bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prejunctional Inhibitory Effect of α-Methylnoradrenaline in the Rat Vas Deferens is Not Mediated via α2-Adrenoceptors
Authors: Oriowo Mabayoje A
Published: April 2011

In field-stimulated rat vas deferens, clonidine (10−9–10−7 m) and α-methylnoradrenaline (10−7–3 times 10−5 m) concentration-dependently inhibited twitch response to electrical field stimulation. The inhibitory effects of clonidine and α-methylnoradrenaline were similarly reduced by phenoxybenzamine (10−6 m). However, idazoxan (3 times 10−7 m) antagonized clonidine but not α-methylnoradrenaline-induced responses. The inhibitory effect of α-methylnoradrenaline was also not antagonized by phentolamine (3 times 10−7 m), SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4-methylthienol[4,3,2 ef][3]benzazepine) 3 times 10−6 m) or yohimbine 3 times 10−7 m). These antagonists however, attenuated the twitch-inhibiting effect of clonidine. The -logKB values were 8·02 ± 0·05, 6·91 ± 0·10, and 7·58 ± 0·07 for phentolamine, SK&F 104856 and yohimbine respectively. In-vivo treatment of rats with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (6 mg kg−1), to inactivate prejunctional α2-adrenoceptors, attenuated clonidine, but not α-methylnoradrenaline-induced responses.

It was concluded that adrenoceptors are not involved in the prejunctional inhibitory effects of α-methylnoradrenaline in the rat vas deferens.
The Involvement of Cytosolic Chymotrypsin-like, Trypsin-like, and Cucumsin-like Activities in Degradation of Insulin and Insulin-like Growth Factor I by Epithelial Tissues
Authors: Bai Jane P F
Published: April 2011

Using specific substrates, benzyloxycarbonyl-Gly-Gly-Leu-p-nitroanilide, benzyloxycarbonyl-Gly-Gly-Arg-2-naphthylamide and benzyloxycarbonyl-Leu-Leu-Glu-2-naphthylamide, cytosolic chymotrypsinlike, trypsin-like and cucumsin-like activities were determined, respectively, in rat epithelial tissues and differentiated human Caco-2 cells.

The cytosolic fractions of rat colonic, rectal, nasal, and alveolar epithelial cells and differentiated human Caco-2 cells contained these three distinct enzyme activities. However, effects of enzyme inhibitors revealed that these three distinctive activities were not extensively involved in cytosolic or homogenate degradation of insulin and insulin-like growth factor I (IGF-I).

It is concluded that proteasome-like activities may not significantly limit nonparenteral absorption of peptide and protein drugs such as insulin and IGF-I.
Enhanced Effectiveness of Dimethyl-4,4‘-dimethoxy-5,6,5’,6‘-dimethylene dioxybiphenyl-2,2’-dicarboxylate in Combination with Garlic Oil against Experimental Hepatic Injury in Rats and Mice
Authors: Kim Sang Geon , Nam Seon Young , Chung Hye Chin , Hong Su Yeun , Jung Ki Hwa
Published: April 2011

The present study was designed to evaluate the effects of dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate (PMC) in combination with garlic oil against chemical-induced hepatic injury in rats and mice.

Rats insulted with carbon tetrachloride were concomitantly treated with PMC and/or garlic oil (50 and 100 mg kg−1, respectively) for four weeks. Whereas treatment of animals with garlic oil alone was ineffective in suppressing carbon tetrachloride-induced hepatotoxicity, administration of PMC in combination with garlic oil more effectively protected the liver against the carbon tetrachloride-induced insult than PMC alone, as monitored by serum aminotransferase activity. Hepatoprotective effects of the formulation were further supported by the changes in the numbers of Kupffer cells and dead hepatocytes.

Although prior treatment of rats with PMC for three days failed to protect hepatotoxicity elicited by allyl alcohol, the formulation of PMC and garlic oil was capable of blocking allyl alcohol-induced hepatotoxicity by ∼ 40%.

To further examine the effect of the agents on lipid metabolism in the liver, hepatic triglycerides and cholesterol contents were assessed in mice after a diet containing PMC and/or garlic oil for one week followed by a single dose of carbon tetrachloride. Garlic oil appeared to be more effective in bringing hepatic lipid levels to those of control than PMC alone. Treatment of animals with PMC in combination with garlic oil synergistically improved chemical-induced impairment of hepatic triglycerides and cholesterol.

These results demonstrated that PMC in combination with garlic oil is effective in protecting (or treating) chemical-induced hepatic injury and that the formulation may be effective against chemical-induced fat-infiltration of the liver.
The Release of Isoconazole Nitrate from Different Suppository Bases: In-vitro Dissolution, Physicochemical and Microbiological Studies
Authors: Asikoglu M , Ertan G , Cosar G
Published: April 2011

The influence of the suppository base on the in-vitro release of isoconazole nitrate was studied by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. Vaginal suppository formulations containing 25 mg isoconazole nitrate for local treatment of vaginitis were prepared by a fusion method, using different hydrophilic and lypophilic suppository bases (PEG 6000, PEG 4000, PEG 1500, Witepsol H15, Novata BD and Cremao). In-vitro release rates were examined by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. In the physicochemical investigations the pH indicators (pH 1–14) erythrosin B, thymol blue, bromocresol green, chlorophenol red, phenol red, and alkali blue were added to agar gels. The discs were placed onto the agar gels and 21 h later, the coloured zone diameters were measured. In the microbiological investigations, the discs were put on the inoculated plates with the suspension of Candida albicans (Institute Pasteur 628). The inoculated plates were incubated at 37°C for 3 days, then the diameters of inhibition zones were measured.

