bluuebunny/crossref_metadata_2025 huggingface dataset:
Solubilities and intrinsic dissolution rates of sulphamethoxazole and trimethoprim
Authors: Dahlan Rajudin , Mcdonald Charles , Sunderland V Bruce
Published: April 2011

The influence of pH on the dissolution rates and solubilities of sulphamethoxazole and trimethoprim have been examined. Sulphamethoxazole was evaluated in buffers of ionic strength 0.5 mol dm−3 over the pH range 0.45–7.8 and at 25, 32 and 37 °C. The minimum solubility of sulphamethoxazole was 28.1 mg/100 mL at pH 3.22 and 25 °C. Solubilities increased significantly with both increased and decreased pH. Intrinsic dissolution rates demonstrated a linear relationship with the solubility data. Trimethoprim solubility was both buffer- and pH-dependent. In both water and hydrochloric acid solution at 32 °C the solubility of trimethoprim increased from 50 mg/100 mL in water at pH 8.54 to a maximum of 1550 mg/100 mL at pH 5.5. This maximum solubility was in excess of that predicted theoretically and may be due to supersaturation. Below pH 2 the solubility of protonated trimethoprim diminished from 1125 mg/100 mL with decreasing pH. This was due to the common ion effect. Intrinsic dissolution rates increased as pH was decreased with hydrochloric acid from 6.00 to 1.78, but decreased at pH 1.48 due to the common ion effect. Dissolution profiles of trimethoprim showed complex patterns dependent upon pH. The profile was zero-order at pH 6.00 and became distinctly stepwise at pH 5.5, this effect becoming less pronounced at lower pH values. This was reconciled in terms of the rate of formation of trimethoprim hydrochloride on the surface of the disc and the differing dissolution rates of this species and trimethoprim. A simple relationship between solubility and dissolution rate was not observed.
A preliminary pharmacokinetic study of the antimalarial drugs, proguanil and chlorproguanil
Authors: Watkins W M , Chulay J D , Sixsmith D G , Spencer H C , Howells R E
Published: April 2011

Pharmacokinetic parameters for cycloguanil and chlorcycloguanil, the active metabolites of proguanil (Paludrine] and chlorproguanil (Lapudrine) have been measured in a bioassay which assesses the in-vitro growth inhibition of a cycloguanil- and chlorcycloguanil-sensitive strain of Plasmodium falciparum produced by dilutions of plasma collected after oral administration of the pro-drugs. A single compartment model is applicable for cycloguanil with mean rate constants of elimination of 0.0624 h−1 and availability of 0.2398 h−1. The elimination profile for chlorcycloguanil indicates partition of drug into more than one compartment. In 2 of 10 subjects dosed with proguanil and 1 of 11 subjects dosed with chlorproguanil, the active metabolite levels were significantly lower than the mean for the other subjects. Abnormally low cycloguanil or chlorcycloguanil plasma levels may be of importance in relation to effective prophylaxis against malaria.
Saturable uptake of cefixime, a new oral cephalosporin without an α-amino group, by the rat intestine
Authors: Tsuji Akira , Hirooka Hideki , Terasaki Tetsuya , Tamai Ikumi , Nakashima Emi
Published: April 2011

The mechanism of intestinal uptake of cefixime, a new oral cephalosporin antibiotic, has been examined using the everted jejunum of rats. The initial uptake rates were apparently pH-dependent with the maximum rate at pH 5.0 and a 3-fold reduction at pH 7.0. The uptake at pH 5.0 followed mixed-type kinetics involving saturable and non-saturable processes in a manner similar to that for several amino-β-lactam antibiotics. Cefixime uptake was inhibited significantly by 20 mM permeants such as cyclacillin, cephradine, benzylpenicillin, propicillin, glycyl-L-proline and glycyl-glycine. Replacement of Na+ in the medium with choline produced a slight but significant inhibition of cefixime uptake. In spite of the absence of significant inhibition by the amino acids glycine and proline, the dipeptide, glycyl-L-proline in Na+-free medium showed a marked inhibitory effect. The inhibition kinetics of cefixime uptake by glycyl-L-proline and cyclacillin were consistent with competitive-type inhibition. This study provides the first evidence of saturable intestinal uptake of a cephem antibiotic without an α-amino group in the side chain, suggesting transport through the dipeptide carrier system(s).
Influence of β-adrenoceptor-mediated relaxation on α-adrenoceptor-mediated contraction of rat pulmonary artery to adrenaline or noradrenaline
Authors: O'donnell Stella R , Wanstall Janet C , Mustafa Marianna B H
Published: April 2011

Concentration-response (contraction) curves to either adrenaline or noradrenaline were obtained on isolated ring preparations of pulmonary artery from rats. In preparations from young rats the curve for adrenaline was bell-shaped, unless β-adrenoceptors were blocked with propranolol (1 × 10−6 M). The maximum contraction to adrenaline was less in the absence than in the presence of propranolol. In preparations from aged rats the adrenaline curve was no longer bell-shaped, even in the absence of propranolol. This reflected a decrease in the β-adrenoceptor-mediated relaxant responses of preparations from aged rats, seen as a separation between the concentration-response (relaxation) curves to adrenaline on preparations (phenoxybenzamine-treated, KCl-contracted) from young and aged rats. In preparations from young rats the noradrenaline curve was not bell-shaped, but if the preparations were from young rats treated with thyroxine (T4), then a bell-shaped curve for noradrenaline was obtained, unless β-adrenoceptors were blocked by propranolol. These data could be explained by an increase in β-adrenoceptor-mediated relaxant responses of preparations from T4-treated rats, seen as a separation in the concentration-response (relaxation) curves to noradrenaline on preparations from control and T4-treated rats, respectively. Thus (i) α-adrenoceptor-mediated contractile responses of rat pulmonary artery preparations, to adrenaline or noradrenaline, can be attenuated by activation of β-adrenoceptors, mediating relaxation, and (ii) the extent of this attentuation changes under the influence of factors, such as ageing or T4-treatment, which modify β-adrenoceptor-mediated relaxation in this blood vessel type.
Differentiation of calcium antagonists with respect to their effects in normal and skinned taenia caeci preparations
Authors: Cortijo J , Foster R W , Small R C
Published: April 2011

