Tissue distribution and targeting evaluation of TMP after oral administration of TMP-loaded microemulsion to mice

The aim of this study was to quantify the oral delivery systems of Tetramethylpyrazine Microemulsion (TMP ME) to heart, liver, spleen, lung, kidney and brain by comparing TMP level after oral administration at a dose of 100?mg kg^?1 with those of TMP tablet suspension (TMP SWW). This study was taken in mice to develop a suitable analytical methodology in pharmacokinetics studies and to manipulate the tissue distribution and targeting evaluation. Drug concentrations in tissues were determined at different times post-mortem. An HPLC method for separation and quantification of TMP was developed and validated by studying mice tissues. Following oral administration, TMP concentrations in different tissues were constantly detected for quite a long time and finally differed significantly from each other. The AUC rank order 3 of ME group is AUC_liver?> AUC_brain?> AUC_lung?> AUC_spleen?> AUC_heart?> AUC_kidney, while the SWW group is AUC_liver?> AUC_lung?> AUC_spleen?> AUC_heart?> AUC_brain?> AUC_spleen. Especially, the AUC value in brain region (AUC_brain) of ME is 6.06-fold of SWW. The drug relative overall targeting efficiency (RTE) are calculated: heart (7.49%), liver (3.54%), spleen (12.60%), lung (6.02%), kidney (2.86%) and brain (12.51%). The results from ME directly showed obvious targeting transport to the brain. These results indicated that this new family of pharmaceutical carriers can be used for the solubilization and targeted delivery of poorly soluble drugs to various pathological sites in the body.     

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in vitro

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10?mg/kg, p.o. and naringenin (25, 50 and 100?mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the C_max and increased the AUC_total of felodipine in dose-dependent manner. The C_max of felodipine was increased from 173.25?±?14.65 to 275.61?±?44.62 and 223.26?±?26.35 to 561.32?±?62.53?ng/mL in SDS and MDS, respectively, at the dose of naringenin 100?mg/kg. The AUC_total of felodipine was significantly (p?max and AUC of felodipine is due to P-gp and CYP3A4 inhibition.     

Penetration enhancing effects of selected natural oils utilized in topical dosage forms

Abstract

Context: Various natural products, including oils, have been utilized as penetration enhancers due to their “safety profiles”. These oils contain fatty acids promoting skin permeability through lipid fluidization within the stratum corneum; and might therefore be able to effectively enhance transdermal drug delivery.

Objective: We investigated possible penetration enhancing properties of selected oils, utilizing flurbiprofen as marker compound in emulgel formulations. The formulations were compared to a liquid paraffin emulgel and a hydrogel to establish any significant penetration enhancing effects.

Methods: Gas chromatographic analysis of the natural oils was performed at ambient temperature to determine the fatty acid composition in each selected natural oils. Franz cell diffusion studies and tape stripping methods were employed to study delivery of the marker into, and through the skin.

Results: The following rank order for the emulgel flux-values was obtained: Hydrogel >>>> olive oil >> liquid paraffin >> coconut oil > grape seed oil >> Avocado oil ≥ Crocodile oil >> Emu oil.

Discussion: Results suggested that oils containing predominantly mono-unsaturated oleic acid, on average increased the flux of the marker to a larger extent than oils containing an almost even mixture of both mono- and poly-unsaturated fatty acids. Oils comprising saturated fatty acids (SFAs) with alkyl chains between C₁₂ and C₁₄, increased the marker flux to a higher extent than oils containing C₁₆–C₁₈ SFAs. Effects observed for branched fatty acids, however, did not vary significantly from effects for unbranched fatty acids with the same carbon chain length.

Conclusion: Natural oils possess penetration enhancing effects.     

Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C

Magnolol (MAG; 5,5′-diallyl-2,2′-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM. The relative contribution of phase I enzymes including CYP to the metabolism of MAG was comparable to that of uridine diphosphate glucuronosyltransferase (UGT) in RLM. Moreover, MAG potently inhibited the metabolic activity of CYP1A (IC₅₀ of 1.62?μM) and 2C (IC₅₀ of 5.56?μM), while weakly CYP3A (IC₅₀ of 35.0?μM) in HLM and RLM. By the construction of Dixon plot, the inhibition type of MAG on CYP activity in RLM was determined as follows: uncompetitive inhibitor for CYP1A (K_i of 1.09–12.0?μM); competitive inhibitor for CYP2C (K_i of 10.0–15.2?μM) and 3A (K_i of 93.7–183?μM). Based on the comparison of the current IC₅₀ and K_i values with a previously reported liver concentration (about 13?μM) of MAG after its seven times oral administration at a dose of 50?mg/kg in rats, it is suggested that MAG could show significant inhibition of CYP1A and 2C, but not CYP3A, in the in vivo rat system. These results could lead to further studies in clinically significant metabolism-mediated MAG–drug interactions.     

Electronic structure and electrical transport characteristics of C60, 2C60 and 4C60 fullerene molecules

The extended Hückel method and the Green’s function method were used to calculate the electronic structure and electrical transport of Au electrode-C₆₀, 2C₆₀ or 4C₆₀ fullerene-Au electrode systems. Furthermore, their electronic structure and electrical transport characteristics were compared and analyzed. The results show that (i) owing to the contact with the Au electrodes, the C₆₀, 2C₆₀ and 4C₆₀ molecules change in their electronic structures significantly, and their energy gaps between LUMO and HOMO are narrow; (ii) the bonding between C₆₀, 2C₆₀ or 4C₆₀ fullerene and Au electrodes is partially covalent and partially electrovalent; and (iii) the conductance of the three fullerenes conforms to the order of C₆₀ > 2C₆₀ > 4C₆₀. Translated from Journal of Materials Science and Engineering, 2006, 24(1): 53–56 [译自: 材料科学与工程学报]     

Aqueous fullerene C60 solution suppresses herpes simplex virus and cytomegalovirus infections

Abstract

Fullerene C₆₀ is known as a promising therapeutic agent due to its antioxidant, anti-inflammatory and other properties, along with the lack of noticeable toxicity. In this article, we describe antiviral properties of aqueous fullerene C₆₀ dispersion (ndC₆₀) produced by biocompatible diafiltration technology and C₆₀ amino derivatives against Herpes simplex virus type 1 (HSV-1) and Human cytomegalovirus (HCMV) infections. Their activity in vitro was evaluated by a plaque reduction assay using Vero and HF cells in pre- and post-treatment modes. Therapeutic efficacy of dnC₆₀ and C₆₀ derivatives was studied in DBA mice using cutaneous model of HSV-1 infection. Data obtained indicated low cytotoxicity of all used compounds for both cell lines (CC₅₀ > 1?mg/ml). The antiviral activity of dnC₆₀ in most tests exceeded the activity of both C₆₀ amino adducts and acyclovir (ACV), and it demonstrated significant therapeutic effect against HSV-1 skin infection in mice.     

Matrix-Product Codes over ? q

Codes C ₁ ,…,C _M of length n over ? _q and an M × N matrix A over ? _q define a matrix-product code C = [C ₁ …C _M ] ·A consisting of all matrix products [c ₁ … c _M ] ·A. This generalizes the (u|u+v)-, (u+v+w|2u+v|u)-, (a+x|b+x|a+b+x)-, (u+v|u-v)- etc. constructions. We study matrix-product codes using Linear Algebra. This provides a basis for a unified analysis of |C|, d(C), the minimum Hamming distance of C, and C ^⊥. It also reveals an interesting connection with MDS codes. We determine |C| when A is non-singular. To underbound d(C), we need A to be `non-singular by columns (NSC)'. We investigate NSC matrices. We show that Generalized Reed-Muller codes are iterative NSC matrix-product codes, generalizing the construction of Reed-Muller codes, as are the ternary `Main Sequence codes'. We obtain a simpler proof of the minimum Hamming distance of such families of codes. If A is square and NSC, C ^⊥ can be described using C ₁ ^⊥, …,C _M ^⊥ and a transformation of A. This yields d(C ^⊥). Finally we show that an NSC matrix-product code is a generalized concatenated code. Received: July 20, 1999; revised version: August 27, 2001     