In the dissolution investigations release rates were in the order PEG 6000 > PEG 4000 > PEG 1500 > > Witepsol H15 > Cremao > Novata BD. The diffusion distance of isoconazole nitrate in the physicochemical investigation was in the order polyethylene glycols > Witepsol H15 > Novata BD. In the microbiological studies release rates were found with polyethylene glycols > Witepsol H15 > Novata BD > Cremao.

The findings in the in-vitro studies suggested that polyethylene glycols are suitable bases for vaginal suppositories.
The Release of Isoconazole Nitrate from Different Suppository Bases: In-vivo Release of Drug Labelled with 99mTc in Rabbits
Authors: Asikoglu M , Ertan G , Ercan M T , Duman Y
Published: April 2011

The influence of the suppository bases on the in-vivo release of 99mTc-labelled isoconazole nitrate was investigated. The single-dose vaginal suppository formulations for local treatment of vaginitis were prepared by a fusion method using polyethylene glycols, Witepsol H15, Novata BD and Cremao.

Prepared vaginal suppositories containing solid-labelled substance were applied to the vagina of rabbits and at 0, 2 and 24 h after administration, the amounts of radioactivity in the vagina were detected by the SPECT Gamma Camera and the release rates of the drug were calculated. The percent released was found to be in the following order; polyethylene glycol (PEG) 6000 > PEG 4000 > Witepsol > PEG 1500 > Novata BD > Cremao. The results obtained in both in-vitro and in-vivo studies indicated that the vaginal suppository of isoconazole nitrate prepared with polyethylene glycols could confidently be used in therapy.
Anti-ulcer Activity of Higher Primary Alcohols of Beeswax
Authors: Carbajal Daisy , Molina Vivian , Valdés Suria , Arruzazabala Lourdes , Más Rosa
Published: April 2011

The anti-ulcer effects of a natural mixture of higher aliphatic primary alcohols, designated D-002, isolated from beeswax, were compared with those of cimetidine on indomethacin-, ethanol-, water-immersion-induced ulcers and on gastric secretion in rats.

D-002 (25–50 mg kg−1 p.o.) was similar to cimetidine in dose-dependently reducing the duration of indomethacin-induced ulcers while also being effective in preventing ethanol-induced ulcers, which are not affected by cimetidine. On the other hand, D-002 (100 mg kg−1) moderately decreased the volume of gastric basal secretion in pylorus-ligated rats, but not the acidity. Nevertheless, it inhibited gastric ulcer induced by pylorus-ligation at doses (50mg kg−1) that were ineffective in decreasing the volume. In addition, 100 mg kg−1 of D-002 prevented the formation of acute gastric ulcers induced in rats by water-immersion stress.

The results demonstrate the anti-ulcer activity of the preparation in different experimental models suggesting its potential value for ulcer therapy.
Gastric and Duodenal Anti-ulcer Activity of SKF 38393, a Dopamine D1-Receptor Agonist in Rats
Authors: Desai Jagruti K , Goyal Ramesh K , Parmar Narayan S
Published: April 2011

The effect of SKF 38393 (1-phenyl-7,8-diol-2,3,4,5-tetrahydro-1H-3-benzazepine), a specific dopamine D1-receptor agonist, was studied on pylorus-ligation and water immersion plus restraint stress-induced gastric ulcers, and cysteamine-induced duodenal ulcers in rats.

Repeated administration of SKF 38393 (5 and 10 mg kg−1, p.o.) for six days was found to be effective in the prevention of gastric ulceration induced by water immersion plus restraint stress in rats. In 19-h pylorus-ligated rats, repeated treatment with SKF 38393 showed a significant reduction in the number and severity of ulcers. SKF 38393 did not alter the total gastric-mucosal carbohydrates: protein ratio; however, the gastric content volume and the free and total acidity were significantly reduced. In cysteamine-induced duodenal ulcers, the treatment with SKF 38393 for 6 days prevented the duodenal lesions.

Our data suggests the involvement of dopamine D1 receptors in the anti-ulcer activity of SKF 38393, which could be largely attributed to its anti-secretory effect. Its anti-ulcer activity against water immersion plus restraint, also points towards a central mode of action, but its failure to alter the carbohydrate: protein ratio rules out any protective effect through the strengthening of the gastric mucosal barrier.
The Role of Nitric Oxide and Sulphydryls in Gastric Mucosal Protection Induced by Sodium Cromoglycate in Rats
Authors: Mobarok Ali A T M
Published: April 2011

The role of endogenous nitric oxide and sulphydryls in gastric protection afforded by sodium cromoglycate against ethanol-induced gastric lesions was studied in rats. Drugs were administered either intraperitoneally (i.p.) or subcutaneously (s.c.) 30, 45 or 60 min before oral administration of ethanol.

