Calculation of skin permeability coefficient for ionized and unionized species of indomethacin.

The contribution of ionized and unionized species to the overall permeation of weak electrolytes through the skin was investigated to determine the effect of pH in the vehicle on the permeability of indomethacin (IDM), as a model drug, through hairless rat skin. The permeability of IDM through polydimethylsiloxane (silicone) and poly(2-hydroxyethyl methacrylate) (pHEMA) membranes which may reflect lipid and aqueous pathway, respectively, was also measured for comparison. As the pH in the vehicle increased, there was an exponential increase in the skin permeation rate of IDM. The permeation rate of IDM through the silicone membrane was constant independent of pH, whereas that through the pHEMA membrane increased with increasing pH, similar to the skin permeation. The permeability coefficients of ionized and unionized species through the skin estimated using the skin permeation rates and solubilities of IDM at various pHs were 1.50 x 10(-7) and 2.79 x 10(-5) cm/s, respectively. These results indicated that the permeation of ionized species greatly contributed to the total permeation of IDM at higher pH, and that the total permeation rate of IDM was determined by the permeation of unionized species at lower pH. These contributions depend on the pH and pKa values and the ratio of permeability coefficient of each species. It was also confirmed that the skin has at least two kinds of permeation pathways and these two species permeate through a different pathway.     

Time decay of solutions to the cauchy problem for time-dependent Schrödinger-Hartree equations

We consider the time-dependent Schrödinger-Hartree equation (1) $$iu_t + \Delta u = \left( {\frac{1}{r}*|u|^2 } \right)u + \lambda \frac{u}{r},(t, x) \in \mathbb{R} \times \mathbb{R}^3 ,$$ (2) $$u(0,x) = \phi (x) \in \Sigma ^{2,2} ,x \in \mathbb{R}^3 ,$$ where λ≧0 and \(\Sigma ^{2,2} = \{ g \in L^2 ;\parallel g\parallel _{\Sigma ^{2,2} }^2 = \sum\limits_{|a| \leqq 2} {\parallel D^a g\parallel _2^2 + \sum\limits_{|\beta | \leqq 2} {\parallel x^\beta g\parallel _2^2< \infty } } \} \) . We show that there exists a unique global solutionu of (1) and (2) such that $$u \in C(\mathbb{R};H^{1,2} ) \cap L^\infty (\mathbb{R};H^{2,2} ) \cap L_{loc}^\infty (\mathbb{R};\Sigma ^{2,2} )$$ with $$u \in L^\infty (\mathbb{R};L^2 ).$$ Furthermore, we show thatu has the following estimates: $$\parallel u(t)\parallel _{2,2} \leqq C,a.c. t \in \mathbb{R},$$ and $$\parallel u(t)\parallel _\infty \leqq C(1 + |t|)^{ - 1/2} ,a.e. t \in \mathbb{R}.$$      

Stereoselective nucleophilic addition reactions to nitro sugars

Nucleophile(s) almost exclusively added from the equatorial side of 2-nitro-β-$\text{D}$-2-enopyranoside and the axial side of 2-nitro-$\text{D}$-$\text{ribo}$-1-enitol. On the other hand, methoxide and $\text{tert}$-butyl peroxide ions approached from the equatorial side of 2-nitro-α-$\text{D}$-2-enopyranoside, whereas methanol and hydrogen peroxide ion from the axial side.     

Amphotericin B covalent dimers forming sterol-dependent ion-permeable membrane channels

Polyenemacrolides such as amphotericin B (AmB) were thought to assemble together and form an ion channel across plasma membranes. Their antimicrobial activity has been accounted for by this assemblage, whose stability and activity are dependent on sterol constituents of lipid bilayer membranes. The structure of this channel-like assemblage formed in biomembranes has been a target of extensive investigations for a long time. For the first step to this goal, we prepared several AmB dimers with various linkers and tested for their channel-forming activity. Among these, AmB dimers that bore an aminoalkyl-dicarboxylate tether covalently linked between amino groups of AmB showed potent hemolytic activity. Furthermore, K+ influx actions monitored by measuring the pH of the liposome lumen by 31P NMR revealed that the dimers formed the molecular assemblage similar to that of AmB in phospholipid membrane. Judging from changes in 31P NMR spectra, the dimers appeared to induce "all-or-none"-type ion flux across the liposome membrane in the presence of ergosterol, which suggested that the ion channel formed by ergosterol/dimer is similar to that of AmB. With these data in hand, we are now trying to elucidate the structure of the ion-channel complex by making the labeled conjugates of AmB for NMR measurements.     

Studies on polyyne polymers containing transition metals in the main chain. VII. Synthesis and characterization of palladium-polyyne polymers

Metal-polyyne polymers consisting of palladium and conjugated acetylenic systems, where P_D and R represent the —Pd(PBu₃)₂—moiety and alkyl groups, respectively, were prepared by polycondensation between palladium chlorides and α,ω-diethynyl compounds in amines using a catalytic amount of cuprous iodide. The molecular weights of the polymers formed were greatly affected by the basicity of the amines and the addition of free phosphines to the polymerization system. Under the optimum conditions, i.e., in the presence of CuI and PBu₃ (in molar ratio 1/4) in piperidine at room temperature, polymer Ia (R¹ = R² = H) having M?_w = 29,000 was obtained.     

