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ABSTRACT: OBJECTIVES: The semi-synthetic bile salt, 12-oxochenodeoxycholate (OCDC also known as 12-monoketocholate), has been shown to enhance drug permeation across biological membranes with low cytotoxicity. Its effect on the analgesic potency and brain concentration of morphine 6-glucuronide (M6G) was studied in male Wistar rats. METHODS: Four groups of animals (n = 8) were given 5, 10 or 20 mg/kg OCDC or normal saline (control) by subcutaneous injection 30 min before a subcutaneous injection of 5 mg/kg M6G after which the hotplate test was performed on each rat at various times. After a 2 week wash-out period, the same rats (n = 30) were randomized to two equal groups and given OCDC (20 mg/kg) or normal saline 30 min before 5 mg/kg M6G. At five time points up to 3 h after M6G administration, three rats from each group were euthanized and blood and brain analyzed for M6G. KEY FINDINGS: The area under the analgesic effect versus time curve (AUAE) was found to be significantly (P < 0.05) greater in rats given 20 mg/kg OCDC than in control rats. Area under the curve (AUC) for M6G in both plasma and brain was greater in OCDC-treated rats than in control rats, but the brain : plasma AUC ratio was lower. CONCLUSIONS: OCDC enhances the analgesic effect of M6G but gives a lower brain : plasma ratio due to increasing M6G plasma levels probably by reducing its renal clearance.
The Journal of pharmacy and pharmacology. 04/2013; 65(4):561-566.
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ABSTRACT: The bile salts (BS) cholate (C) and 12-monoketocholate (12-MKC) have been shown to inhibit the transcellular permeation of methotrexate (MTX) across Caco-2 cell monolayers. The aim of this study was to investigate the mechanism of this inhibition by comparing the effects of C, 7-MKC, 12-MKC, 3,7-diketocholate (DKC) and triketocholate (TKC) on MTX uptake by Caco-2 cells.
Critical micelle concentrations (CMCs) and cytotoxicities of BS and their effects on membrane fluidity Caco-2 cells were determined by standard methods. MTX uptake by Caco-2 cell monolayers was determined using LC-MS/MS.
Replacing hydroxyl groups in C with keto groups and changing from 7-MKC to 12-MKC resulted in BS with lower cytotoxicity, higher CMC and decreased ability to inhibit the uptake of MTX. 7- and 12-MKC increased membrane fluidity of hydrophilic regions of Caco-2 cell membranes, DKC and TKC increased membrane fluidity of hydrophobic regions and C had little effect on membrane fluidity of either region.
Replacing hydroxyl groups in C with keto groups produces BS with different physicochemical properties and biological effects. Since ketocholates (but not C) decrease MTX uptake in parallel with increasing membrane fluidity, it is suggested that ketocholates inhibit MTX influx transporters indirectly through disturbing their lipid environment.
International journal of pharmaceutics 05/2012; 433(1-2):89-93. · 2.96 Impact Factor
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ABSTRACT: Delivering drugs to the brain is challenging given the selective permeability of the blood brain barrier (BBB). Targeted colloidal carriers containing drug payloads offer some promise for enhanced and perhaps selective delivery to brain. This review examines the recent literature and identifies issues to be addressed if these systems are to be rationally designed. These include opsonization of nanoparticles and off-target clearance; the cerebral microvasculature, flow of nanoparticles in capillaries and binding to the capillary wall; and transcytosis. Capillary architecture, blood flow and BBB permeability are affected by disease and age and there are species differences. These complexities caution against making extravagant claims for a particular nanosystem but they also highlight the rich opportunities and need for critical research in this field.
Journal of Microencapsulation 05/2012; 29(5):475-86. · 1.55 Impact Factor
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ABSTRACT: Coalescence of polymer particles on thermal treatment plays an important role in effective control of drug release from these matrix systems. The water content of the polymer may influence coalescence since it is well established that sorbed water may act as a plasticizer, or cause other changes in mechanical properties. However, these effects depend on the amount and type (plasticizing/nonplasticizing) of water present. The purpose of this study was to determine the accuracy of different methods used to determine moisture content of a polymer (Eudragit RLPO) and to determine the types water present. The polymer powder was stored at various relative humidities (33, 56, 75, 94%). Four water determination methods, [weight loss on drying, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and Karl Fischer titration (KFT)] were utilized to determine moisture content. DSC was used to study the thermal behaviour of moist and dry samples. The Gordon-Taylor equation was used to calculate the amount of plasticizing water. Scanning electron microscopy was employed to examine the morphology of the polymer particles after thermal analyses. It is concluded that KFT accurately determines the total water content but that the thermal methods underestimate total water content. However KFT does not indicate the type of water present. The Gordon-Taylor model suggests that only about 25% of the water in the polymer containing 10% water was acting as a plasticizer. Complementary methods should be used to measure the water content of pharmaceutical polymers.