Administration of cromoglycate before ethanol dose-dependently inhibited ethanol-induced gastric lesions. Pretreatment with NG-nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide biosynthesis, dose-dependently aggravated gastric lesions and reduced cromoglycate-induced gastric protection. The attenuating effect of L-NAME on gastric protection elicited by cromoglycate was reversible by pretreatment with l-arginine but not by d-arginine. On the other hand, ethanol-induced gastric lesions were found to be associated with a reduction of nonprotein sulphydryl content of glandular stomachs. Pretreatment with cromoglycate prevented non protein sulphydryl depletion and afforded protection. Pretreatment with N-ethylmaleimide, a sulphydryl blocker, caused dose-dependent enhancement of ethanol-induced gastric lesions and further depletion of non protein-sulphydryl. Treatment with N-ethylmaleimide before cromoglycate reduced the gastric protection that was associated with depletion of nonprotein sulphydryls. Furthermore, combined N-ethylmaleimide and L-NAME pretreatment caused a greater aggravation of ethanol-induced gastric lesions and significantly produced a higher reduction of the protective effects of cromoglycate. However, pretreatment with l-arginine only partially restored the protective effects of cromoglycate.

These results suggest that the protective effects of cromoglycate may be dependent on the maintenance of a critical level of both endogenous nitric oxide and nonprotein sulphydryls in the gastric mucosa.
Evidence that the Secretory Response of Rat Intestine to 5-Hydroxytryptamine In-vivo Involves More than One 5-Hydroxytryptamine-receptor Subtype
Authors: Hardcastle J , Hardcastle P T
Published: April 2011

The transintestinal potential difference (PD) across rat mid-small intestine and proximal colon was measured in-vivo. The 5-hydroxytryptamine (5-HT)-induced increase in PD, which reflects a stimulation of electrogenic Cl secretion, was mimicked by both 2-methyl-5-hydroxytryptamine (2-CH3-5-HT), an agonist at 5-HT3 receptors, and 5-methoxytryptamine (5-MT), an agonist that lacks affinity for 5-HT3 receptors. The 5-HT3 antagonist granisetron caused a marked inhibition of the response to 2-CH3-5-HT in both regions, but only produced a small inhibition of the small intestinal response to 5-HT, with a more pronounced effect in the colon. The failure of granisetron to produce a marked antagonism of the 5-HT-induced rise in the transintestinal PD, coupled with the ability of 5-MT to induce a secretory response, indicates that 5-HT3 receptors are not the only ones involved in the stimulation of Cl secretion.

The 5-HT2 antagonist ketanserin failed to influence the response to 5-HT in either the small intestine or the colon, but it did inhibit the action of 5-MT, having a much greater effect in the small intestine. In the presence of granisetron however, ketanserin also inhibited the small intestinal response to 5-HT, having only a minimal effect in the colon. This suggests that 5-HT2 receptors can also play a role in the activation of Cl secretion.

These observations suggest that both 5-HT2 and 5-HT3 receptors contribute to the stimulation of electrogenic Cl secretion by 5-HT, with 5-HT2 receptors playing a more prominent role in the small intestine and 5-HT3 receptors being more important in the colon.
Effect of KBT-3022, a New Diphenylthiazole Derivative, on Platelet Functions
Authors: Yokota Koichi , Yamamoto Noriko , Morimoto Yasuo , Yamashita Akira , Oda Minoru
Published: April 2011

The effects of KBT-3022 and its metabolite desethyl KBT-3022 on platelet aggregation were determined in rat, guinea-pig, rabbit and human platelets in-vitro and ex-vivo.

KBT-3022 and desethyl KBT-3022 inhibited platelet aggregation induced by arachidonic acid and collagen in-vitro more potently than aggregation induced by adenosine diphosphate, platelet-activating factor or thrombin, as well as by acetylsalicylic acid, and their effects were approximately 100 times more potent than those of acetylsalicylic acid.

Desethyl KBT-3022, but not KBT-3022 or acetylsalicylic acid, inhibited thrombin-induced aggregation and 5-hydroxytryptamine release from platelets more potently than ticlopidine hydrochloride at higher concentrations. Oral administration of KBT-3022 inhibited both arachidonic acid- and collagen-induced platelet aggregation and reduced platelet retention in a glass-bead column approx. 100 times more potently than acetylsalicylic acid. KBT-3022 showed little or no anti-inflammatory effect on either ultraviolet-induced erythema or arachidonic acid induced ear oedema, and had lower gastro-ulcerogenicity than acetylsalicylic acid.

These results suggest that KBT-3022 is a potent inhibitor of platelet activation with weak side-effects.
Comparative Study of Separation of Non-encapsulated Drug from Unilamellar Liposomes by Various Methods
Authors: Dipali Satish R , Kulkarni Shirish B , Betageri Guru V
Published: April 2011

The purpose of this study was to compare the various methods available to separate non-encapsulated drug from large unilamellar liposomes (LUV). Multilamellar liposomes (MLV) were prepared by thin film hydration using distearoylphosphatidylcholine:cholesterol (2:1 molar ratio). MLVs were passed through a 0.2-μm polycarbonate membrane using an extruder to prepare LUVs. Particle size of liposome preparations was characterized using a submicron particle-size analyser. The non-encapsulated drug was separated by: filtering through Centrifree tubes; passing through gel (Sepharose-4B and Sephadex G-25M); passing through minicolumn; ficoll density gradient; protamine aggregation; or dialysis.

