor hypoactivity.

These results suggest that the effects of dexamethasone on clonidine-induced locomotor hypoactivity depend on the stimulating effects that dexamethasone exerts on the protein synthesis via the glucocorticoid receptor in the brain.
Sympathomimetic Effects of Scoparia dulcis L. and Catecholamines Isolated from Plant Extracts
Authors: Freire Sonia Maria De Farias , Torres Luce Maria Brandão , Souccar Caden , Lapa Antonio José
Published: April 2011

The herb Scoparia dulcis L. is used in Brazilian folk medicine to treat bronchitis, gastric disorders, haemorrhoids, insect bites and skin wounds, and in oriental medicine to treat hypertension. A previous study has shown that extracts of S. dulcis have analgesic and anti-inflammatory properties; in this work the sympathomimetic activity of an ethanolic extract of Scoparia dulcis L. has been investigated in rodent preparations in-vivo and in-vitro.

Administration of the extract (0.5-2 mg kg−1, i.v.) to anaesthetized rats produced dose-related hypertension blocked by the α-adrenoceptor antagonist prazosin (1 mg kg−1). Partition of the extract in chloroform-water yielded an aqueous phase 20 times more potent than the extract; this produced hypertension in either reserpine-treated or pithed rats. In untreated and reserpine-treated rats the same fraction (1–3 × 103 μg mL−1) produced concentration-dependent contractions of the vas deferens musculature parallel to those obtained with noradrenaline (10−8-10−4 m). Prazosin (10−7 m) reduced the maximum contractile effect of the aqueous fraction, and shifted the concentration-response curves for noradrenaline to the right. The aqueous fraction (25 and 50 μg mL−1) increased the inotropism of electrically driven left atria of rats, the effect being blocked by propranolol (0.4 μg mL−1). In preparations of guinea-pig tracheal rings the aqueous fraction (1–3 × 103 μg mL−1) relaxed the muscle contraction induced by histamine (10−4 m) in proportion to the concentration. The effect was antagonized competitively by propranolol (1.5 μm). High-performance liquid-chromatographic analysis of the aqueous fraction revealed the presence of both noradrenaline and adrenaline in the plant extract.

The results indicated that both catecholamines may account for the hypertensive and inotropic effects obtained after parenteral administration of S. dulcis extracts. This sympathomimetic activity is, however, unrelated to the previously reported analgesic and anti-inflammatory properties of the plant extract, but may explain its effectiveness upon topical application in the healing of mucosal and skin wounds.
Interactions of Cephradine and Cefaclor with the Intestinal Absorption of D-Galactose
Authors: Idoate Isabel , Mendizábal M Victoria , Urdaneta Elena , Larralde Jesús
Published: April 2011

Oral cephalosporins are frequently prescribed β-lactam antibiotics. Although it has been well established that cephalosporins compete with dipeptides for absorption in the intestine, using the same transport mechanism, little is known about the action of the drugs on the absorption of other nutrients. In this work the effect of cephradine and cefaclor on the absorption of d-galactose has been studied. Intestinal sugar uptake was measured in-vitro in pieces of intestine (50 mg) and brush-border membrane vesicles, and in-vivo in intestinal loops.

Galactose uptake was inhibited by cephalosporins in a dose-related, time-dependent manner. In-vivo the inhibition appeared when the antibiotics were on the luminal side of the enterocyte and when they reached the gut from the basolateral side. Only the active transport of the sugar was modified; passive transfer did not change in the presence of cephalosporins. In brush-border membrane vesicles, cephradine and cefaclor did not alter sugar uptake in either sodium or potassium gradients. Both antibiotics non-competitively inhibited basolateral Na+,K+-ATPase activity.

These findings show that cephradine and cefaclor inhibit the active-transport component of galactose absorption because they reduce the activity of the basolateral Na+,K+-ATPase.
Elcatonin Raises Levels of Vasoactive Intestinal Peptide in Human Plasma
Authors: Takeyama Masaharu , Ikawa Kazuro , Nagano Toshiaki , Mori Kazuo
Published: April 2011

Elcatonin, used for treatment of hypercalcaemia, Paget's disease and osteoporosis, causes flushing of the face and hands. To determine whether this was because of increased levels of vasoactive intestinal peptide, which is known to induce vasodilation, the effect of elcatonin on the plasma levels of vasoactive intestinal peptide was studied in five healthy volunteers.