International journal of pharmaceutics 01/2012; 422(1-2):68-74. · 2.96 Impact Factor
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ABSTRACT: To examine the ability of bile salts (BS) to act as permeation enhancers at the blood brain barrier, the effect of four BS (cholate, deoxycholate, monoketocholate and taurocholate) on accumulation of rhodamine 123 (R123) in rat brain endothelial (RBE4) cells was investigated. Experiments were performed using BS concentrations shown to be noncytotoxic to RBE4 cells. Uptake and efflux of R123 in the absence and presence of BS were studied by fluorescence spectroscopy and confocal microscopy. Changes in RBE4 cell membrane fluidity in the presence of BS were evaluated using fluorescence anisotropy. The direct interaction between BS and R123 (ion pairing) and the effect of BS on distribution of R123 into liposomes were studied by capillary electrophoresis. All BS influenced R123 uptake in a concentration-dependent manner and increased cell membrane fluidity. Monoketocholate produced the greatest increase in uptake and also significantly reduced R123 efflux probably by inhibition of P-glycoprotein (P-gp). Direct interaction of BS and R123 was weak, but distribution of R123 into liposomes was increased by BS. The results suggest that BS increase R123 uptake by increasing cell membrane fluidity and, in the case of MKC, by inhibiting P-gp.
Molecular Pharmaceutics 11/2011; 9(1):29-36. · 4.78 Impact Factor
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ABSTRACT: The objective of this study was to study the effect of four different bile salts, cholate (C), deoxycholate (DC), taurocholate (TC), monoketocholate (MKC), on the membrane binding of a cationic model drug, propranolol, using capillary electrophoresis. The apparent distribution coefficient of propranolol in a buffer/liposome system, in the absence and presence of various concentrations of the bile salts, was measured using capillary electrophoresis frontal analysis. At bile salt concentrations which did not disrupt the liposomes, the bile salts increased the apparent distribution coefficient of propranolol in a concentration-dependent manner, to various extents (DC>C>TC>MKC). The mechanisms for these increases were inferred from studies of ion pairing between bile salts and propranolol using mobility shift affinity capillary electrophoresis and from zeta potential measurements. The bile salts ion-paired with propranolol to different extents as indicated by the estimated complexation constants (K range: 30-58 M(-1)). This was found to have a minor effect on the membrane distribution of propranolol only. The major effect is proposed to be due to the insertion of bile salt into the liposomal membranes leading to a more negatively charged membrane surface thereby providing stronger electrostatic interactions with the positively charged propranolol.
Journal of pharmaceutical and biomedical analysis 11/2011; 56(3):553-9. · 2.45 Impact Factor
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ABSTRACT: Penethamate (PNT) is a diethylaminoethyl ester prodrug of benzylpenicillin used to treat bovine mastitis via the intramuscular route. Because of its instability, PNT products must be reconstituted before administration and the reconstituted injection has a short shelf life (7 days at 2-8°C). The purpose of this paper was to investigate whether the stability of PNT can be improved in order to achieve a chemically stable ready-to-use aqueous-based PNT formulation or at least to extend the shelf life of the reconstituted suspension. A chemical stability study of PNT in aqueous-based solutions as a function of pH, buffer strength, solvent mixtures and temperature, supported by studies of its solubility in mixed solvents, allowed predictions of the shelf life of PNT solution and suspension formulations. PNT degraded in aqueous solutions by several pathways over the pH range 2.0-9.3 with a V-shaped pH-rate profile and a minimum pH of around 4.5. The stability of PNT solutions in mixed solvents was greater than in aqueous solutions. For example, in propylene glycol:citrate buffer (60:40, v/v, pH 4.5), the half-life of PNT was 4.3 days compared with 1.8 days in aqueous buffer. However, solubility of PNT in the mixed solvent was higher than that in aqueous solution and this had an adverse effect on the stability of suspensions. By judicious choosing of pH and mixed solvent, it is possible to achieve a storage life of a PNT suspension of 5.5 months at 5°C, not sufficient for a ready-to-use product but a dramatic improvement in the storage life of the reconstituted product.