The dialysis method was found to be unsuitable for separation of non-encapsulated drug due to equilibration of encapsulated drug as the free drug was dialyzed. The upper limit for lipid concentration was 5 mg mL−1 using the Centrifree method. Separation using gel chromatography led to dilution of liposome preparation. Minicolumn and density gradient techniques did not lead to sample dilution, however the minicolumn method was tedious. The time required for separation of liposomes by protamine aggregation was longer for neutral liposomes.

Thus it was concluded that the Centrifree was the fastest method to estimate encapsulation; the density gradient method was ideal to separate non-encapsulated drug; and protamine aggregation was the least expensive method to estimate encapsulation efficiency.
The Influence of Moisture Content on the Consolidation Properties of Hydroxypropylmethylcellulose K4M (HPMC 2208)
Authors: Nokhodchi Ali , Ford James L , Rowe Philip H , Rubinstein Michael H
Published: April 2011

The effect of moisture content, compression speed and compression force on the compaction properties of HPMC K4M has been evaluated.

As the moisture content increased from 0 to 14.9% w/w, the thickness of HPMC K4M compacts increased at constant compression force and speed. This increase in moisture content also resulted in a marked increase in the tensile strength of the tablets. At a speed of 15 mm s−1 and force of 10 kN, as the moisture content increased from 0 to 14.9% w/w, the tensile strengths increased from 1.34 to 8.54 Mpa. Equivalent tensile strengths could be obtained with less compression force as the moisture content in the polymer was increased. Increasing the compression speed generally decreased the tensile strength of HPMC K4M tablets.

The dependence of tablet porosity and tensile strength on compression speeds showed that HPMC K4M is consolidated by plastic deformation. At all compression speeds, an increase in moisture content reduced the percentage elastic recovery of HPMC compacts due to greater tablet consolidation. The lowest elastic recovery (1.18%) was found for tablets made at 15 mm s−1 and 5 kN, containing 14.9% w/w moisture content.
Niosomal Plumbagin with Reduced Toxicity and Improved Anticancer Activity in BALB/C Mice
Authors: Naresh R A Raja , Udupa N , Devi P Uma
Published: April 2011

Plumbagin niosomes were prepared using a lipid layer hydration method, and drug entrapment was measured. The acute toxicity studies were conducted following treatment with free and niosomal plumbagin.

The antitumour activity of niosomal plumbagin in a solid tumour (sarcoma-180) and Ehrlich ascites model was evaluated. Niosome-encapsulated plumbagin was less toxic than free drug. The antitumour activity of the drug was also better after encapsulation.

The better anticancer activity can be justified with the help of LD50 survival studies and study of tumour volume doubling time.
Enhancing Effects of Unsaturated Fatty Acids with Various Structures on the Permeation of Indomethacin through Rat Skin
Authors: Morimoto Kazuhiro , Tojima Hideki , Haruta Tatsuo , Suzuki Masao , Kakemi Masawo
Published: April 2011

Effects of straight-chain, cis-type, unsaturated fatty acids with various structures (alkyl chain lengths, numbers of double bonds, position of double bonds and cis- and trans-positional isomers) on the skin permeation of indomethacin were examined by using rat skins in-vitro. Furthermore, the disordering degrees of the intercellular lipid domain in the stratum corneum, which were treated with preparations of unsaturated fatty acids, were measured by the Fourier transform infrared (FT-IR) method using excised rabbit ear skins.

Unsaturated fatty acids enhanced the permeation of indomethacin through rat skins. These permeation-enhancing effects by unsaturated fatty acids were affected by changes of their alkyl chain length from C14 to C22. The lag-times on the permeation of indomethacin were shortened by unsaturated fatty acids in the following order: C20 = C18 = C22 < C16 < C14. These fluxes were increased by unsaturated fatty acids in the following order: C20 > C22 = C18 = C13 > C14. Therefore, gondoic acid (cis-11-eicosenoic acid; C20H38O2) mostly enhanced the skin permeation of indomethacin. However, the enhancing effects of unsaturated fatty acids (C18 chain) were not affected by their differences of position and numbers of double bonds.

These permeation-enhancing effects which were evaluated by flux were related to the degrees of wave-number shift in the frequency of the antisymmetric CH bond stretching absorbance (near 2920 cm−1) on FT-IR spectra of the fatty acid-treated stratum corneum. Therefore, the perturbation increase of lipid domain in the stratum corneum by these fatty acids probably was the cause of the enhancing effects of permeation of indomethacin.
Terbutaline Transdermal Delivery: Preformulation Studies and Limitations of In-vitro Predictive Parameters
Authors: Tenjarla Srini N , Puranajoti Porranee , Kasina Ram , Mandal Tarun
Published: April 2011

A transdermal dosage form of terbutaline may be useful to prevent nocturnal wheezing by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of the drug would be an additional advantage as this will reduce the intersubject variablity. Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of terbutaline.

The drug solubility in propylene glycol was 6.3 mg mL−1. The apparent partition coefficient (n-octanol/deionized-water, pH 6.5) of terbutaline was 0.03. A pH-partition coefficient (octanol/buffer) profile indicated that the partition coefficient values were 0.02, 0.05 and 04 in buffers of pH 3, 7.4 and 9, respectively. The required drug flux through the human skin to attain therapeutic concentrations in the blood was calculated to be 3.3 μg cm−2 h−1 for a 10-cm2 transdermal delivery system. Rabbit, guinea-pig and human skin was tested as the penetration barrier using modified Franz diffusion cells. Terbutaline flux values through the rabbit and guinea-pig skin were 8.3 and 7.7 μg cm−2 h−1, respectively. The flux through human full-thickness skin and human epidermis were 0.6 and 3.6 μg cm−2 h−1. Azone (3% w/v), a skin penetration enhancer, significantly increased the drug flux through all the membranes tested.

