Formulation study of topically applied O/W lotion containing vitamin D3 derivative, focusing on skin permeability of the drug

Permeation of 22-oxacalcitriol-1α, 25-dihydroxyvitamin D(3) (OCT) through excited hairless mouse skin was determined after application of OCT as solutions and O/W lotions consisted of different polarities of solvents: medium-chain fatty acid triglyceride (MCT), myristate isopropyl (IPM), 1,3-butylene glycol (1,3-BG), and propylene glycol (PG). OCT concentration in skin was also followed after applying these formulations. A two-layer diffusion model was composed to analyze dermatopharmacokinetic profiles of OCT for each vehicle. In the OCT solutions, skin permeation profile of OCT differed depending on solvent polarity. The O/W lotion with a high MCT content led to a low amount of OCT in skin. On the other hand, the O/W lotion with a high 1,3-BG content led to a high amount of OCT in skin. This dermatopharmacokinetic analysis indicated that addition of MCT to the formulation decreases the skin/vehicle partition coefficient of OCT and increases the diffusion coefficient of OCT in skin. However, the opposite effects on these two parameters were found in the case of 1,3-BG. Thus, skin permeability of OCT differed depending on the solvents used in the formulation. These results indicate that skin permeability of OCT is influenced by the physicochemical properties (i.e. polarity) of OCT, solvent, and skin. Our findings on the solvent effects of the skin permeability of OCT are thus useful for designing topical drug formulation, especially in aiming for bioequivalent dosage formulas.     

Environmental ecological modeling of human blood lead levels in East Asia

Environmental ecological modeling (EEM), which unifies models simulating transport of chemicals and exposure of humans to chemicals, was used to simulate long-term trends of female adult human blood lead levels (BLLs) and historical exposure to the atmospheric lead in four East Asian countries: Japan, Korea, China, and Vietnam. Anthropogenic lead emissions to the atmosphere in Vietnam were estimated from energy statistics to be 1931 t yr(-1). Calculated BLLs generally agreed with those observed in samples collected in these countries as the error factors were less than 2. The model results revealed that BLLs decreased significantly in Tokyo (by 58%) and Seoul (by 45%) in recent decades and confirmed the effects of efforts to reduce environmental lead in Japan and Korea. The model results also revealed that BLLs in Beijing did not decrease in this decade as much as in Tokyo and Seoul, despite the phasing out of leaded gasoline, and that the contribution from the atmospheric component was increasing (43% in 2009). Finally, we applied EEM to simulate BLLs of children in Hanoi. The probability of children having BLLs greater than 50 μg L(-1) was 7.5%, which was greater than those observed in developed countries.     

Identification and analysis of the plant peroxisomal targeting signal 1 receptor NtPEX5

Protein translocation into peroxisomes takes place via recognition of a peroxisomal targeting signal present at either the extreme C termini (PTS1) or N termini (PTS2) of matrix proteins. In mammals and yeast, the peroxisomal targeting signal receptor, Pex5p, recognizes the PTS1 consisting of -SKL or variants thereof. Although many plant peroxisomal matrix proteins are transported through the PTS1 pathway, little is known about the PTS1 receptor or any other peroxisome assembly protein from plants. We cloned tobacco (Nicotiana tabacum) cDNAs encoding Pex5p (NtPEX5) based on the protein's interaction with a PTS1-containing protein in the yeast two-hybrid system. Nucleotide sequence analysis revealed that the tobacco Pex5p contains seven tetratricopeptide repeats and that NtPEX5 shares greater sequence similarity with its homolog from humans than from yeast. Expression of NtPEX5 fusion proteins, consisting of the N-terminal part of yeast Pex5p and the C-terminal region of NtPEX5, in a Saccharomyces cerevisiae pex5 mutant restored protein translocation into peroxisomes. These experiments confirmed the identity of the tobacco protein as a PTS1 receptor and indicated that components of the peroxisomal translocation apparatus are conserved functionally. Two-hybrid assays showed that NtPEX5 interacts with a wide range of PTS1 variants that also interact with the human Pex5p. Interestingly, the C-terminal residues of some of these peptides deviated from the established plant PTS1 consensus sequence. We conclude that there are significant sequence and functional similarities between the plant and human Pex5ps.     

Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis

The presence of nitric oxide (NO) in the kidney has been implicated in the pathogenesis of human glomerulonephritis. However, the exact type of glomerular cells that express NO synthase (NOS) and the NOS isoform involved in the local production of NO has not been identified in the human diseased kidney. We examined the expression of three isoforms of NOS, inducible NOS (iNOS), endothelial NOS (eNOS) and brain NOS (bNOS) in the renal tissue of patients with IgA nephropathy (IgAN, N = 10), lupus nephritis (LN, N = 5), membranous nephropathy (MN, N = 5) and minimal change nephrotic syndrome (MCNS, N = 5). Sections were immunostained and the correlation between the expression of each NOS and the degree of glomerular injury in that section was also examined. Normal portions of surgically resected kidneys served as controls. eNOS was present in glomerular endothelial cells and endothelium of cortical vessels in the control and diseased kidneys. iNOS was localized in mesangial cells, glomerular epithelial cells and infiltrating cells in the diseased glomeruli, whereas immunostaining for iNOS was hardly detected in control kidneys. In addition, the expression pattern of eNOS in each glomerulus was the reverse of that of iNOS. In IgAN and LN, the extent of staining for eNOS correlated negatively with the degree of glomerular injury, while the extent of staining for iNOS correlated positively with the degree of glomerular injury in the same tissues. bNOS was not detected in normal or nephritic glomeruli. Our results indicate the presence of a NO pathway in human diseased kidney, and suggest that NO derived from eNOS and iNOS may be involved in the progression of renal diseases and that NO derived from each NOS may play an important role in different way in human inflamed glomeruli.     