In taenia preparations, depolarized by a K+-rich medium, Ca2+ caused contraction and cinnarizine (0.4–100 μM), trifluoperazine (2–100 μM) and verapamil (0.02–10 μM) caused concentration-dependent antagonism of Ca2+, displacing the Ca2+ log concentration-effect curve to the right and depressing the maximal response. Equieffective (IC75) antispasmogenic concentrations were selected. The antispasmogenic effects of verapamil were readily offset by removing the drug from the bathing fluid but those of the other drugs were not. The calcium antagonists (antispasmogenic IC75) were then tested for spasmolytic activity in tissues generating tension in response to the EC80 of Ca2+. Verapamil was more effective in producing spasmolysis than cinnarazine or trifluoperazine. In skinned taenia preparations, verapamil (100 μM) did not inhibit Ca2+-induced contractions. High concentrations of cinnarizine (100 μM) and trifluoperazine (100 μM) inhibited Ca2+-induced activation of the contractile proteins. However, antispasmogenic IC75s from intact taenia were not able to produce this effect on skinned preparations. It is concluded that there are differences between calcium antagonists. The action of verapamil on intact taenia is mainly exerted on the plasma membrane. Cinnarizine and trifluoperazine act both on the plasma membrane and upon the intracellular contractile machinery.
Dissolution mechanism of tablets produced from coated lactose powder
Authors: Igwilo C , Pilpel N
Published: April 2011

The use of the equation of Kitazawa et al in the analysis of the dissolution process of tablets produced from lactose powder coated with paraffin has suggested either an initial breaking of the tablets into particles that subsequently break down into smaller particles or a progressive breaking of the tablet into smaller particles. The former produces a change in rate constant from k1 to k2.
Effects of applied load and particle size on the plastoelasticity and tablet strength of some directly compressible powders
Authors: Esezobo S , Pilpel N
Published: April 2011

Correlations have been established between the particle size and packing fraction of microcrystalline cellulose, calcium phosphate dihydrate, corn starch and lactose, and the elastic recovery, stress relaxation, and tensile strengths of their tablets.
Enhanced gastrointestinal absorption of drugs in rats pretreated with the synthetic immunomodulator, levamisole
Authors: Utsumi Eriko , Yamamoto Akira , Kawaratani Toshitaka , Sakane Toshiyasu , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

The effect of levamisole on drug absorption from the rat small intestine has been investigated by means of an in-situ recirculation technique. The absorption of salicylic acid, sulphanilamide and aminopyrine was significantly increased by the intraperitoneal administration of levamisole (2 mg) 1 day before the absorption studies, but there was no significant effect on absorption from the small intestine of indomethacin, bromthymol blue, sulphafurazole (sulfisoxazole), quinine, sulphanilic acid, phenol red (phenolsulfonphthalein), l-tryptophan and fluorescein isothiocyanate-dextrans. The effect of levamisole on the absorption from the small intestine of salicylic acid was marginally dose- and time-dependent, the maximal effect being observed after pretreatment with 2 mg of levamisole 1 day before the absorption studies. Sulphanilamide, similarly, was better sorbed from the small intestine and also from the stomach in the presence of levamisole. The intraperitoneal administration of levamisole may influence the absorption of some low molecular weight drugs from the gastrointestinal tract.
Binding parameters and microbiological activity of macrolides, lincosamides and streptogramins against Staphylococcus aureus
Authors: Fournet M P , Barre J , Zini R , Deforges L , Duval J , Tillement J P
Published: April 2011

Parameters of erythromycin binding to Staphylococcus aureus were measured in-vitro using an equilibrium method with [3H]erythromycin. The dissociation constant of the complex, erythromycin-S. aureus sensitive strain, was KD = 0.11 μM. The maximal binding, representing the density of binding sites was 14 847 molecules/cell. No binding was detectable on the constitutive resistant strain. Macrolides, streptogramins and lincosamides displaced bound [3H]erythromycin by a competitive process indicating that these compounds share common binding sites on the bacteria, i.e. 50 S ribosomal subunits. A good correlation (r = 0.99) was demonstrated between the corresponding inhibition constants (Ki) and the minimal inhibitory concentration. It is proposed that knowledge of the binding parameters provides a good indication of bacterial susceptibility and may serve as a useful adjunct in developing new compounds.
Tamoxifen inhibits 5-lipoxygenase in human polymorphonuclear leucocytes
Authors: Tavares I A , Stamford I F , Bennett A
Published: April 2011

Breast cancer patient survival is increased by tamoxifen, and we therefore need to understand how this drug exerts its effect. We describe a novel action of tamoxifen, the inhibition of LTB4 and 5-HETE production from [14C]-arachidonic acid by human polymorphonuclear leucocytes.
Potentiation of contractile response and increase in tissue sodium content induced by aconitine in the guinea-pig vas deferens
Authors: Ohizumi Yasushi , Kajiwara Akiko
Published: April 2011