Based on these studies, transdermal delivery of terbutaline appears to be promising.
Improved Ocular Bioavailability of Indomethacin by Novel Ocular Drug Carriers
Authors: Calvo Pilar , Alonso María J , Vila-Jato José L , Robinson Joseph R
Published: April 2011

The ability of different drug carriers to improve the ocular bioavailability of drugs was investigated in the rabbit eye. The assayed drug carriers were suspensions of nanoparticles, nanocapsules and microparticles made of poly-ε-caprolactone (PECL) and a submicron emulsion.

Results indicated that the three submicron systems, nanoparticles, nanocapsules and emulsion, increased more than 3-fold the indomethacin concentration in the cornea, aqueous humour and iris-ciliary body at 0.5 and 1 h post-instillation. Furthermore, an increased indomethacin ocular bioavailability of 300% was observed after instillation of the submicron systems in comparison with the value obtained for a commercial solution. In contrast, the microparticles hardly increased the ocular bioavailability of indomethacin. The mechanism of interaction of the colloidal carriers with the corneal epithelium was investigated by confocal laser scanning microscopy. Confocal images indicated that submicron particles penetrate into the corneal epithelium cells by an endocytic mechanism. The similar behaviour of the three colloidal carriers suggests that any of their specific ingredients (PECL, lecithin and oil) acts as a penetration enhancer or an endocytotic stimulator. On the other hand, the favourable ocular penetration of indomethacin when encapsulated in the colloidal carriers, but not in the microparticles, led us to assume that the colloidal nature of these carriers is the main factor responsible for the increased ocular bioavailability of indomethacin.

PECL nanoparticles and nanocapsules as well as submicron emulsions are shown to be novel corneal drug carriers, thus representing a useful approach for increasing the ocular bioavailability of drugs.
The Acute Effects of FK-506 on Renal Haemodynamics, Water and Sodium Excretion and Plasma Levels of Angiotensin II, Aldosterone, Atrial Natriuretic Peptide and Vasopressin in Pigs
Authors: Golbækdal K , Nielsen C B , Pedersen E B
Published: April 2011

FK-506 has been shown to be an effective immunosuppressive drug with possible nephrotoxic side effects. In this study we have investigated the acute effects of FK-506 on renal haemodynamics, water, sodium and lithium excretion rates and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and vasopressin in 29 anaesthetized Lancaster/Yorkshire female pigs. A continuous intravenous infusion was given over a 2-h period to 4 groups: A: 0.075 mg kg−1 (n = 7), B: 0.15 mg kg−1 (n = 8), C: 0.3 mg kg−1 (n = 6) and P: placebo vehicle (n = 8). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion clearance technique using 125-I-iothalamate and 131-I-hippuran as reference substances. Hormonal parameters were measured by radioimmunoassay.

In all three FK-506 groups, fractional lithium excretion was significantly decreased 2 h after FK506 infusion (P: + 0.4%, A: − 8.8% (P < 0.05), B: −12.9% and C: −11.2% (P < 001 for both). Mean arterial blood pressure (MBP) was significantly increased in the two highest dosage groups (B,C) at 2 h of infusion: (MBP; P: +2.9%, A: +3.5%, B: +12.0%, C: + 15.3% (P < 0.01 for both). GFR and RPF showed minor and inconsistent changes while all other parameters measured showed similar or no changes.

In conclusion, acute infusion of FK-506 to pigs does not change overall renal function significantly, but increases mean arterial blood pressure and decreases fractional excretion of lithium.
Transport and Metabolic Pathway of Thymocartin (TP4) in Excised Bovine Nasal Mucosa
Authors: Lang Steffen , Langguth Peter , Oschmann Rainer , Traving Birgit , Merkle Hans P
Published: April 2011

Thymocartin (TP4, Arg-Lys-Asp-Val) is the 32–35 fragment of the naturally occuring thymic factor (thymopoietin). Here studies on the nasal transport and metabolism of TP4 were performed. Freshly excised bovine nasal mucosa was taken as a model membrane. For permeation studies typical donor-receiver experiments (side-by-side) and finite-dose experiments with small volumes of highly concentrated solutions were carried out.

The metabolic pathway of TP4 in nasal mucosa was found to occur according to a typical aminopeptidase cleavage pattern, stepwise forming Lys-Asp-Val and Asp-Val. TP4 metabolism experiments under reflection kinetics showed a saturation profile above 0.5 μmol mL−1. A non-linear kinetic model consisting of three steps in sequence was sufficient to describe the kinetics: for the first step saturable Michaelis-Meat kinetics, and for the second and the third step first-order kinetics were assured. The model was capable of simultaneously fitting the data for the full range of initial concentrations from 0.1 up to 1.0 μmol mL−1. Saturation kinetics was also found to be the prominent feature of the permeation experiments performed. In the lower concentration range (<0.4 μmol mL−1), transport of TP4 across nasal mucosa was controlled by metabolism, in the higher concentration range (>0.85 μmol mL−1) diffusion control became more important.