Drug Development and Industrial Pharmacy 06/2011; 38(1):55-63. · 1.49 Impact Factor
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ABSTRACT: Bile salts are known to enhance the permeability of biological barriers but little is known about their effects on drug permeability across the blood-brain barrier (BBB). In this paper, the rat brain endothelial 4 (RBE4) cell monolayer incubated with astrocyte-conditioned medium was used as an in vitro model of the BBB to investigate the effects of cholate (C), 12-monoketocholate (MKC), deoxycholate (DC), and taurocholate (TC) on the transport of the hydrophilic drug, morphine-6-glucuronide (M6G). C, MKC, and TC at a concentration of 5 mM each and DC at 1 mM increased the permeability of M6G through the paracellular pathway based on a similar permeability pattern to that of sucrose. RBE4 cell uptake of M6G was unaffected by 5 mM C and TC, whereas 1 mM DC dramatically increased it due to an effect shown to be cytotoxicity as measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Surprisingly, 1 mM MKC significantly increased M6G uptake without any cytotoxicity. In summary, all bile salts increased paracellular permeation of M6G but MKC also enhanced transcellular transport with little cytotoxicity. MKC appears to have the potential to modulate biophysical properties of the cell membrane or membrane-bound transporters and may therefore enhance drug delivery to the brain. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci.
Journal of Pharmaceutical Sciences 11/2010; · 3.06 Impact Factor
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ABSTRACT: Post-injection precipitation may cause poor and erratic drug absorption and tissue irritation at the injection site. Tissue tolerance and pharmacokinetics of a low pH ricobendazole (RBZ) injectable containing 20% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were simultaneously investigated after subcutaneous injection in sheep compared to a reference formulation without HP-beta-CD. Each animal received a RBZ containing formulation on one side of the back and the respective vehicle on the contralateral side. The HP-beta-CD vehicle showed good tissue tolerance and the acidic solution caused minimal injection site reactions. Both RBZ containing formulations caused pain on injection and tissue histological changes in some animals. Lack of elevation of plasma creatine kinase indicated that none of the formulations caused significant damage to the underlying muscle tissue. Compared to the reference formulation, AUC and C(max) of the HP-beta-CD formulation were 1.6 and 2.2 times higher, respectively, whereas t(max), MRT and t(1/2) were significantly shorter suggesting faster and greater absorption of RBZ in the presence of HP-beta-CD. This was attributed to the effect of inhibition of post-injection drug precipitation and drug absorption enhancement of HP-beta-CD. In conclusion, HP-beta-CD was shown to be a tissue-compatible excipient with potential to inhibit post-injection precipitation and increase absorption of poorly water soluble drugs. Additionally, the HP-beta-CD formulation showed promise as an injectable that potentially minimizes irritation by reducing the dose required.
International journal of pharmaceutics 09/2010; 397(1-2):96-102. · 2.96 Impact Factor
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ABSTRACT: The aim of the study was to investigate the tissue tolerance and bioavailability of four formulations containing 5% ricobendazole solubilised at low pH, following subcutaneous injection in sheep. Formulations were: a water-in-oil emulsion, a microemulsion, a hydroxypropyl-beta-cyclodextrin (HP-beta-CD, 20%) drug solution, and a low-pH drug solution (reference).
In-vitro cytotoxicity of the formulations was investigated in L929 fibroblasts using MTS viability and lactate dehydrogenase leakage assays. Each formulation and respective vehicle was injected into either side of the back of a sheep to investigate the tissue tolerance and pharmacokinetics.
In-vitro studies suggested that both the emulsion and the microemulsion are unlikely to give a burst release of the low-pH drug solution in aqueous media. The microemulsion showed the greatest in-vitro cytotoxic effect but no significant difference was observed between the other formulations. In sheep, the three new formulations and vehicles caused little or no injection-site reactions compared with a marked response to the reference formulation. Bioavailabilities of HP-beta-CD formulation, emulsion and microemulsion formulations, relative to the reference formulation, were 194, 155 and 115%, respectively.
The three new subcutaneous injectables showed promise for reducing irritation of low-pH solubilised ricobendazole. HP-beta-CD significantly enhanced the drug absorption. Controlling the burst release of the low-pH drug solution may improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. The in-vitro cytotoxicity studies did not predict the in-vivo irritation effects.
The Journal of pharmacy and pharmacology. 07/2010; 62(7):873-82.