Aconitine potentiated the contractile response of the guinea-pig vas deferens and increased the tissue Na and Ca content. These effects were abolished in the presence of tetrodotoxin. These results suggest that aconitine causes an increasing Na+ permeability of the smooth muscle membrane to increase Ca2+ availability and thus induces potentiation.
Evaluation of electrical conductivity-temperature curves using a mathematical model: temperature-dependent changes during thawing of frozen aqueous pharmaceuticals
Authors: VAN GORP J A , SALEMINK P , VERMEULEN M , BANKEN P
Published: April 2011

The information contained in the electrical conductivity curves of pharmaceuticals measured as a function of temperature can be represented by a small set of parameters. This is achieved by approximating the electrical conductivity curve as a number of consecutive steps, using a suitable empirical model. The three parameters describing each step are: transition temperature, slope factor and step height. The validity of the calculated transition temperatures was established by applying the model to electrical conductivity curves measured on aqueous solutions of KCl, NaCl and on a KCl-NaCl mixture. It appears that the transition temperatures calculated for these inorganic salts are in good agreement with the respective eutectic temperatures reported in the literature. Subsequently, the method was applied to the corticosteroids prednisolone sodium succinate and prednisolone disodium phosphate. The mathematical model yields a satisfactory fit for both experimental conductivity curves. The actual consequences of freeze-drying an aqueous solution of prednisolone sodium succinate below and above the respective transition temperatures calculated are discussed in relation to the experimental conductivity data.
Influence of solvent on the availability of testosterone propionate from oily, intramuscular injections in the rat
Authors: AL-HINDAWI M K , JAMES K C , NICHOLLS P J
Published: April 2011

The suggestion that the biological response to an oily intramuscular injection of testosterone ester is regulated by rapid accumulation of the steroid in body fat, followed by a slow release, has been tested by comparing the release rates of 14C-labelled testosterone propionate from different solvents following intramuscular injection into rats. Disappearance from the injection site was rectilinearly related to in-vitro partition coefficients, but elimination of radioactivity in urine and faeces was significantly longer, and the same for all four solvents. Testosterone and testosterone propionate were found in equal concentration in body fat, 2 and 3 days after injection, but their concentrations were too low to form an effective depot. It is suggested that the delay in release, and the independence of the delay on the nature of the solvent is a consequence of biliary recycling of testosterone.
Depressant action of oxybutynin on the contractility of intestinal and urinary tract smooth muscle
Authors: TONINI M , RIZZI C A , PERUCCA E , DE PONTI F , D'ANGELO L , DEL VECCHIO A , CREMA A
Published: April 2011

Experiments were carried out in-vitro using segments of guinea-pig ileum, taenia caeci, ureter and detrusor. In the ileum, oxybutynin (30, 100 nM) competitively antagonized acetylcholine-induced contractions but did not alter those induced by histamine. Higher concentrations of oxybutynin (up to 10 μM) induced a non-competitive depression of responses to both agonists and caused a parallel shift to the right of the Ca2+-induced contractions in taenia caeci strips bathed in a Ca2+-free, high-K+ medium. In the ureter, oxybutynin (1–10 μM) impaired rhythmic muscular contractions in normal medium and after CaCl2 addition in Ca2+-free medium. Similarly to verapamil (10, 30 μM), oxybutynin (10, 30 μM) depressed both the cholinergic and non-adrenergic, non-cholinergic components of the electrically-induced contractions of detrusor strips. It is concluded that oxybutynin has anticholinergic properties and, at higher concentrations, exerts a direct spasmolytic activity possibly mediated by blockade of the transmembrane Ca2+ fluxes responsible for smooth muscle contraction.
Sodium nitroprusside: pharmacological aspects of its interaction with hydroxocobalamin and thiosulphate
Authors: HEWICK D S , BUTLER A R , GLIDEWELL C , McINTOSH A S
Published: April 2011

Hydroxocobalamin (HOCb), when mixed with sodium nitroprusside (SNP) in a 10:1 or 1:1 molar ratio and injected (i.v.) into the anaesthetized rat, prolonged the depressor response to SNP by 25–50%, but did not affect the degree of blood pressure lowering. Both the ‘onset’ and ‘offset’ components of the response were prolonged. Injecting [14C]SNP along with a 10-fold molar excess of HOCb resulted in a 2- to 3-fold elevation of plasma radioactivity which was maintained during the first 10 min of a 40 min experimental period. These effects of HOCb on the pharmacodynamics and pharmacokinetics of SNP are probably due to complex formation between the two compounds. Sodium thiosulphate (ST) added to SNP (12:1 molar ratio) had no effect on the depressor response to SNP. This mixing of ST and SNP had a less-marked influence on the plasma [14C]SNP-derived radioactivity than occurred with HOCb. There was no initial elevation of radioactivity, but the levels were raised by 50–60% at 4, 6 and 10 min. Since the depressor response to SNP was unaffected by ST, it is presumed that the higher concentrations of radioactivity were due to inactive degradation products rather than the active species itself.
Does brain 3,4-dihydroxyphenylacetic acid reflect dopamine release?
Authors: Soares-da-Silva P
Published: April 2011

After sulpiride (75 mg kg−1) administration, a significant increase in dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) occurred in the rat striatum. No attenuation in the sulpiride-induced dopamine and DOPAC increase was seen in the striatum from rats previously treated with benztropine (25 mg kg−1). On the other hand, in the benztropine + sulpiride-treated group, HVA levels were significantly lower compared with those of rats to which only sulpiride had been given. The results presented suggest that under appropriate conditions, as when sulpiride is used, dopamine can be deaminated before its release has occurred.
Temporal changes in bupivacaine kinetics
Authors: Bruguerolle Bernard , Prat Marin
Published: April 2011