We conclude that enhancement of absorption can be achieved when nasal aminopeptidases are saturated, e.g. at high TP4 concentrations.
In-vivo Clearance Study of Vancomycin in Rats
Authors: Nakamura Tsutomu , Takano Mikihisa , Yasuhara Masato , Inui Ken-Ichi
Published: April 2011

The renal handling of vancomycin in rats and the effects of various drugs (probenecid, cimetidine and quinidine) on urinary excretion of the antibiotic were investigated by in-vivo clearance.

The vancomycin-to-inulin excretion ratio (ER) was greater than unity at various infusion rates of vancomycin. Quinidine, co-administered with vancomycin, significantly decreased the total, renal and net secretory clearance of the antibiotic. Cimetidine also decreased, though not significantly, the secretory clearance of vancomycin by about 20%, but probenecid did not.

These results suggested that vancomycin is secreted in renal tubules in rats, and that quinidine decreases the total clearance of vancomycin partly by inhibiting its tubular secretion in the kidney.
The Effect of Gamma-irradiation on the Antibacterial Activity of Honey
Authors: Molan P C , Allen K L
Published: April 2011

There is increasing usage of honey as a dressing on infected wounds, burns and ulcers, but there is some concern that there may be a risk of wound botulism from the clostridial spores sometimes found in honey. It is well-established that the antibacterial activity is heat-labile so would be destroyed if honey were sterilized by autoclaving, but the effect of gamma-irradiation on the antibacterial activity of honey is not known. Therefore an investigation was carried out to assess the effect on the antibacterial activity of honey when the honey was subjected to a commercial sterilization procedure using gamma-irradiation (25 kGy).

Two honeys with antibacterial activity due to enzymically-generated hydrogen peroxide and three manuka honeys with non-peroxide antibacterial activity were investigated. The honeys were tested against Staphylococcus aureus in an agar well diffusion assay. There was no significant change found in either type of antibacterial activity resulting from this form of sterilization of honey, even when the radiation was doubled (to 50 kGy).

Testing of honey seeded with spores of Clostridium perfringens and C. tetani (10 000 and 1000 spores g−1 of honey, respectively) showed that 25 kGy of gamma-irradiation was sufficient to achieve sterility.
Antitumour Activity of Mitoxantrone-loaded Chitosan Microspheres Against Ehrlich Ascites Carcinoma
Authors: Jameela S R , Latha P G , Subramoniam A , Jayakrishnan A
Published: April 2011

Glutaraldehyde cross-linked chitosan microspheres containing the antineoplastic agent mitoxantrone were prepared and the antitumour activity was evaluated against Ehrlich ascites carcinoma in mice by intraperitoneal injections. The tumour inhibitory effect was followed by monitoring animal survival time and change in body weight for a period of 60 days.

While the mean survival time of animals which received 2 mg and 1 mg of free mitoxantrone intraperi-toneally was 2.1 and 4.6 days, respectively, animals which received 2 mg mitoxantrone via microspheres showed a mean survival time of 50 days. Five out of 8 animals treated using microspheres lived beyond 60 days. The percentage ratio mean survival time of the treated group divided by the mean survival time of the untreated group for animals treated using mitoxantrone-loaded chitosan microspheres containing 2 mg of the drug was 290 compared with 12.2 for those which received 2 mg of the free drug.

The antitumour effect of mitoxantrone-loaded microspheres against Ehrlich ascites carcinoma was much higher than that of doxorubicin-loaded microspheres reported by previous workers. Our data demonstrate the potential of mitoxantrone-loaded chitosan microspheres for sustained drug delivery to minimize drug toxicity and maximize therapeutic efficacy.
Development and Validation of a Pig Model for Colon-specific Drug Delivery
Authors: Gardner Naomi , Haresign Will , Spiller Robin , Farraj Nidal , Wiseman Julian , Norbury Heather , Illum Lisbeth
Published: April 2011

The purpose of this investigation was to develop a pig model for colonic drug delivery and to validate the model by determining whether the physiology of the pig colon had been significantly altered after the surgical implantation of a gut cannula into the terminal ileum of the pig.

A fistula was created in the terminal ileum of the pig, and a cannula fitted for the purpose of directly administering drug formulations to a point just anterior to the ileocaeco-colonic valve of the gastrointestinal tract. The cephalic vein of the pig was also cannulated to enable continued blood sampling.

Sulphasalazine was used as the model drug for the validation study. In the intact colon, sulphasalazine is metabolized by the gut microflora to sulphapyridine which is then absorbed. Sulphasalazine was administered orally to non-fistulated and fistulated pigs and then ileally, via the gut cannula, to fistulated pigs. Absorption of sulphapyridine was monitored by HPLC analysis of plasma samples. There was no significant difference in the absorption obtained for the three groups. Thus it is demonstrated that the colon physiology had not been altered.