Comparative Investigation of Elastic Diffuse Neutron Scattering in C60 Powder

Abstract

C₆₀ powder samples of varying impurity content have been investigated by neutron scattering techniques. For Q > 2.5 Å^?1 (Q = transferred momentum) strong elastic diffuse scattering is found below T_c ~ 260 K providing evidence of static disorder in the low temperature phase. The elastic scattering increases on cooling from T_c to 150 K but remains virtually constant below this temperature. There is no marked dependence on the impurity level. For Q > 2.5 Å^?1 elastic diffuse scattering obeying a sin(QR)/(QR) law is observed both above and below the phase transition (R= radius of C₆₀ molecule). This scattering is nearly independent of temperature, however, depends strongly on the amount of impurities in the sample. In order to account for the unusually strong elastic diffuse scattering intensity model calculations have been performed which relate orientational disorder in C₆₀ to the elastic scattering observed in powder samples.     

Structure of KLa(WO4)2 with a novel isolated La polyhedron

The compound KLa(WO₄)₂ crystallizes in the tetragonal with space group 14(l)/a (C_4h ⁶) and cell parameters a=b=5.447 ?, c=12.080 ?, Z=1, V=358.41 ?³, D=3.121 g/cm³, F(000)=288, final R=0.079. R_w=0.082 for 208 observed reflections with I ≥ 3 σ > (I). The structure consists of WO₄ tetrahedron, KO₈ and LaO₈ polyhedrons. LaO₈ polyhedrons are isolated from each other, with La³⁺ ions joined by means of La-O-W-O-La. This structural characteristic will result in a weak interaction between active ions and a lower fluorescence concentration quenching effect. Electronic Publication     

ESR Studies on C60.OX and C60.HMTTEF

Abstract

The electron spin resonance (esr) of C₆₀.O_x and C₆₀.HMTTEF (hexamethylentetratellurafulvalene) has been investigated at 9.36 GHz as a function of temperature. T (298 T 4 K). C₆₀.O_x shows an esr absorption of equal ‘g’ value to that of C₆₀ exposed to O₂ and light but is more intense. The C₆₀ in its pure form is in a singlet state. The impurity sites introduced by O₂ produce the esr absorption. The Curie - Weiss plots of inverse esr absorption intensity versus temperature indicate an antiferromagnetic TH = 50 for air exposed C₆₀ and 90K for C₆₀O_x. From the esr intensity at room temperature, the calculated number of free spins (S = 1/2) is =1/3 per mole of C_60-O_x. In case of C₆₀.HMTTEF, there is a very weak esr absorption at room temperature suggesting that the room temperature form is diamagnetic with very small charge transfer between C₆₀ and HMTTEF. This conclusion is consistent with the structure and magnetic susceptibility of this cocrystal. As the temperature is lowered, the equilibrium: AD <=> A?^? + D?⁺ is displaced towards the formation of free radical species, A?^? and D?⁺.     

Properties of TixC1 − x films coated on molybdenum by magnetron sputtering

Properties of Ti_xC_{1 ? x} (0.3 ? x ? 0.6) films deposited onto molybdenum have been examined as functions of their chemical composition. Ti_xC_{1 ? x} films about 4–6 μm thick were deposited onto a sintered molybdenum substrate at 600 °C by magnetron sputtering. The near-stoichiometric Ti_xC_{1 ? x} (x ≈ 0.5) was found to be the most thermally stable. Titanium excess Ti_xC_{1 ? x} (x > 0.5) loses titanium by evaporation and changes its surface morphology above 1200 °C. However, excess titanium will improve the ductility of deposited films. Strong compressive stress was observed in carbon excess Ti_xC_{1 ? x} (x < 0.5). The carbon excess Ti_xC_{1 ? x} is more resistant against thermal evaporation than the stoichiometric compound. However, enhanced diffusion of molybdenum atoms into the carbon excess Ti_xC_{1 ? x} takes place, with the formation of Mo₂C. This Mo₂C formation nearly prohibits the use of carbon excess Ti_xC_{1 ? x} films coated on molybdenum as the first-wall material in fusion devices.     