Effect of sucrose on the structure of a cubic phase formed from a monoolein/water mixture

The effect of sucrose on the structure of molecular assemblies formed in an MO/H2O mixture has been studied using a small-angle X-ray scattering method. It was found that the phase transition Ia3d --> Pn3m --> H(II) occurs with increased sucrose concentration in the mixture with the composition 70 wt% MO at 20 degrees C. This structural change induced by sucrose addition would be ascribed to a cosmotropic property of sucrose, which leads to the dehydration of the MO head group and hence causes a decrease in the effective area occupied by the MO molecule at the polar/apolar interface, which facilitates the formation of molecular assemblies with a high curvature for the reversed liquid-crystal mesophase.     

Structures and ligand exchange of N-confused porphyrin dimer complexes with group 12 metals

N-confused 5,20-diphenylporphyrin (NCDPP, 1) formed 2:2 dimer complexes with group 12 metals both in the solid state and in solution. X-ray single-crystal analyses of the Zn(II) and Cd(II) complexes (7, 8) revealed that each metal ion is coordinated with three inner core nitrogens and a peripheral nitrogen of the other NCDPP in the pair. In the (1)H NMR spectra of 7, 8, and the Hg(II) complex (9), the outer alpha-H signals of the confused pyrrole ring appeared in the upfield region at 2.57, 3.44, and 3.60 ppm, respectively, due to the ring current effect by the coordinated porphyrins. In the case of the Cd(II) and Hg(II) complexes (8, 9), additional magnetic couplings with the metal nuclei of the partner rings were observed. The equilibrium constants (K) of the monomer exchange reaction at 25 degrees C were determined to be 2.5, 1.3, and 0.6 for the (Zn-Cd), (Cd-Hg), and (Zn-Hg) heterodimer complexes, respectively, from the (1)H NMR spectra of a solution containing two different dimers. Furthermore, a metal-transfer reaction from a Zn(II) NCP dimer complex to the free base porphyrin was demonstrated.     

Stimulatory effect of red light on starch accumulation in a marine green alga,chlamydomonas sp. strain MGA161

A marine green alga,Chlamydomonas sp. strain MGA161 was cultivated under illumination of red and white lights. The growth rate under red light illumination was almost the same as that in the basic conditions under white light illumination, but red light-grown cells accumulated almost twice as much starch as white light-grown cells. Although there was a slight decrease in carbonic anhydrase activity, red light-illuminated cells had almost 2.3 times the fructose-l,6-diphos-phatase activity of white light-illuminated cells. Red light might stimulate starch accumulation by increasing the amounts of enzymes related to carbon fixation through the phytochrome system. Cells grown under red light degraded 1.6 times as much starch and produced 1.7 times as much hydrogen and 1.6 times as much ethanol compared with cells grown under white light during 12 h of dark anaerobic fermentation.     

Stereochemistry of nucleophilic addition reactions 13 : Kinetically controlled nucleophilic addition reactions to methyl 4,6-0-benzylidene-2,3- dideoxy-2-nitro-β-D-erythro-hex-2-enopyranoside: an important role of a(1,3) strain

An improved synthesis of methyl 4,6-0-benzylidene-2,3-dideoxy-2-nitro-β-D-erythro-hex-2-enopyranoside and its reactions with various nucleophiles are described; all the nucleophiles were found to approach exclusively or predominantly from the equatorial side of the molecule, giving the β-D-glucopyranoside derivatives as the major or exclusive product. The stereochemical course of approach of a nucleophile observed in the present reactions and in the literature are discussed.     

Destabilization of whole skin lipid bio-liposomes induced by skin penetration enhancers and FT-IR/ATR (Fourier transform infrared/attenuated total reflection) analysis of stratum corneum lipids.

Whole skin lipid bio-liposomes (skin bio-liposomes), in size ranging from 2 to 8 microns, were prepared by a reverse phase evaporation technique using rat full thickness skin. Leakage of an encapsulated fluorescence probe, ANTS (delta-amino-1,3,6-naphthalene-trisulfonate), was measured by adding transdermal penetration enhancers (penetrants) into the medium where the skin bio-liposomes were present. Oleylamine induced a fast release of ANTS from the liposomes compared to lauryl-amine which showed a weak action. With these penetrants, the degree of ANTS release from the prepared bio-liposomes was found to correlate well with the results of frequency changes in the CH-asymmetric stretching band near 2920 cm-1 in the rat stratum corneum. The penetrant which caused relatively strong leakage of ANTS induced the significantly large shift of the peak toward the higher wave-numbers due to the perturbation in the structure of lipids of the stratum corneum. The skin bio-liposomes prepared from the rat full thickness skin could be useful in evaluating the penetrants.