The colonic pig model is ideal for studying factors affecting the colonic absorption of drugs and as a means for developing drug delivery systems with improved absorption properties.
Synergistic Inhibition of Human Polymorphonuclear Function by Prostaglandin E1 and Linsidomine
Authors: Gladis-Villanueva Mar , Schrör Karsten
Published: April 2011

Polymorphonuclear cells (PMN) are the dominating inflammatory cell population in acute tissue injury and contribute to host-defence mechanisms by formation and release of chemical mediators. The aim of the present study was to investigate whether chemoattractant-induced PMN stimulation can be synergistically antagonized by vasodilatory prostaglandins and nitric oxide (NO), both being formed by the vasculature in inflamed areas. PGE1 (10 nM−10 μM) inhibited concentration-dependently formyl-methionyl-leucyl-phenylalanine (fMLP)-induced β-glucuronidase and oxygen radical (O2) release from human PMN. The NO donor linsidomine (100 μM) was ineffective, but significantly enhanced PGE1 effects on oxygen radical generation and enzyme release. The non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM) potentiated PGE1 effects on all parameters measured. The combination linsidomine (100 μM) plus IBMX (0.5 mM) did not additionally reduce β-glucuronidase release, but abolished fMLP-stimulated O2 generation. There was a stimulation of cAMP formation by PGE1 but not by linsidomine, both in the absence and presence of IBMX.

It is concluded that the effects of linsidomine on PMN function and its synergism with PGE1 are not tightly correlated with total cAMP accumulation. Alternatively, the inhibition of O2 generation by linsidomine may be related to its ability to modulate the activation of the NADPH oxidase system or to scavenge free oxygen radicals.
Rat Protein Binding and Cerebral Phospholipid Affinity of the H3-receptor Antagonist Thioperamide
Authors: Plazzi P V , Mor M , Silva C , Bordi F , Morini G , Crivori P , Caretta A
Published: April 2011

The binding of thioperamide, a known H3-receptor antagonist, to rat plasma proteins and its affinity for rat cerebral phospholipids are investigated.

Thioperamide is strongly bound to plasma proteins (95−80% at plasma concentrations of 3.5−400 μg mL−1), and its binding can be resolved into two components: a high-affinity, saturable component and a non-specific component. The drug has a high affinity for cerebral phospholipids, with a partition coefficient of approximately 100 (log K = 2.06 ± 0.14), which should promote brain penetration and accumulation.

Protein binding and cerebral phospholipid affinity can suggest the explanation of some differences reported in the literature on thioperamide distribution data: at low plasma concentrations of the drug, its protein binding (95% at 3.5 μg mL−1) can prevent brain accumulation, while at higher concentrations the free plasma fraction suddenly increases (> 10% at 18 μg mL−1) and it allows passive distribution to lipophilic tissues such as brain tissue.
Mefloquine Effect on Disposition of Halofantrine in the Isolated Perfused Rat Liver
Authors: Leo Kathleen U , Wesche David L , Marino Mark T , Brewer Thomas G
Published: April 2011

Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine.

Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean ± s.d.) were: volume of distribution (Vd), 7.53 ± 1.45 mL (g liver)−1; clearance (CL), 0.11 ± 0.07 mL min−1 (g liver)−1; initial distribution half-life (initial t1/2), 14.62 ± 2.38 min; terminal half-life (terminal t1/2), 138.7 ± 178.8 min; AUC 606 ± 194 mg mL−1 min−1 (g liver)−1; elimination rate constant (Ke), 0.0135 ± 0.012 min−1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, Ke, initial and terminal t1/2 (P > 0.05). A single dose, short term (4−6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefioquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 005) and biliary clearance (P < 005) of halofantrine in mefioquine-pretreated livers.

These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.
The Podiatric Treatment of Hallux Abducto Valgus and Its Associated Condition, Bunion, with Tagetes patula
Authors: Khan M Taufiq
Published: April 2011

To assess the effectiveness of marigold therapy using Tagetes patula preparations, a double-blind placebo-controlled trial was designed to be carried out over a period of eight weeks. Sixty patients were entered in the trial. Twenty patients with bilateral hallux abducto valgus and its associated condition, bunion, were randomly selected from 37 subjects for group A. For group B, 40 patients with unilateral hallux abducto valgus and bunion were randomly selected from 69 subjects and subdivided into groups Ba and Bb. Patients with ulcerated conditions, those on medication and those who had undergone surgery for the condition were excluded.

The results obtained were highly significant (P < 0.001), suggesting that T. patula preparations, plus protective pad, were effective in reducing the width of the lesion and level of pain of hallux abducto valgus.
Clinical Pharmacokinetics of Ondansetron. A Review
Authors: Simpson Karen H , Hicks Fiona M
Published: April 2011

5−HT3 receptors are ubiquitous in the enteric, sympathetic, parasympathetic and sensory nervous systems and in the central nervous system (CNS) (Kilpatrick et al 1990). In man 5−HT3 receptors are mainly situated on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferents (Reynolds et al 1989), and the area postrema of the brain stem, which forms the chemoreceptor trigger zone. Ondansetron is a selective antagonist at 5−HT3 receptors. It is 100 times more potent than metoclopramide at this site (Tyers 1992). It shows limited binding to other receptors and has a wide therapeutic window. Ondansetron is a useful antiemetic which probably has both central and peripheral actions in patients undergoing radiotherapy, cytotoxic chemotherapy or general anaesthesia (Naylor & Rudd 1992). This paper reviews the pharmacokinetics of ondansetron in health and disease to provide information for clinicians; it might alter prescribing and alert them to possible drug interactions.
Solidification Studies of Polyethylene Glycols, Gelucire 44/14 or their Dispersions with Triamterene or Temazepam
Authors: Dordunoo Stephen K , Ford James L , Rubinstein Michael H
Published: April 2011

The solidification of polyethylene glycols (PEG 1500, PEG 2000, PEG 4000, PEG 6000), gelucire 44/14 or their dispersions containing triamterene or temazepam were studied to assess the feasibility of using these dispersions to liquid-fill hard gelatin capsules.