Pharmacokinetic interaction study between flavanones (hesperetin,naringenin) and rasagiline mesylate in wistar rats

Cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp) play an important role in the oral bioavailability and first-pass-metabolism (FPM) of many drugs. Rasagiline is a selective, monoamine oxidase-B inhibitor and it undergoes significant FPM in the liver prior to excretion by CYP1A2. Hesperetin and naringenin are naturally occurring flavanones and are reported as modulators of CYP enzymes and P-gp. The objective of the present investigation was to evaluate the effect of hesperetin and naringenin on the pharmacokinetics (PK) of rasagiline in rats. Rats were treated orally with rasagiline (2?mg/kg) alone and co-administered with hesperetin and naringenin (12.5 and 25?mg/kg) for 15 consecutive days. Blood samples were collected from tail vein on the 1st day in a single dose PK study (SDS) and on 15th day in the multiple dose PK study (MDS). Hesperetin and naringenin co-administration significantly enhanced the area under the curve (AUC), maximum plasma concentration (C_max) and elimination half life (t_1/2) of rasagiline with a concomitant reduction in clearance (CL/F) in both SDS and MDS. Rasagiline concentrations were significantly increased when co-administered with hesperetin and naringenin in the brain. No significant difference was found in rasagiline transport from mucosal to serosal side in the presence of hesperetin and naringenin ex vivo (rat everted gut sacs used). Our findings suggested that hesperetin and naringenin enhanced the systemic exposure of rasagiline might be through the inhibition of CYP1A2 but not P-gp. Further studies are needed on CYP1A2 and P-gp over expressed cells to confirm this interaction at cellular level.     

Biodegradable nanoparticles for improved kidney bioavailability of rhein: preparation,characterization, plasma,and kidney pharmacokinetics

The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6?±?5.95?nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71?±?3.02%, and the drug loading was 1.56?±?0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUC_kidney/AUC_plasma?=?0.586?±?0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.     

Comparisons and analyses of the properties of laser-induced damage to SiO2 and ZnS

To compare the optical damage resistance ability of SiO₂ and ZnS, the processes of electrons reproduction of the two materials have been studied. The relationship of multiphoton ionization rate, avalanche ionization rate and the multiphoton parameter <?x?+?1?> with the intensity of the incident laser is calculated. The damage thresholds induced by the laser with different pulse widths are calculated too. In addition, the respectable role of the recombination and diffusion for an electron in the electronic proliferation processes is examined. Calculation results show that SiO₂ has a higher damage threshold while τ?<?1?ns, and ZnS has a higher damage threshold while τ?>?1?ns.     

Calorimetric study of the molecular mobility in a filled plasticized epoxide resin

Results are presented on the observed dependence of the thermophysical parameters C_p, , anda on temperature, filler content, and plasticizer concentration for ÉD-5 epoxide resin.Notation C_p specific heat capacity at constant pressure - thermal conductivity - a thermal diffusivity - C_p specific heat discontinuity - T_v vitrification point - density - u_so velocity of sound - l phonon mean free path - f frequency Translated from Inzhenerno-Fizicheskii Zhurnal, Vol. 20, No. 5, pp. 853–858, May, 1971.     

A Robust Molecular Porous Material for C2H2/CO2 Separation

A molecular porous material, MPM-2, comprised of cationic [Ni₂(AlF₆)(pzH)₈(H₂O)₂] and anionic [Ni₂Al₂F₁₁(pzH)₈(H₂O)₂] complexes that generate a charge-assisted hydrogen-bonded network with pcu topology is reported. The packing in MPM-2 is sustained by multiple interionic hydrogen bonding interactions that afford ultramicroporous channels between dense layers of anionic units. MPM-2 is found to exhibit excellent stability in water (>1 year). Unlike most hydrogen-bonded organic frameworks which typically show poor stability in organic solvents, MPM-2 exhibited excellent stability with respect to various organic solvents for at least two days. MPM-2 is found to be permanently porous with gas sorption isotherms at 298 K revealing a strong affinity for C₂H₂ over CO₂ thanks to a high (ΔQ_st)_AC [Q_st (C₂H₂) − Q_st (CO₂)] of 13.7 kJ mol⁻¹ at low coverage. Dynamic column breakthrough experiments on MPM-2 demonstrated the separation of C₂H₂ from a 1:1 C₂H₂/CO₂ mixture at 298 K with effluent CO₂ purity of 99.995% and C₂H₂ purity of >95% after temperature-programmed desorption. C-H···F interactions between C₂H₂ molecules and F atoms of AlF₆³⁻ are found to enable high selectivity toward C₂H₂, as determined by density functional theory simulations.     