The chronokinetics of bupivacaine have been examined in the mouse. Different groups of adult male NMRI mice maintained under controlled environmental conditions received a single intraperitoneal injection of bupivacaine (20 mg kg−1) at one of four different fixed time points in a 24 h period i.e. 1000, 1600, 2200 and 0400h. Blood samples were taken 0.25, 0.5, 0.75, 1, 1.5, 3, 4 and 6 h after drug administration and total serum levels of bupivacaine were determined by a gas-liquid chromatography with a flame ionization detector. Statistically significant temporal changes were found in the following pharmacokinetic parameters: highest Cmax value = 0.900 ± 0.080 μg mL−1 at 2200h (amplitude, maximum-minimum/mean × 100, is 64%); highest Cmax/Tmax ratio = 3.596 ± 0.339 at 2200h (amplitude = 85%); highest β elimination half-life, T½β;, = 3.950 ± 0.246 h at 2200h (amplitude = 35%); area under concentration curve (AUC0∞) was not found to be significantly different among the hours of administration. The temporal kinetic changes demonstrated suggest a possible circadian difference in bupivacaine efficacy and/or toxicity.
Salivary secretion of paracetamol in man
Authors: Kamali F , Fry J R , Bell G D
Published: April 2011

Plasma and saliva paracetamol levels were measured by HPLC in ten healthy volunteers who took a therapeutic dose after an overnight fast. Salivary levels of the drug were consistently and significantly higher than those in plasma for the first 50 min after oral ingestion, but saliva and plasma levels correlated closely during the elimination phase. There was a highly significant correlation between the AUC 0-α calculated from saliva and plasma paracetamol concentration-time curves. The elevated saliva/plasma ratio for the first 50 min was not due to loss of paracetamol from plasma during sample preparation, binding to plasma protein or adsorption to the buccal mucosa. Administration of probenecid in an attempt to block possible active secretion of paracetamol into saliva did not significantly alter the saliva/plasma concentration ratio for the first 50 min, but did significantly reduce this ratio in the time period 125–360 min. The experimental data conformed to a recently proposed model in which elevated saliva/plasma ratios during the early stages following oral ingestion were related to ongoing absorption into the arterial system.
The packing characteristics of physical and formulated mixtures of Oxytetracycline and lactose powders
Authors: Adeyemi M O , Pilpel N
Published: April 2011

Measurements have been made of the tap densities and angles of internal flow of physically mixed and formulated mixtures of oxytetracycline and lactose powders. The differences between the two types of mixtures are ascribed to differences in the packing and surface morphologies of the particles.
Evaluation of reversible polymorphic phase transitions by thermal analysis
Authors: Shah A C , Britten N J
Published: April 2011

Crystalline states of 1,2-dihydro-6-neopentyl-2-oxonicotinic acid, an investigational antidiabetic drug, were evaluated by thermal analyses. Two polymorphs were detected for the drug, Form I (m.p. 193 °C) and Form II (m.p. 196 °C). Interconversion of the polymorphs upon cyclic solid-melt transitions provided confirmation of the crystal forms. Solidification of the melt was observed to occur either at 162 or 182°C with the formation of Form I or Form II crystals, respectively. Form I underwent partial conversion to Form II upon heating at 10°C min−1 when nucleating crystals of Form II were present in the sample. Differential scanning calorimetry (DSC) thermograms were recorded for different lots of the drug, solventrecrystallized samples, and a series of known mixtures of Form I and II polymorphs. The study illustrates the usefulness of cyclic heat-cool studies to characterize polymorphic crystal forms of drugs.
Determination of the aryltetralin lignan content of podophyllum resins and roots/rhizomes
Authors: Drew Sheila E , Conway Sarah J , Jennings Penny , Helliwell Keith
Published: April 2011

A simple, quantitatively reproducible method for determining the aryltetralin lignan content of the resins and roots/rhizomes of Podophyllum hexandrum and P. peltatum is described. The method confirms that P. hexandrum resins and roots/rhizomes contain approximately four times the quantity of lignans as do those of P. peltatum and also that there is a significant variation in the lignan content of P. hexandrum resins.
Prostaglandin D2-induced catalepsy in rats: role of 5-hydroxytryptamine
Authors: Bhattacharya S K , Rao P J R Mohan
Published: April 2011

Prostaglandin D2 (PGD2), the major PG in the rat brain, induced a dose-related catalepsy in rats on intracerebroventricular (i.c.v.) administration. This cataleptic response was significantly attenuated following the i.c.v. administration of pharmacological agents that decrease rat brain 5-hydroxytryptamine (5-HT) activity. PGE1 synergized but PGF2α antagonized the catalepsy induced by PGD2. PGD2 and PGE1 have previously been shown to augment rat brain 5-HT activity, whereas PGFα inhibited it. It is therefore likely that the observed effects of these PGs on catalepsy involve a central 5-HT mechanism.
β-Adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea
Authors: Jordan Roy , Midgley John M , Thonoor C Mohan , Williams Clyde M
Published: April 2011

The activities of the (-)- and (+)-forms of m- and p-octopamine and m- and p-synephrine on β1- and β2- adrenoceptors in guinea-pig atria and trachea have been compared with that of noradrenaline. The rank order of potency of the (-)-forms on β1-adrenoceptors was noradrenaline > m-synephrine. m-octopamine = p-octopamine > p-synephrine. m-Synephrine was 100-fold, m-and p-octopamine about 6000-fold, and p-synephrine about 40 000-fold less active than noradrenaline. The (+)-forms were 1-2 orders of magnitude less active than their (-)-counterparts. The four (-)-compounds were more than four orders of magnitude less active than noradrenaline on β2,-adrenoceptors, and the (+)-forms had no detectable activity in concentrations as high as 10−4 M. If m-and p-octopamine are co-released with noradrenaline in amounts proportional to their concentration, their activities at these structures are too low to be physiologically significant.
Effects of chronic treatment with amiodarone on hepatic demethylation and cytochrome P450
Authors: Duenas-Laita Antonio , Barry Michael G , Mathuna Padraic Mac , Feely John
Published: April 2011