Solidification from melts, investigated by differential scanning calorimetry using cooling cycles, showed a tendency of the drugs, carriers or their dispersions to supercool. The degree of supercooling depended on the rate of cooling, the drug content and, for the PEGs, on the molecular weight. PEG 1500 and PEG 2000 gave one morphological form, irrespective of cooling rate; PEG 4000 and PEG 6000 solidified into at least two forms, depending on the cooling rate. Incorporation of drugs affected the morphology of the PEGs during solidification. The rate of crystal growth was, furthermore, influenced by the fusion temperature, molecular weight and the degree of supercooling. The degree of crystallinity, as measured by the enthalpies of solidification, decreased with increasing cooling rate.

The results show that reducing the rate of solidification could lead to incomplete solidification, giving products that are liable to change on storage.
Physicochemical Characterization of Bisphosphonic Carboxyfluorescein for Osteotropic Drug Delivery
Authors: Fujisaki Jiro , Tokunaga Yuji , Takahashi Toshiya , Murata Saburo , Shimojo Fumio , Hata Takehisa
Published: April 2011

Disodium (fluorescein-6−carbonyloxy)acetoaminomethylene bisphosphonate (CF-BP), a prodrug of 6−carboxy-fluorescein, is efficiently absorbed by the skeleton where it hydrolyses to carboxyfluorescein. An osteotropic drug-delivery system based on this bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. In this study the physicochemical properties of the prodrug have been characterized by investigating the affinity of CF-BP for hydroxyapatite and the hydrolysis of the compound to carboxyfluorescein.

In the binding study, CF-BP bound very rapidly to hydroxyapatite without degradation and carboxyfluorescein was subsequently gradually released by hydrolysis of bound CF-BP. Hydrolysis of CF-BP in buffer solutions followed pseudo-first-order kinetics, and quantitative regeneration of carboxyfluorescein was observed. In addition, regeneration of carboxyfluorescein from CF-BP was accelerated in the presence of fresh rat plasma.

These results suggest that CF-BP has the physicochemical properties required for site-specific and controlled delivery of carboxyfluorescein to bones.
An In-vitro Study of the Effect of Hydrocolloid Patch Occlusion on the Penetration of Triamcinolone Acetonide through Skin in Man
Authors: Ladenheim D , Martin G P , Marriott C , Hollingsbee D A , Brown M B
Published: April 2011

The aim of this study was to evaluate the effect of occlusion using hydrocolloid-containing patches on in-vitro triamcinolone acetonide (TACA) penetration of the epidermis while monitoring the uptake of water by the patches as a result of transepidermal water loss.

The hydrocolloid patches were a laminate of a pressure-sensitive hydrophobic adhesive (containing a dispersion of 39% of either pectin or carmellose sodium) and a polyethylene film. The diffusion of a representative corticosteroid (TACA) through isolated epidermal sheet was shown to depend on the site from which the skin was removed. The two patch-types exhibited markedly different hydration rates when applied to the membranes. For example, after 96 h the carmellose sodium patch showed ten times the weight increase of the pectin patch. Epidermal diffusion rates were, however, similar, both showing a 3−4−fold enhancement over unoccluded conditions.

The increase in TACA diffusion with the patches can be explained by the increase in skin hydration that occurs during occlusion. Despite the large differences in transepidermal water transfer through the epidermal membranes with the two types of hydrocolloid patch, however, this level of stratum corneum hydration was apparently similar. As the rate of diffusion was also independent of hydrocolloid patch component, it seems possible that the hydrophobic component of the patch matrix may also influence the level of skin hydration and consequent drug diffusion.
Amelioration of Disordered Hepatic Protein Synthesis by the Deleted Form of Hepatocyte Growth Factor in Models of Liver Failure in Rats
Authors: Masunaga Hiroaki , Fujise Nobuaki , Shiota Akira , Yamashita Yasushi , Yasuda Hiroshi , Higashio Kanji
Published: April 2011

Because the liver plays an important role in protein synthesis and cholesterol metabolism and reductions in these functions are observed in almost all hepatic disorders, the effects of the deleted form of hepatocyte growth factor (dHGF) on disordered hepatic protein synthesis were studied in various liver-injured rat models using Wistar male rats.

In the 70% hepatectomized rats, plasma clotting time was prolonged and the serum level of total protein and the liver protein content were decreased. The treatment of the animals with dHGF (100−500 μg kg−1, i.v., twice daily) ameliorated these parameters at 48 or 72 h. The administration of carbon tetrachloride or D-galactosamine to hepatectomized rats induced a marked prolongation of plasma clotting time and hypoproteinaemia. In the animals treated with dHGF (500 μg kg−1, i.v., twice daily) these parameters were rapidly reversed compared with those of control groups. In a hepatocellular necrosis model induced by dimethylnitrosamine, the plasma clotting time was extremely prolonged, and liver protein content, serum total protein, albumin, HDL-cholesterol (as an index of lipoprotein) and plasma lecithin-cholesterol acyltransferase activity severely reduced. In this severely injured model, dHGF (5−500 μg kg−1, i.v., twice daily for 28 days) dose-dependently prevented the loss of liver protein content and improved the disordered plasma coagulability and serum protein levels.

These results suggest that dHGF is useful for ameliorating the disorders in hepatic functions such as protein synthesis.