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ABSTRACT: Purpose: To investigate the effect of oral co-administration of the P-glycoprotein inhibitor cyclosporin A (CsA) on the pharmacokinetics of mitoquinone, a mitochondria-targeted antioxidant, in rat. Methods: Male Wistar rats (weight 300 ± 20 g) were divided into four groups (n =4–5 per group) two of which were treated with an oral dose of CsA (40 mg/kg). Thirty minutes later, one group of treated and one group of untreated rats received an aqueous solution of mitoquinone mesylate either by the oral (25 mg/kg) or intravenous (i.v.) (5 mg/kg) route. Blood, urine and feces were collected for up to 24 h and analysed for mitoquinone and metabolites. Results: The major metabolite detected in plasma after both i.v. and oral administration was the monoglucuronide of the reduced quinol form of mitoquinone (mitoquinol). This formed extremely rapidly after the i.v. dose and subsequently accounted for most of the dose in the 24 h feces. Orally administered mitoquinone produced a plasma concentration-time profile with multiple peaks. Bioavailability was very low (1.0%) and not significantly changed by CsA (0.7%). However, CsA reduced the multiple peaks in the plasma concentration-time profile of mitoquinone and produced a significantly higher plasma level of mitoquinol glucuronide. It also decreased the recovery of mitoquinol glucuronide in feces. An explanation for these results based on enterohepatic recycling of mitoquinone and its interruption by CsA is discussed. Conclusion: Oral administration of CsA increases the total concentration of mitoquinone and mitoquinol glucuronide in plasma but has little or no effect on the bioavailability of mitoquinone in rat.
Asian Journal of Pharmaceutical Sciences 01/2010; 5:106-113.
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ABSTRACT: In normal and malignant human cells, the folate antagonist methotrexate (MTX) is converted to a series of polyglutamates (MTXGlu(n), n=2-5) which play a role in its therapeutic efficacy. Here we report an assay to determine MTX and MTXGlu(n) in Caco-2 cells exposed to MTX. After a simple protein precipitation step, cell homogenates (2 x 10(6) cells) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using aminopterin as internal standard. Separation was by reversed phase HPLC on a C8 column using gradient elution with 0.1% formic acid and acetonitrile. Detection was by electrospray ionization in the positive ion mode followed by multiple reaction monitoring of the transitions of the [M+H](+) ions of MTX and MTXGlu(n) to their common product ion at m/z 308.2 and of aminopterin at m/z 441.3-->294.2. Calibration curves for all analytes were linear in the range 2-250 nM (r(2)>0.996). Intra- and inter-day precisions (as coefficient of variation) were 3.4-15.1% and 4.3-18.4%, respectively with corresponding accuracies (as relative error) of -3.6 to +6.6% and -5.5 to +7.5%, respectively. Recoveries were in the range 60+/-4 to 108+/-13%. It was found that MTX undergoes only limited polyglutamation in Caco-2 cells exposed to MTX over 24 h.
Journal of pharmaceutical and biomedical analysis 10/2009; 50(2):262-6. · 2.45 Impact Factor
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ABSTRACT: Coalescence of polymer particles has been identified as a crucial step in film formation on tablets, pellets and granules. Though the significance of thermal treatment on matrix dosage forms is well established the process of coalescence in matrix formation and the forces driving it remain unexplored. The aim of this study was to investigate whether stresses in tablets, caused by deformation of excipient during compression, provide a driving force for polymer matrix formation. Polymer matrix tablets containing Eudragit-RLPO, a pH independent and permeable polymer at two levels 10 and 40% (w/w) were prepared by direct compression. Either lactose monohydrate (brittle) or mannitol (plastic) was used as a diluent at 80 or 50% (w/w) and indomethacin, a model drug was present at 10% (w/w). Tablets from each formulation type were prepared at two compression pressures either 221 MPa (above the yield pressure of both excipients) or 74 MPa (below the yield pressure of both excipients). Tablets from each formulation type compressed at the two compression pressures were thermally treated at 40 degrees C (below Tg) or 70 degrees C (above Tg) for 24 h. The rotating basket (100 rpm) method was used for the release studies conducted at 37 degrees C in 900 ml phosphate buffer (0.2 M) pH 7.2 as the dissolution medium. Morphological characteristics of the tablets were observed by scanning electron microscopy. Differences in tablet structure due to the formulation and processing variables were further evaluated by disintegration and tensile strength testing. Data from this factorial study were analysed by analysis of variance. Excipient mechanical properties determine matrix properties only at low polymer level independent of curing temperature and at high polymer level cured at 40 degrees C only. Though lactose and mannitol have different mechanical properties and therefore different deformation behaviors, this did not influence the properties of tablets containing 40% (w/w) polymer cured at 70 degrees C, suggesting stresses in these tablets are not a significant driving force for matrix formation.
