Biomedical subjects

M Ikeda

Publications and source records attributed to M Ikeda.

At least 325 records · Page 18Linked to original sources

PubMed2000

Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3.

The activated vitamin D3 derivative 26,27-F6-1alpha,25(OH)2D3 (2a), its three A-ring diastereomers (2b, 2c, 2d), and 5,6-trans isomer (2e) were prepared. Two analogues (2b, 2c) of these isomers were synthesized by a palladium catalyzed coupling reaction using vinyl bromide 5 and enynes (6a, 6b), which were derived from readily commercially available 2S-(+)-glycidyl p-toluenesulfonate 7, as a common starting material. Competitive vitamin D receptor (VDR) binding affinities of these diastereomers of 2a were evaluated. Interestingly, the stereochemical effects at C-1,3 of 2a were considerably more moderate than those of 1alpha,25(OH)2D3 (1). In particular, isomerization at the 5,6-double bond of 2a only slightly reduced VDR affinity, whereas 5,6-trans-1alpha,25(OH)2D3 had a significantly lower binding affinity than 1.

Animals↗

PubMed2000

Peroxynitrite formation by diesel exhaust particles in alveolar cells: Links to pulmonary inflammation.

Diesel exhaust particles (DEP) are assumed to be a causal substance for pulmonary inflammation. As peroxynitrite is recently implicated in inflammation and cytotoxity, the hypothesis was tested that instillation of DEP induces formation of peroxynitrite in cells migrated in lung. Rats were intratracheally instilled with DEP suspension (2 mg/0.5 ml/kg) and killed 24 h later. Alveolar cells were collected by broncho-alveolar lavage. Population of alveolar cells increased more than twice by DEP exposure, mainly due to a large increase of neutrophils. Peroxynitrite formation (N(G)-nitro-L-arginine methylester and superoxide dismutase inhibitable chemiluminescence) was detected in alveolar cells from treated rats, and 12-O-tetradecanoylphorbol 13-acetate-stimulation enhanced it. In addition, DEP induced expression of inducible NO synthase mRNA in these cells. But peroxynitrite was not detectable in cells from control. These results indicate that DEP exposure results in peroxynitrite formation in migrated cells, which leads to pulmonary inflammation.

Journal Article↗

PubMed2000

Development of an industrially stable process for L-threonine fermentation by an L-methionine-auxotrophic mutant of Escherichia coli.

Escherichia coli KY10935, an L-methionine-auxotrophic mutant, has the ability to produce 100 g/l of L-threonine under limited conditions of DL-methionine, but occasionally exhibits overgrowth with a concomitant decrease in L-threonine production. We found that the growth of the producer depended not only on the availability of DL-methionine but also on that of iron, and that the dependence on iron caused abnormal fermentations in response to fluctuations in the iron concentration among lots of corn steep liquor, a cheap natural material used as the production medium. To overcome this problem, culture conditions were re-optimized with respect to the amounts of both dl-methionine and iron added in the medium so that the growth was controlled irrespective of the lot of corn steep liquor, to establish a stable industrial process with high productivity.

Journal Article↗

PubMed2000

Comparison of the water-holding capacity of wheat bran products prepared by wet and dry smashing methods in vitro and effect on the gastrointestinal retention time in rats in vivo.