The effect of chronic treatment with amiodarone on hepatic oxidative metabolism using an in-vivo [14aminopyrine breath test and on hepatic cytochrome P450 was examined in Wistar rats. Aminopyrine demethylation was significantly impaired but returned to pretreatment values following amiodarone for 4 weeks. In contrast the levels of cytochrome P450 were significantly depressed during treatment and at 4 weeks following treatment. While an inhibitory effect on oxidative metabolism may explain the reported drug interactions with amiodarone, the discrepancy between its in-vivo effects and cytochrome P450 levels may suggest the development of ‘compensatory’ extra-hepatic site of drug metabolism.
A new nasal decongestant, A-57219: a comparison with oxymetazoline
Authors: DeBernardis John F , Winn Martin , Kerkman Daniel J , Kyncl John J , Buckner Steven , Horrom Bruce
Published: April 2011

2-(4-Amino-3,5-dichlorobenzyl)imidazolin hydrochloride (A-57219), has α1-agonist/α2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1ṁ65 μg, atomized from a 1 μg mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.
Preparation of Biodegradable Poly(±)lactide Microparticles Using a Spray-Drying Technique
Authors: Bodmeier Roland , Chen Huagang
Published: April 2011

Drug containing biodegradable poly(±)lactide microparticles were prepared by using a spray-drying technique. Formulations containing model drugs in either a dissolved (progesterone) or dispersed state (theophylline) were spray-dried. The spray-drying method was less dependent on the solubility characteristics of the drug when compared with traditional microencapsulation techniques such as phase separation or solvent evaporation techniques. Differential scanning calorimetry and scanning electron microscopy were used to characterize the microparticles. The drug release profiles were characterized by a rapid release phase (burst effect) followed by a slow release phase, the extent of each phase being dependent on the drug loading.
The Effect of Acute Dyflos (DFP) Treatment on [3H]Nicotine Binding to Mouse Brain Homogenate
Authors: Scimeca Joseph A , Martin Billy R
Published: April 2011

One possible adaptive mechanism that might arise due to inhibition of cholinesterase in the brain is a down regulation of central cholinergic receptors. Therefore studies were performed to determine the effect of acute dyflos exposure on [3H]nicotine binding. Specific [3H] nicotine binding was demonstrated to be saturable, reversible, stereospecific, and inhibited by a number of nicotinic compounds. Scatchard analysis of specific [3H]nicotine binding produced a curvilinear plot that was resolved into high- and low-affinity sites with Kd values of 6.1 ± 2.5 and 114 ± 13 nM, and Bmax values of 11.8 ± 3.5 and 182 ± 24 fmol (mg protein)−1, respectively. The nicotinic binding sites in brain homogenate from dyflos-treated mice that were killed 20 min or 10 h after exposure did not exhibit significant alterations in binding parameters from control mouse brain homogenate. However, brain homogenate from treated mice that were killed 24 h after exposure resulted in statistically significant differences in the low-affinity KD and Bmax values from controls. Since no alterations were found in the high-affinity binding parameters and dyflos had only a minimal effect on the low-affinity site at 24 h, it was concluded that nicotinic receptor down regulation does not appear to be the mechanism through which the mouse functionally adapts to cholinesterase inhibition caused by acute dyflos treatment.
Selective β2-adrenoceptor antagonists: derivatives of ICI 118,551 and a binary aryloxypropanolamine
Authors: Nathanson James A , Hunnicutt Edward J
Published: April 2011

Recent studies indicate that selective β2-adrenoceptor antagonists may be of use in the treatment of glaucoma. ICI 118,551, its desmethyl-, didesmethyl-, and ethyl- analogues, and a putative highly β2-selective binary aryloxypropanolamine (4d) have been evaluated for their ability to inhibit β-adrenergic-stimulated adenylate cyclase activity in rabbit ciliary process and heart. Potency ratios (Ki heart/Ki ciliary process) were 440 for ICI 118,551; 9.3 for the desmethyl analogue; 8.2 for the didesmethyl analogue; 720 for the ethyl analogue; and 11 for the binary aryloxypropanolamine. The values for the ethyl derivative of ICI 118,551 indicate that it is the most oculoselective β-adrenoceptor antagonist yet reported.
Equilibrium binding of spermine and histamine to salmon sperm DNA and poly(dGdC)
Authors: Winkle Stephen A , Crooks Peter A
Published: April 2011

Studies using the solute-enhanced phase partition technique demonstrate that the endogenous amines histamine and spermine bind to both salmon sperm DNA and poly(dGdC) in a markedly cooperative fashion. Both compounds exhibited DNA sequence-dependence effects in their mode of binding. The linear aliphatic spermine molecule binds more strongly than histamine to both DNA types.
The influence of components on the rectal absorption of cefazolin in rats
Authors: van Hoogdalem Ewoud J , Geerts Joan A M , de Boer Albertus G , Breimer Douwe D
Published: April 2011