After a single intramuscular administration of elcatonin (20 int. units), peak plasma elcatonin levels (approx. 30 pg mL−1) were achieved 30 min after injection. Plasma vasoactive intestinal peptide concentrations rose similarly with peak levels of about 17 pg mL−1 after 30 min. Side-effects such as cutaneous flushing (most obvious in the face and hands) occurred to an extent dependent on the amount of elcatonin administered, and declined over 45 min in parallel with the fate of plasma vasoactive intestinal peptide.

The side-effects of elcatonin, especially cutaneous flushing, seem to be closely connected with vasoactive intestinal peptide.
Effect of Application Volume and Area on the Absorption of Phenol Red, as a Model Drug, from the Liver Surface in Rats
Authors: Nishida Koyo , Sato Norihito , Nakakoga Yuki , Mukai Takahiro , Sasaki Hitoshi , Nakamura Junzo
Published: April 2011

To determine the influence of the method of administration of a pharmaceutical formulation we have examined the importance of application volume and area in the absorption of phenol red, as a model drug, from the rat-liver surface.

When 1 mg phenol red was applied to the rat-liver surface, in-vivo, in three volumes (0.1, 0.2 or 0.334 mL) using a cylindrical glass cell (i.d. 9 mm), the shape of the plasma concentration profile differed greatly, particularly the maximum concentration. These patterns were well fitted by a two-compartment model with first-order absorption, and the absorption-rate constant Ka obtained was inversely proportional to the application volume. The absorption ratio and biliary recovery of phenol red after 6 h increased with glass cell area (i.d. 6, 9 or 14 mm; area 0.28, 0.64 or 1.54 cm2). Furthermore, the permeability coefficient Papp derived from Ka did not depend on application area, indicating no difference in the absorption characteristics of the liver surface. This also implies transport of the drug by passive diffusion from the liver surface. After intraperitoneal administration to the rat-liver surface for clinical application, increasing the application volume resulted in the delayed disappearance of phenol red from the plasma. However, the difference was not as marked as that obtained by use of the glass cell. The assumption that the effective area relating to the absorption changed with the application volume enabled us to estimate Papp. Consequently, we speculate that absorbability can be estimated precisely by consideration of application volume and area.
Nitric Oxide Modulates the Acute Increase of Gastrointestinal Transit Induced by Endotoxin in Rats: a Possible Role for Tachykinins
Authors: Martínez-Cuesta M A , Barrachina M D , Beltrán B , Calatayud S , Esplugues J
Published: April 2011

Because of the evidence that endogenous nitric oxide (NO) plays an essential role in the physiological regulation of gastrointestinal motility we have investigated, by use of the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), the role of endogenous NO in the acute endotoxin-induced changes of gastrointestinal transit.

Pre-treatment with E. coli endotoxin (100 μg kg−, i.v.) induced a significant increase in the gastrointestinal transit of a charcoal suspension in anaesthetized rats. Previous administration of the NO synthase inhibitor, l-NAME (10 mg kg−, i.v.) significantly prevented the effects of endotoxin. l-arginine (200 mg kg−, i.v.) and the substance P antagonist [d-Pro2, d-Trp7,9]-substance P (SPA), significantly reversed the effects of l-NAME on gastrointestinal transit in rats treated with endotoxin. Pre-treatment with dexamethasone (5 mg kg−, s.c., twice), an inhibitor of the expression of inducible NO synthase, did not affect the increase in the gastrointestinal transit through constitutive NO synthesis.

The results suggest that constitutive nitric oxide is involved in the increase of gastrointestinal transit induced by endotoxin and that the reduction in transit induced by l-NAME in endotoxin-treated rats is mediated by endogenous tachykinins.
Impulse-response Studies on Tracer Doses of [14C]Lignocaine and its Multiple Metabolites in the Perfused Rat Liver
Authors: Mellick George D , Roberts Michael S
Published: April 2011

The outflow-concentration-time profiles for lignocaine (lidocaine) and its metabolites have been measured after bolus impulse administration of [14C]lignocaine into the perfused rat liver.