Microfibril wheat bran (MFW) prepared by wet smashing of wheat bran using a colloidal mill has the advantages of being more palatable than other wheat bran and easier to apply to various foods. In this study, we investigated water-holding capacity (WHC) and physiological effects of a novel food material, MFW, focusing on shortening of the retention time of the gastrointestinal contents compared to those of dry smashing of wheat bran (DWB) prepared by conventional method, and wheat bran (WB), which is the raw materials. The mean particle size of MFW was 35 microns, and WHC was 5.1 g/g. In contrast, those of DWB were 61 microns and 3.0 g/g, respectively. Those of WB were 420 microns and 5.0 g/g, respectively. The WHC of MFW was 1.7 times greater than that of DWB and comparable to that of WB. The dietary fiber content in MFW, DWB, and WB were 73.5, 66.9 and 70.2%, respectively. Six-week-old Fisher rats were divided into three groups, and fed for 20 days with AIN-76 chow supplemented with MFW, DWB, or WB to a dietary fiber content of 10%. On days 14-16 of the experimental period, the mean retention time (MRT) of gastrointestinal content and fecal weight were measured using solid phase and liquid phase markers. On day 20 of the experimental period, animals were killed, and the water content, pH, composition of short chain fatty acids (SCFAs) in the cecal content and total amounts of SCFAs in the cecum were investigated. MRT in the MFW group was 15.2 +/- 0.8 h in the solid phase, which was significantly shorter than that in the DWB group (18.0 +/- 0.9 h) (p < 0.05), and comparable to that in the WB (15.5 +/- 2.4 h). MRT in the liquid phase was almost the same as that in the solid phase: 14.7 +/- 1.0, 18.4 +/- 0.8, and 16.0 +/- 2.5 h in the MFW, DWB, and WB groups, respectively. The fecal weight, pH, the concentration of SCFA in the cecal content and total amounts of SCFAs in the cecum did not differ among the groups, but the cecal water content was in the order of MFW > WB > DWB, showing a significant difference between each group (p < 0.05). The above finding suggested that MFW is a novel food material with a greater WHC and the ability of shortening the retention time of the gastrointestinal contents compared to DWB.

Animals↗

PubMed2000

Nutrient intake of working women in Bangkok, Thailand, as studied by total food duplicate method.

OBJECTIVES: To establish a general view of food habits in Thailand, and to make a quantitative assessment of rice dependency of Thai people. DESIGN: Cross-sectional study. SETTING: Community. SUBJECTS: 52 non-smoking and non-habitually drinking adult women in Bangkok participated in the study. METHODS: The participants offered 24 h food duplicates and peripheral blood samples, and underwent clinical examination including anthropometry. The duplicates were subjected to nutritional evaluation taking advantage of the Thai food composition tables (FCTs), and analyzed for eight nutrient elements by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: The participants took 1630 kcal from 55 g protein (63% from animal sources), 57 g lipid (mostly from vegetable oil), and 224 g carbohydrate (60% from rice) daily. Nutrient intake at lunch was as large as that at dinner. About a half of the women had insufficient energy intake (ie <80% RDA) whereas 4% had an excess (>120%). Protein intake was sufficient in most cases, whereas lipid intake was in excess in more than a half of the women. Ca, Fe, Mg, Zn and possibly P intakes were below the RDA values in many participants. FCT-based estimates agreed well with the ICP-MS measures in cases of Fe and Ca but tended to be greater than the measures by 50% with regard to P. CONCLUSIONS: Lunch as substantial as dinner for Thai urbanites. There was a marked dependency on rice as an energy source. Whereas protein intake is generally sufficient, the intake of Ca (and to a lesser extent Fe) was insufficient in a majority of the study participants. SPONSORSHIP: Dai-ichi Mutual Life Insurance, Japan; the Ministry of Health and Welfare, the government of Japan.

Adult↗

PubMed2000

Nutrient intake of adult women in Jilin Province, China, with special reference to urban-rural differences in nutrition in the Chinese continent.

OBJECTIVES: The objectives of this study were to investigate possible urban-rural differences in food intakes in Jilin province and in continental China as a whole, and to examine possible implications for nutritional status of urban and rural populations. DESIGN: Cross-sectional study. SETTING: Communities. SUBJECTS: In total, 499 adult women in six urban sites and four rural sites, 10 sites in total, including two sites in Jilin province. METHODS: A pair of surveys were conducted in September, 1999, in the provincial capital of Changchun and a farming village in Dehui county, both in Jilin province, in northeast China. Each of 50 adult women per survey site provided a 24 h duplicate food sample and a blood sample, and had an interview on health history including anthropometry and blood pressure measurement. Nutrient intakes were estimated from the food duplicates, using national food composition tables. Results from the two sites were supplemented with data from eight sites where surveys had been conducted following the same protocol, and the pooled material were subjected to analyses for possible urban-rural differences. RESULTS: The Jilin participants consumed daily, on average, about 1600 kcal energy, 44 g protein, and 60 g lipid with a lipid energy ratio (i.e. the ratio of lipid over total nutrients in terms of energy) of 33%. When nutrient intakes were compared between the urban (i.e. Changchun) and rural (Dehui) groups, urban women consumed more energy, protein (especially animal protein) and lipid than rural women. Similar examination of data from six urban and four rural sites, including the present two, showed that adult women in urban areas eat more animal protein and animal fat than their counterparts in villages, and suggested that the observation on urban rural difference in Jilin province can be extrapolated to a nationwide scale. CONCLUSIONS: Urban rural differences in nutrient intakes still persist in 1999 not only in Jilin but in other provinces, typically in the terms of intakes of animal-based foods.