A study has been made to identify the component(s) responsible for the absorption-promoting effect of MGK medium chain glyceride preparation commercially available as a mixture of glyceryl-1-monooctanoate, glyceryl-1,3-dioctanoate, glyceryl-1,2-dioctanoate, glyceryl trioctanoate, octanoic acid and glycerol. The action of the individual constituents has been evaluated on the rectal absorption of cefazolin in conscious rats. The results indicate that the action of MGK can be completely explained by the effect of glyceryl-1-monooctanoate, which both enhanced the extent and rate of cefazolin uptake.
Action of a chronic arecoline administration on mouse motility and on acetylcholine concentrations in the CNS
Authors: Molinengo L , Fundaró A M , Cassone M C
Published: April 2011

The modifications of mouse motility and of the levels of acetylcholine (ACh) in two sections of the CNS caused by a chronic administration of 4.5; 9.5; 28.5 and 60 mg kg-−1 day−1 of arecoline for 20 days have been studied. At low doses (4.5 and 9.5 mg kg−1 day−1), arecoline caused no modification of the ACh levels and of the motility. The higher doses (28.5 and 60 mg kg−1 day−1) caused a reduction of the mouse motility and an increase of the ACh levels in the subcortical structures of the CNS of the mouse.
Ocular distribution of aspirin and salicylate following systematic administration of aspirin to rabbits
Authors: Valeri P , Romanelli L , de Paolis L , Martinelli B
Published: April 2011

The distribution of aspirin and salicylate 30 min after the intravenous administration of different doses of aspirin has been investigated in the rabbit eye. HPLC enabled a rapid and sensitive determination of both substances. A considerable dose-dependent penetration into all ocular tissues was observed with both aspirin and salicylate. Aspirin concentrations were higher than in plasma in all ocular tissues with the exception of the lens. These results show that an unhydrolysed drug may have a direct local effect by acetylating lens protein or other ocular constituents.
The Biochemical Actions of Phentolamine and Papaverine on Rat Perfused Skeletal Muscle
Authors: Preedy Victor R , Garlick Peter J
Published: April 2011

The direct actions of the vasodilators, papaverine and phentolamine, on skeletal muscle metabolism were investigated in an isolated perfusion system. Eviscerated male rats were hemisected above the diaphragm and perfused, via the aorta, with a physiological perfusion medium containing erythrocytes. Papaverine, but not phentolamine, reduced vascular resistance throughout the 80 min study. Papaverine caused marked reductions in muscle concentrations of ATP and phosphocreatine, when compared with muscle from preparations without added vasodilators. This was accompanied by elevations in lactate concentrations. Water content of papaverine-treated muscle was also higher than values in unperfused muscle taken in-vivo. Phentolamine, in contrast, had no effect on muscle ATP, phosphocreatine, lactate or water content. The metabolism of the entire preparation was also investigated. Papaverine induced increases in lactate output while phentolamine treatment caused an initial uptake, followed by an increased output of lactate. There was no significant effect of either papaverine or phentolamine on the metabolism of K+ and glucose. Arteriovenous differences in oxygen-saturation of haemoglobin and pH were also unaltered. Investigations on aspects of protein metabolism demonstrated that papaverine and phentolamine caused significant reductions in muscle protein synthesis when compared with control perfusions or in-vivo values. The reductions in synthesis were not due to reductions in cAMP or limitations in branched-chain amino acid supply. However, there was the suggestion that phentolamine caused a decrease in protein breakdown. The overall data indicated that papaverine and phentolamine may cause impairment of skeletal muscle metabolism. This has important implications for their therapeutic or experimental use.
Differential displacement of opioids from plasma protein binding sites by di-isopropylfluorophosphate in the mouse
Authors: Green Paul G , Kitchen Ian
Published: April 2011

Di-isopropylfluorophosphate (DFP) displaced the opioid drug, alfentanil, from plasma proteins in-vivo and in-vitro in mice but was without effect on the structurally related compound, fentanyl. This action probably accounts for the enhanced entry of alfentanil into the brain of DFP-treated animals and its enhanced antinociceptive activity.
Stereospecific Absorption and Degradation of Cephalexin
Authors: Tamai Ikumi , Ling He-Yan , Timbul Simanjuntak-Matheus , Nishikido Jyou , Tsuji Akira
Published: April 2011

Stereospecific absorption and degradation of two stereoisomers about the α-amino group at the 7-position of cephalexin (CEX) have been investigated in the rat intestine. The L-isomer (L-CEX) was not found to be present either in serum or urine after oral administration, but the D-isomer (D-CEX) was well absorbed. In contrast to the saturable uptake of D-CEX (Kt = 10.54 ± 1.73 mM, pH = 6.0) by the in-vitro everted intestinal sac, no appreciable uptake of L-CEX was observed. However, L-CEX competitively inhibited the uptake of D-CEX by the in-vitro everted intestine and the inhibitory constant (Ki) of L-CEX was determined to be 0.67 ± 0.09 mM. L-CEX was rapidly degraded in-vitro in the intestinal tissue homogenate, serum and urine, while there was no appreciable degradation of D-CEX. Analysis of the major metabolite of L-CEX by high-performance liquid chromatography identified it as 7-aminodeacetoxycepha-losporanic acid (7-ADCA). Furthermore, 7-ADCA was detected in serum after oral administration of L-CEX, indicating significant absorption of L-CEX as well as D-CEX. The results obtained suggest that both L- and D-CEX can be absorbed through the intestinal brush-border membrane via the same mechanism, most likely through the dipeptide transport system, and that the affinity of L-CEX to the carrier system is higher than that of D-CEX. However, owing to L-CEX having a higher affinity to the hydrolysing enzymes that are present in the intestinal tissue, serum, and urine, intact L-CEX was immediately hydrolysed after absorption and was not detectable in these samples. These results, demonstrating stereospecific transport and metabolism of CEX, provide strong evidence for a mechanism of carrier-mediated uptake in the absorption of CEX.
Toxicity of Solubilized and Colloidal Amphotericin B Formulations to Human Erythrocytes
Authors: Forster D , Washington C , Davis S S
Published: April 2011