Livers from female Sprague-Dawley rats were perfused in a once-through fashion with red-blood-cell-free Krebs-Henseleit buffer containing 0 or 2% bovine serum albumin. Perfusate flow rates of 20 and 30 mL min− were used and both normal and retrograde flow directions were employed. Significant amounts of metabolite were detected in the effluent perfusate soon after lignocaine injection. The early appearance of metabolite contributed to bimodal outflow profiles observed for total 14C radioactivity. The lignocaine outflow profiles were well characterized by the two-compartment dispersion model, with efflux rate «influx rate. The profiles for lignocaine metabolites were also characterized in terms of a simplified two-compartment dispersion model. Lignocaine was found to be extensively metabolized under the experimental conditions with the hepatic availability ranging between 0.09 and 0.18. Generally lignocaine and metabolite availability showed no significant change with alterations in perfusate flow rate from 20 to 30 mL min− or protein content from 0 to 2%. A significant increase in lignocaine availability occurred when 1200 μm unlabelled lignocaine was added to the perfusate. Solute mean transit times generally decreased with increasing flow rate and with increasing perfusate protein content.

The results confirm that lignocaine pharmacokinetics in the liver closely follow the predictions of the well-stirred model. The increase in lignocaine availability when 1200 μm unlabelled lignocaine was added to the perfusate is consistent with saturation of the hydroxylation metabolic pathways of lignocaine metabolism.
Synthesis of Several Substituted Phenylpiperazines Behaving as Mixed D2/5HT1A Ligands
Authors: Dukić Sladjana , Kostić-Rajačić Sladjana , Dragović Deana , Šoškić Vukic , Joksimović Jelena
Published: April 2011

Twenty-two different compounds have been synthesized with the aim of creating new, mixed D2/5HT1A ligands. For this purpose 1-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2-thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure-affinity requirements of 1-arylpiperazines.

All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D1 and D2) and 5-HT1A receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8-OH-[3H]DPAT (5-HT1A selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[3H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [3H]spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d–3f, 4a, and 4d) affinity in the [3H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]-1-(2-methoxyphenyl)piperazine, 3a (Ki = 1.7 nm). In the 8-OH-[3H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c–3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT1A receptors (Ki = 2.6 nm).

Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D2 and 5-HT1A receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.
Pharmacokinetic and Pharmacodynamic Response after Intranasal Administration of Diazepam to Rabbits
Authors: Bechgaard Erik , Gizurarson Sveinbjörn , Hjortkjær Rolf K
Published: April 2011

Nasal application of drugs might be an alternative to intravenous administration in acute situations such as epileptic or fever seizures. In the search for a nasal formulation leading to a peak plasma concentration of diazepam at a tmax ≤5 min bioavailability in rabbits has been studied after intranasal administration of the drug in ten vehicles of different polarity.

The animals were dosed with 3 mg diazepam, dissolved in 100 μL vehicle, the solution being administered into both nostrils. The bioavailability, measured during the first 30 min, because periods after this are not relevant for acute treatment, was found to be between 49 and 62% for the four most promising vehicles, pure glycofurol 75, tetraethyleneglycol, poly(ethylene glycol) 200 and 30% glycofurol in tetraethyleneglycol. The tmax for these vehicles was achieved after 5 min, and they induced a very rapid pharmacodynamic response after 1.5 to 3.5 min. The bioavailability was reduced when more polar liquids such as ethanol and tween 20, or lipid oils, e.g. vegetable oil and miglyol 840 were added to the glycofurol. There was a good correlation between tmax and the induction of pharmacodynamic response.

These results suggest that nasal application of diazepam in a water-free low-molecular-weight glycol might be of clinical importance as an alternative to intravenous injection, especially in acute situations.
Detection of Carbamazepine-induced Changes in Valproic Acid Relative Clearance in Man by Simple Pharmacokinetic Screening
Authors: Yukawa Eiji , Honda Tomoo , Ohdo Shigehiro , Higuchi Shun , Aoyama Toshinobu
Published: April 2011

Selecting the optimum dose of valproic acid is difficult because the pharmacokinetics are complicated by inter-patient variability and by effects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effect of age, total body weight, dose, gender and co-medication (carbamazepine-induced change) on population estimates of valproic acid relative clearance.