Coronary sinus pacing initiates counterclockwise atrial flutter while pacing from the low lateral right atrium initiates clockwise atrial flutter. Analysis of episodes of direct initiation of atrial flutter

INTRODUCTION: Rapid atrial pacing in sinus rhythm may directly induce atrial flutter without provoking intervening atrial fibrillation, or initiate atrial flutter indirectly, by a conversion from an episode of transient atrial fibrillation provoked by rapid atrial pacing. The present study was performed to examine whether or not the direct induction of clockwise or counterclockwise atrial flutter was pacing-site (right or left atrium) dependent. METHODS AND RESULTS: We analyzed the mode of direct induction of atrial flutter by rapid atrial pacing. In 46 patients with a history of atrial flutter, rapid atrial pacing with 3 to 20 stimuli (cycle length = 500 - 170 ms) was performed in sinus rhythm to induce atrial flutter from 3 atrial sites, including the high right atrium, the low lateral right atrium, and the proximal coronary sinus, while recording multiple intracardiac electrograms of the atria. Direct induction of atrial flutter by rapid atrial pacing was a rare phenomenon and was documented only 22 times in 15 patients: 3, 11, and 8 times during stimulation, respectively, from the high right atrium, low lateral right atrium, and the proximal coronary sinus. Counterclockwise atrial flutter (12 times) was more frequently induced with stimulation from the proximal coronary sinus than from the low lateral right atrium (8 vs 1, P = .0001); clockwise atrial flutter (10 times) was induced exclusively from the low lateral right atrium (P = .0001 for low lateral right atrium vs proximal coronary sinus, P = .011 for low lateral right atrium vs high right atrium). CONCLUSIONS: Direct induction of either counterclockwise or clockwise atrial flutter was definitively pacing-site dependent; low lateral right atrial pacing induced clockwise, while proximal coronary sinus pacing induced counterclockwise atrial flutter. Anatomic correlation between the flutter circuit and the atrial pacing site may play an important role in the inducibility of counterclockwise or clockwise atrial flutter.     

Effect of amezinium metilsulfate on the finger skin vasoconstrictor response to cold stimulation and venoconstrictor response to noradrenaline

Orthostatic hypotension can be caused by an inadequate vasoconstrictor response. The effects of amezinium on vasoconstrictor response to sympathetic stimulation and to exogenous noradrenaline were investigated and compared with those of midodrine. In 8 healthy men, the following experiments were performed after a single oral dose of 10mg of amezinium, 2mg of midodrine or a placebo. First, finger-tip blood flow (FTBF) was recorded using a laser Doppler flowmeter before and during the contralateral hand cooling and a reduction ratio of FTBF was calculated as an index of the vasoconstrictor response. Second, dose-response curves to increasing doses (1-512ng/min) of noradrenaline infused locally to the dorsal hand vein were determined using a linear variable differential transformer. The reduction ratio of FTBF was significantly increased (p<0.05) by amezimium [placebo, 75.9 +/- 9.8(mean +/- SD)%; amezinium, 85.1 +/- 7.9%; midodrine, 78.1 +/- 9.3%]. The infusion rate of noradrenaline producing a half-maximum venoconstriction was significantly decreased (p<0.05) by amezinium (placebo, 40.6 +/- 33.9 ng/min; amezinium, 21.0 +/- 21.3 ng/min; midodrine, 33.2 +/- 31.5 ng/min). These findings indicate that amezinium increases the vasoconstrictor response to sympathetic stimulation and to noradrenaline in normal subjects, and this mechanism might contribute to the improvement by amezinium of the symptoms of orthostatic hypotension.     

An autopsy case of adult onset glycogen storage disease type Ia

A 3-week tour of the Far East was coordinated by Dr. Ronald DeWald, senior travelling fellow appointed by the Scoliosis Research Society. Three junior fellows appointed by the Education Committee of the Scoliosis Research Society accompanied him. The purpose of this fellowship was to develop a comaraderie and exchange ideas, thoughts, and experiences in the field of spinal deformity.     

Effect of losartan, an angiotensin II receptor antagonist, on response of cortisol and aldosterone to adrenocorticotrophic hormone

Many imidazole derivatives are shown to inhibit adrenal steroid biosynthesis. The present study was undertaken to examine an effect of another imidazole derivative, losartan (an angiotensin II receptor antagonist), on responses of cortisol and aldosterone to adrenocorticotrophic hormone (ACTH). Nine patients with essential hypertension were given placebo orally for 7 days and 50 mg of losartan for the next 9 days. Response of serum cortisol and plasma aldosterone to intramuscular ACTH injection were determined before and at the end of the treatment with losartan. Serum cortisol and plasma aldosterone significantly increased after ACTH injection in both periods of treatment (placebo and losartan). The increments in these parameters during treatment with losartan were not significantly different from those during treatment with placebo. These results suggest that the inhibitory effect of losartan on adrenal steroid biosynthesis is negligible.