The toxicity of a number of solubilized or colloidal amphotericin B formulations to human erythrocytes has been studied in-vitro. All the solubilized formulations studied, using poloxamer F127 or L92, or sodium deoxycholate as solubilizing agents, showed similar toxicity, erythrocyte lysis being greater than 90% for amphotericin B concentrations between 4 to 8 μg mL−1. Emulsion formulations stabilized by poloxamers showed reduced toxicity, while those stabilized by egg lecithin showed less than 5% erythrocyte lysis up to an amphotericin B concentration of 200 μg mL−1. The mechanisms of the differential toxicity is considered to be due to the differences in the equilibrium concentration of free amphotericin B in the aqueous phase.
Tissue Distribution and Excretion of Amodiaquine in the Rat
Authors: Winstanley P A , Edwards G , Curtis C G , Orme M L'E , Powell G M , Breckenridge A M
Published: April 2011

14C-Labelled amodiaquine ([14C]AQ) has been administered to male Wistar rats by oral and intravenous routes (n = 6 for each route of administration). Excretion of total 14C-activity was predominantly in the faeces after both oral and intravenous administration. After oral administration 86 ± 8.3% (mean ± s.d.) of the 14C administered had been excreted (77 ±9% in the faeces, 7 ± 1 % in the urine and 2 ± 2% in cage washings) over 72 h. Of the 14C administered, 4 ± 1% was recovered from the tissues, and this was widely distributed, with the main organs of accumulation being kidney, liver, red bone marrow and spleen. After intravenous administration, 102.6 ± 9.7% of the 14C had been excreted (90.9 ± 9.6% in faeces, 10.9 ± 0.8% in urine and 0.5 ± 0.2% in cage washings) over 72 h. High-performance liquid chromatographic analysis of urine and faeces samples following oral administration of 14C-AQ (8.6 mg kg−1; base) revealed recoveries of 210 ± 70 μg amodiaquine (AQ) and 123 ± 32 μg desethylamodiaquine (AQm) in the faeces, and 2.4 ± 0.5 μg AQ and 18.5 ± 4.1 μg AQm in the urine. Female Wistar rats (n = 6) each received [14C]AQ orally and were killed at the following times: 0.5, 1, 3, 6, 24 and 48 h. Autoradiographs were prepared from each animal and these revealed significant amounts of radioactivity in the tissues at 48 h. This was accumulated maximally by liver and kidney. Radioactivity was detected in bone marrow at 48 h. These data show that after oral administration of [14C]AQ to rats, significant amounts of radiolabel were accumulated in the liver, and haemopoietic tissues, which are the sites of observed toxicity in man. Of the excreted radiolabel, only a small proportion was in the form of AQ or AQm.
Differences in the development of tolerance to two anticonvulsant benzodiazepines in the amygdaloid kindled rat
Authors: Young N A , Lewis S J , Harris Q L Gg , Jarrott B , Vajda F J E
Published: April 2011

The effects of chronic treatment with two benzodiazepines were studied on kindled amygdaloid seizures in rats. Clobazam (4 mg kg−1), clonazepam (0.3 mg kg−1) or vehicle (1 mL kg−1) was administered, by intraperitoneal injection, to fully kindled rats twice daily for nineteen days. Each rat was electrically stimulated 30 min after the morning dose on alternate days of treatment. Tolerance developed rapidly to the anticonvulsant effects of clobazam after only three days of treatment, following which only a small residual protection was maintained. Tolerance to clonazepam developed gradually over the course of the experiment, although this effect was relatively minor.
Retention and Distribution of Liposome-entrapped [3H]Methotrexate Injected into Normal or Arthritic Rabbit Joints
Authors: Foong W C , Green K L
Published: April 2011

Normal or arthritic rabbits were injected intra-articularly (i.a.) with free [3H]methotrexate ([3H]MTX) or liposomes containing [3H]MTX with [14C]cholesteryl oleate as a lipid marker. The distribution of 3H and 14C in the injected joint and other tissues was determined. Free [3H]MTX was rapidly cleared from the joint, 79% being excreted in the urine within 24 h of injection. Liposome-entrapment retarded [3H]MTX clearance from the joint (P < 0.001), 45.5% being recovered from the joint 24 h after injection. Uptake of liposomes by the inflamed synovium was lower than expected, 4% liposomal [3H]MTX injected being associated with the synovium after 24 h. Nevertheless, this was 40-fold greater than when free [3H]MTX was injected. Liposome entrapment should improve the efficacy and reduce the side effects of drugs injected directly into the joint cavity.
Facile plasma-catalysed degradation of penicillin alkyl esters but with no liberation of the parent penicillin
Authors: Nielsen Niels Mørk , Bundgaard Hans
Published: April 2011

The methyl ester and some glycolamide esters of benzyl-penicillin and ampicillin were shown to be rapidly degraded by human plasma at 37 °C with no parent penicillin being produced. The plasma-catalysed degradation which was also observed in rat plasma proceeds most likely through hydrolytic cleavage of the β-lactam bonds of the penicillin esters and is suggested to be due to the presence of an ester-specific β-lactamase in plasma. The results show that the failure of simple alkyl esters of penicillins to function as prodrugs is not due to a high enzymatic stability of the esters, as widely believed, but rather to a pronounced susceptibility to undergo hydrolytic cleavage of their β-lactam ring in-vivo. Since double ester prodrugs of penicillins, such as the pivaloyloxymethyl ester of ampicillin, are readily hydrolysed in plasma to yield the parent penicillin although at a rate lower than e.g. that of inactivation of a simple methyl ester, the plasma enzyme apparently attacking the β-lactam bond of penicillin esters appears to have a high degree of specificity for the ester structure.
The effect of ciprofibrate on gastric secretion in the rat
Authors: Eason C T , Pattison A , Howells D D , Bonner F W
Published: April 2011