Routine clinical pharmacokinetic data (n = 479) were collected from 207 epilepsy patients on combination therapy. The data were analysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that enables pooling of data. NONMEM estimates suggested that the rate of valproic acid clearance in patients receiving concomitant administration of valproic acid and carbamazepine decreased non-linearly with increasing total body weight in the maturation process, and increased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggested that the rate of valproic acid clearance increased non-linearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an increase in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL = 606TBW0.168 ×DOSE0.414 × CBZDOSE0.095 × 0.943GEN × 1.10CO, where CL is the clearance (mL kg− h−), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for males and 1 for females and CO = 0 for concomitant administration of valproic acid and carbamazepine and 1 for concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs.

This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent to which patient characteristics influence drug pharmacokinetics.
Prediction of Changes in the Clinical Pharmacokinetics of Basic Drugs on the Basis of Octanol-Water Partition Coefficients
Authors: Ishizaki Junko , Yokogawa Koichi , Nakashima Emi , Ichimura Fujio
Published: April 2011

A physiologically based pharmacokinetic model for basic drugs has been established on the basis of octanol-water partition coefficients of the non-ionized, unbound drugs (Poct).

The parameters for the physiological model in man were estimated from a regression equation obtained for the relationships between the Poct and the tissue-plasma partition coefficient, the hepatic intrinsic clearance (CLint,h) and the blood-to-plasma concentration ratio in rabbits. The plasma concentrations observed after intravenous administration of ten basic drugs (3.2 mg kg−) to rabbits agreed with the levels predicted using the physiological model (r = 0.710–0.980). In man, the predicted plasma concentrations of basic drugs were in good agreement with reported values (r = 0.729–0.973), except for diazepam and pentazocine. Variations in plasma and brain-concentration profiles of clomipramine and nitrazepam in various disease states were simulated using the model. We assumed that the changes in unbound fraction of drug in serum (fp), CLint,h and the hepatic blood flow rate were from 0.25- to 4-fold that of the control and that fat volume changed by 0.2- to 5-fold. With regard to changes in fp, we predicted that the brain-plasma concentration ratio of clomipramine was 1.5- to 25-fold that of the control 24 h after intravenous administration, although the variations in the plasma concentration-time profiles were less marked.

Plasma concentrations predicted for several basic drugs were in good agreement with reported values and this physiological model could be useful for predicting drug-disposition kinetics in man.
Relationships between the Hepatic Intrinsic Clearance or Blood Cell-Plasma Partition Coefficient in the Rabbit and the Lipophilicity of Basic Drugs
Authors: Ishizaki Junko , Yokogawa Koichi , Nakashima Emi , Ichimura Fujio
Published: April 2011

The relationships between drug lipophilicity and hepatic intrinsic clearance (CLint,h) or red blood cell-plasma partition coefficients (D) have been elucidated for ten highly lipophilic basic drugs with apparent octanol-water partition coefficients at pH 7.4 (Papp, oct) of 150 or above.

The true octanol-water partition coefficients of the non-ionized drugs (Poct) were used to determine CLint,h and D for the unbound drugs (CLint,h,f and Df, respectively), and CLint,h,f and Df for the non-ionized and unbound drugs (CLint,h,fu and Dfu, respectively). The total clearance values were determined at steady state by infusion studies of individual drugs in rabbits. There was better correlation between log Poct, and log CLint,h,fu (r = 0.974) than between log Poct, and log CLint,h,f (r = 0.864). The D values were calculated from the blood-plasma concentration ratio. There was a better correlation between log Poct and log Dfu (r = 0.944) than between log Poct, and log Df (r = 0.612). The regression equations obtained were CLint,h,fu = 0.0875 × Poct1.338 and Dfu = 0.0108 × Poct0.970, respectively.

These results show that the CLint,h and D of highly lipophilic basic drugs can be predicted from Poct by taking fu into consideration. By applying these parameters to a physiologically based pharmacokinetic model it might be possible to predict the pharmacokinetics of unknown basic drugs.
In-vivo Microdialysis Study of the Distribution of Cisplatin into Brain Tumour Tissue after Intracarotid Infusion in Rats With 9L Malignant Glioma
Authors: Nakashima Mikiro , Shibata Shobu , Tokunaga Yoshiharu , Fujita Hideshi , Anda Takeo , Arizono Koji , Tomiyama Naoki , Sasaki Hitoshi , Ichikawa Masataka
Published: April 2011

Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats.

Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg−) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%.

It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.