International journal of pharmaceutics 10/2009; 384(1-2):87-92. · 2.96 Impact Factor
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ABSTRACT: Bile salts have been shown to decrease the absorption of methotrexate in the rat intestine by an unknown mechanism. We aimed to examine this effect.
We assessed apical-to-basolateral (AP-BL) permeation of methotrexate (5 muM) across Caco-2 cell monolayers pretreated with various concentrations (0, 0.25, 0.5, 1, 3 and 5 mM) of sodium cholate or its semisynthetic analogue, sodium 12-monoketocholate. We also determined the effect of orally administered 12-monoketocholate on the intestinal absorption of methotrexate in rats to evaluate a possible in-vitro-in-vivo correlation.
It was found that sodium cholate and sodium 12-monoketocholate decreased the AP-BL permeation of methotrexate at low concentrations (maximal inhibition at 0.25 and 1 mM, respectively) and increased it at higher concentrations. Determination of [(14)C] mannitol permeation and electrical resistance of monolayers during experiments showed that membrane integrity was not compromised at low concentrations of bile salts but was disrupted at higher concentrations. Subsequently, we examined the effect of the simultaneous oral administration of sodium 12-monoketocholate (4, 20, 40 and 80 mg/kg) on the intestinal absorption of methotrexate in rats after an oral dose (5 mg/kg). The pharmacokinetic study showed that 12-monoketocholate at 4 and 20 mg/kg did not change the methotrexate area under the serum concentration-time curve whereas sodium 12-monoketocholate at 40 and 80 mg/kg significantly reduced it.
Sodium 12-monoketocholate appears to decrease the intestinal absorption of methotrexate in rats by inhibition of transcellular active transport.
Journal of Pharmacy and Pharmacology 08/2009; 61(7):953-9. · 2.17 Impact Factor
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ABSTRACT: The aim of this study was to develop a stability-indicating HPLC assay for the determination of penethamate (PNT), an ester prodrug of benzylpenicillin (BP), in aqueous solutions. The method was validated by subjecting PNT to forced decomposition under stress conditions of acid, alkali, water hydrolysis and oxidation. A quenching solution was developed to limit degradation to negligible levels before and during the analysis. Both PNT and BP were simultaneously determined and separated in presence of degradation products on a C(18) column using a mobile phase consisting of methanol-acetonitrile-acetate buffer. Different degradation products were formed in the stress conditions. The peak purity indexes of PNT and BP obtained by diode array detection were >0.999, confirming the absence of other co-eluting substances. The assay was linear for both analytes in the concentration range 1-100 microg mL(-1). The LOD and LOQ of PNT were 0.03 and 0.09 microg mL(-1) respectively. Degradation of PNT followed pseudo-first-order kinetics with t(1/2) of 43.6 min at pH 2.01 and 4.2 min at pH 9.31. In addition, the absence of BP in the acidic solutions of PNT emphasises the futility of monitoring BP to assess the stability of PNT. In conclusion, the assay is rapid and stability-indicating with adequate precision and accuracy, and in conjunction with the quenching solution, can be used for stability studies of PNT with simultaneous quantitation of BP. The degradation studies provide useful information for formulation development of PNT.
Journal of pharmaceutical and biomedical analysis 07/2009; 50(5):841-6. · 2.45 Impact Factor
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ABSTRACT: Selenomethionine (SeMet) is a widely used nutritional supplement that has potential benefit for people living in selenium-deficient areas. Previous research has shown that selenium administered as SeMet undergoes significant enterohepatic recycling which may involve the gut microflora. In order to investigate this we have developed a simple method for the quantitation of l-SeMet in rat gut content suspensions prepared from jejunum, ileum, caecum and colon. After incubation of l-SeMet with gut content suspensions, samples were deproteinized with sulfosalicylic acid and derivatized with o-phthaldialdehyde (OPA) and N-acetyl-l-cysteine (NAC). Mass spectrometry confirmed the formation of a 1:1:1 derivative of l-SeMet with OPA and NAC. Samples were analysed by reversed-phase high-performance liquid chromatography with fluorescence detection. The assay was linear in the concentration range 0.5-100 microg/mL (r(2) = 0.9992) with a limit of detection of 0.025 microg/mL (signal-to-noise ratio of 5). Intra-day and inter-day accuracies were 91.1-92.8 and 91.7-95.5%, respectively with corresponding precisions as relative standard deviation of <5%. Incubation of l-SeMet with gut content suspensions from different parts of the rat intestine showed that l-SeMet metabolism occurs mainly in the caecum.