Inclusion complexes of bendamustine with β-CD,HP-β-CD and Epi-β-CD: in-vitro and in-vivo evaluation

Abstract

The objective of the present work was to investigate the inclusion behavior of bendamustine (BM) with β-cyclodextrin and its hydrophilic derivatives (HP-β-CD and Epi-β-CD) for the enhancement of aqueous solubility, dissolution and bioavailability. The supramolecular binary complexes were prepared by three different methods, viz. physical mixture (PM), kneading (KND) and co-evaporation (COE). Phase-solubility study revealed the higher solubilizing and complexing ability of polymerized cyclodextrin (K_s?=?645?M^?1) than parent cyclodextrin (K_s?=?43?M^?1) and chemically derived cyclodextrin (K_s?=?100?M^?1). Meanwhile, the solubility of BM was significantly enhanced in phosphate buffer of pH 6.8, which was 24.5 folds greater compared with the phosphate buffer pH 4.5 and four times greater than aqueous medium. The dissolution efficiency was found to be highest for BM: Epi-β-CD complex (87%) compared to BM: HP-β-CD complex (84%), BM: β-CD (79%) and pure drug (20%). In-vivo pharmacokinetic study revealed that the bioavailability of BM was enhanced 2.55 times on complexation with Epi-β-CD using KND method. The t_1/2 of BM was increased from 34.2?min to approximately 75.7?min, allowing the absorption for longer time. The order of increase in solubility, dissolution and bioavailability of BM was KND?>?COE?>?PM?>?pure drug. Thus, the strategy of host–guest inclusion was very effective and could be successfully used in the development of suitable pharmaceutical dosage form with enhanced therapeutic activity.     

MOLECULAR AND CRYSTAL STRUCTURE OF THE ADDUCTS OF C60F18 WITH AROMATIC HYDROCARBONS

ABSTRACT

The solubility of C₆₀F₁₈ in aromatic hydrocarbons, benzene, toluene, and xylenes (0.48–1.23?mg/mL), and decomposition enthalpies for the 1?:?1 and 1?:?2 complexes (31–70?kJ/mole) have been determined. The C₆₀F₁₈ molecule has near perfect C_3v symmetry, and the x-ray single-crystal structures of the C₆₀F₁₈?L complexes (L=hexamethylbenzene, o-, m-, p-xylene, and bromobenzene) are compared in terms of 12 types of C?C and four types of C–F bonds. Analysis of the packing modes in the crystals shows an influence of the size and polarity of the aromatic hydrocarbon molecule.     

The real analytic Feigenbaum–Coullet–Tresser attractor in the disc

We consider a real analytic diffeomorphism ψ₀ on an n-dimensional disc 𝒟, n ≥ 2, exhibiting a Feigenbaum–Coullet–Tresser (FCT) attractor. We assume that in the C ^ω(𝒟) topology it is far from the standard FCT map φ₀ fixed by the double renormalization. We prove that ψ₀ persists along a codimension-one manifold ? ? C ^ω(𝒟), and that it is the bifurcating map along any one-parameter family in C ^ω(𝒟) transversal to ?, from diffeomorphisms exhibiting sinks to those which exhibit chaos, filling a gap in the usually accepted proof of this assertion. The main tool in the proofs is a theorem of functional analysis, which we state and prove in this article, characterizing the existence of codimension-one submanifolds in any abstract functional Banach space.