The potential of ciprofibrate to inhibit gastric secretion has been investigated in the rat. A significant gastric antisecretory effect was observed following a single oral administration of 300 and 500 mg kg−1 and following a single intraduodenal dose of 100, 300 and 500 mg kg−1. The toxicological significance of this finding is discussed in the light of a spate of recent publications linking changes in gastric morphology with hypergastrinaemia produced as a secondary effect of inhibition of acid secretion.
Protective effect of salicylate against 2,4-dinitrophenol-induced protein thiol loss in the small intestine of rats
Authors: Nishihata Toshiaki , Suzuka Takumi , Yata Noboru , Sakai Kiyoshi
Published: April 2011

The effect of the content of protein thiols and non-protein thiols in the tissue of the rat small intestinal loop on the absorption of cefmetazole has been investigated. 2,4-Dinitrophenol (DNP), at a concentration of 500 μM, caused rapid protein thiol loss, followed by non-protein thiol loss, along with a decrease of cefmetazole absorption by the intestine. The coadministration of 75 mM salicylate with DNP inhibited the effect of DNP on protein thiols and cefmetazole absorption but not on non-protein thiol loss by DNP.
The Oral Disposition of Zinc Following the Use of an Anticalculus Toothpaste Containing 0.5% Zinc Citrate
Authors: Gilbert R J , Ingram G S
Published: April 2011

Zinc is retained in the mouth after use of a toothpaste containing 0.5% zinc citrate. More than one third of the dose was found to be retained after normal brushing. Elevated zinc levels were also found in plaque. Saliva zinc levels were significantly above background for at least 2 h after brushing. In-vitro experiments demonstrated that zinc can bind to the pellicle-coated tooth surface and can subsequently desorb into saliva. Plaque can calcify to form calculus containing appreciable levels of hydroxyapatite. Zinc adsorbs to hydroxyapatite inhibiting crystal growth. Levels of zinc in plaque were found to be considerably higher than those taken up by hydroxyapatite in an in-vitro test of crystal growth inhibition indicating the potential of zinc to inhibit calculus formation.
Sex-related Differences in Disposition and Response to Phenprocoumon in Rats
Authors: Trenk D , Jähnchen E , Øie S
Published: April 2011

The pharmacokinetics and the pharmacological response to phenprocoumon have been studied in female and male inbred Lewis-Wistar rats. A significantly lower clearance was found in female than in male rats (7.9 ± 1.4 vs 24.5 ± 2.5 mL h−1 kg−1, respectively; t = 15.09, P < 0.001) as well as a lower apparent volume of distribution (288 ± 46 vs 617 ± 105 mL kg−1; t = 7.58, P < 0.001) and a longer half-life (25.5 ± 3.4 vs 17.5 ± 1.8 h; t = 5.16, P < 0.001). The binding of phenprocoumon was higher in female than in male rats (fu: 0.0096 ± 0.0008 vs 0.0124 ± 0.0007, respectively; t = 6.66, P < 0.001). The total (C) as well as the unbound concentration (Cu) needed to elicit a 50% decrease in the prothrombin complex synthesis rate was substantially higher in female rats: C50 was 377 ± 98 ng mL−1 in female and 155 ± 29 ng mL−1 in male rats (t = 5.32, P < 0.001), whereas Cu50 was 3.6 ± 0.7 ng mL−1 in female and 1.9 ± 0.3 ng mL−1 in male rats (t = 5.50, P < 0.001). However, because of the lower clearance and volume of distribution and the longer half-life in female rats, the female rats experienced a higher cumulative effect than male rats to 0.34 mg kg−1 i.v. doses.
Time-dependent distribution and excretion of radiolabelled, semipermeable, stable magnetic microcapsules
Authors: Povey A C , Godeneche D , O'Neill I K
Published: April 2011

The time-dependent excretion and potential body retention of magnetic polyethyleneimine (PEI) microcapsules, methylated with [14C]methyl iodide have been investigated after intragastric administration to mice. Gastric emptying was rapid but about 10% of the administered dose was still present in the stomach after 6 h; the number of microcapsules within the small intestine remained approximately constant over 1–6 h. Excretion of microcapsules in the faeces was virtually complete (98.7% excretion within 72 h), with small amounts of radioactivity excreted via the urine or as [14C]CO2. There was no detectable adsorption or retention of microcapsules within the body as measured by either a whole-body autographic study or by direct quantitation of tissue radioactivity.
Prodrug behaviour of nicotinoylmorphine esters
Authors: Broekkamp C L , Oosterloo S K , Rijk H W
Published: April 2011

Morphine and its nicotinoyl esters, dinicotinoylmorphine (nicomorphine), 6-mononicotinoylmorphine (6-MNM) and 3-mononicotinoylmorphine (3-MNM) were tested in mice for central activity to obtain time-effect profiles of these compounds in rats. Two effects, analgesia with the hot plate test and locomotor stimulation in activity cages were measured and nicomorphine, 6-MNM and 3-MNM were found to have a faster onset of action compared with morphine. The effects of 3-MNM and morphine lasted longer than the effect of nicomorphine and 6-MNM. The prodrug behaviour of 3-MNM and nicomorphine for morphine and 6-MNM, respectively, is discussed.