Biomedical Chromatography 06/2009; 23(11):1169-74. · 1.97 Impact Factor
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ABSTRACT: Agmatine is a metabolite of L-arginine by arginine decarboxylase. Recent evidence suggests that it exists in mammalian brain and is a novel neurotransmitter. The present study measured agmatine levels in several memory-associated brain structures in aged (24-month-old), middle-aged (12-month-old), and young (4-month-old) male Sprague Dawley rats using liquid chromatography/mass spectrometry. Agmatine levels were significantly decreased in the CA1, but increased in the CA2/3 and dentate gyrus, subregions of the hippocampus in aged and middle-aged rats relative to the young adults. In the prefrontal cortex, a dramatic decrease in agmatine level was found in aged rats as compared with middle-aged and young rats. There were significantly increased levels of agmatine in the entorhinal and perirhinal cortices in aged relative to middle-aged and young rats. In the postrhinal and temporal cortices, agmatine levels were significantly increased in aged and middle-aged rats as compared with young adults. The present findings, for the first time, demonstrate age-related changes in agmatine levels in memory-associated brain structures and raise a novel issue of the potential involvement of agmatine in the aging process.
Hippocampus 06/2008; 18(9):853-6. · 5.18 Impact Factor
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ABSTRACT: Miscibility of 17beta-estradiol and Eudragit RS in solid dispersions was determined by modulated temperature differential scanning calorimetry (MTDSC). A reduction of the 17beta-estradiol melting point in Eudragit RS solid dispersions was observed by MTDSC using heating program I in which the maximum temperature in the first heating run was lower than the 17beta-estradiol melting point. The melting point depression of 17beta-estradiol in solid dispersions as a function of composition could be explained by the Nishi-Wang equation indicating an interaction between 17beta-estradiol and Eudragit RS in the system. A variation of glass transition temperature (T(g)) of 17beta-estradiol in Eudragit RS solid dispersion was observed by MTDSC using heating program II in which the maximum temperature in the first heating run reached the 17beta-estradiol melting point. In the second heating run of heating program II, 17beta-estradiol was in an amorphous form blended with Eudragit RS. The variation in T(g) of amorphous 17beta-estradiol blended with Eudragit RS could be explained by the Kwei equation, a modified version of the Gordon-Taylor equation. The parameter estimates from the Kwei equation were consistent with an interaction between 17beta-estradiol and Eudragit RS, which was due to inter-associated hydrogen bonding as deduced from the FTIR spectra of the blends.
Journal of Pharmaceutical Sciences 04/2008; 97(11):4879-88. · 3.06 Impact Factor
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08/2007;
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ABSTRACT: Mitoquinone (MitoQ(10) mesylate) is a mitochondria-targeted antioxidant formulated for oral administration in the treatment of neurodegenerative diseases. We have investigated the absorption and metabolism of MitoQ(10) in Caco-2 cell monolayers. The intracellular accumulation of MitoQ(10) was 18-41% of the total amount of MitoQ(10) added. Some of the intracellular MitoQ(10) was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Transport of MitoQ(10) was polarized with the apparent permeability (P(app)) from basolateral (BL) to apical (AP) (P(appBL-->AP)) being >2.5-fold the P(app) from apical to basolateral (P(appAP-->BL)). In the presence of 4% bovine serum albumin on the basolateral side, the P(appAP-->BL) value increased 7-fold compared with control. The P(appBL-->AP) value decreased by 26, 31 and 61% in the presence of verapamil 100 microM, ciclosporin 10 and 30 microM, respectively, whereas the P(appAP-->BL) value increased 71% in the presence of ciclosporin 30 microM. Apical efflux of mitoquinol sulfate and mitoquinol glucuronide conjugates was significantly decreased by ciclosporin 30 microM and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 microM, respectively. These results suggested that the bioavailability of MitoQ(10) may be limited by intracellular metabolism and the action of P-glycoprotein and BCRP. However, the dramatic increase in absorptive P(app) in the presence of bovine serum albumin on the receiver side suggests these barrier functions may be less significant in-vivo.
Journal of Pharmacy and Pharmacology 04/2007; 59(4):503-11. · 2.17 Impact Factor