Adult↗

PubMed2000

PAP-1, a novel target protein of phosphorylation by pim-1 kinase.

Protooncogene, pim-1, has been reported to be a predisposition for lymphomagenesis along with myc, and its protein product, Pim-1, has been shown to be a serine/threonine protein kinase, whose activity is involved in proliferation and differentiation of blood cells. The signal transduction pathways neither to nor from Pim-1, however, have been clarified. We have cloned a cDNA encoding a novel Pim-1 binding protein, PAP-1, comprising 213 amino acids with a basic amino-acid cluster near the C-terminus. PAP-1 was colocalized with Pim-1 in human HeLa cell nuclei. The in vitro binding assays using GST fusion proteins of the wild-type and various deletion mutants revealed that the whole molecule of Pim-1 is required for the binding activity to PAP-1 and that Pim-1 binds to the region from amino-acid numbers 1-147 of PAP-1, or to two segments in the region. The association of PAP-1 with Pim-1 was also shown in vivo in transfected cells. Furthermore, PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase.

Amino Acid Sequence↗

PubMed2000

Evaluation of gut motility in type II diabetes by the radiopaque marker method.

BACKGROUND: The clinical usefulness of the radiopaque marker method for detecting diabetic gastrointestinal motility disturbances, was evaluated by examining 21 type II diabetes subjects who did not have any neuropathic symptoms. METHODS: After administration of a Sitzmark capsule, markers were located using plain abdominal radiographs, and the transit time of the markers through seven areas of digestive tract was calculated by Arhan's methods. The plasma concentration of acetaminophen at 45 min after oral administration was measured to evaluate gastric emptying time. The coefficient of variation of R-R intervals on the electrocardiograms (CV(R-R)) was measured to evaluate parasympathetic autonomic function. RESULTS: In the diabetics, the average (+/- SD) transit time through upper digestive tracts was slightly but not significantly elongated compared with control subjects (14.4 +/- 8.3 vs 9.9 +/- 6.1 h). Significant elongation was observed in transit time through the lower digestive tracts or the whole gut (44.6 +/- 20.9 and 57.9 +/- 22.3 h, respectively) compared with control subjects (23.3 +/- 8.5 and 33.2 +/- 11.0 h). The transit time of the markers from stomach to small intestine was highly correlated (r = 0.693) with plasma concentration of acetaminophen. The transit time through either the whole colon (r = 0.564) or the whole gut (r = 0.630) was highly correlated with CV(R-R). CONCLUSIONS: These findings suggest that the radiopaque marker method is a useful tool for detecting the sections of the digestive tract responsible for gut motility disturbances. In type II diabetics with no neuropathic symptoms, the lower digestive tracts may deteriorate prior to the impairment of upper digestive tracts.

Acetaminophen↗

PubMed2000

Distribution of amyloid beta protein precursor in the Alzheimer's disease brain.

In order to clarify the distribution and pathological changes of the amyloid beta protein precursor (betaAPP), 10 Alzheimer's disease (AD) brains and seven normal control brains were examined by immunocytochemistry and in situ hybridization histochemistry. All betaAPP isoforms were distributed evenly in neuronal cell bodies and their axons and dendrites. The betaAPP-positive neuronal processes showed mesh-like networks. In AD brains, betaAPP-positive neurons and mesh-like networks were generally decreased in spite of some intensely labeled neurons. All betaAPP isoforms accumulated in neuronal processes, dystrophic neurites and senile plaques. In situ hybridization histochemistry confirmed that all isoforms of betaAPP were expressed in neurons in control brains. In AD brains, the betaAPP mRNA signal was generally decreased besides some intense signal neurons corresponding to immunostaining findings. Few astrocytes expressed betaAPP. Thus, uniform expression and distribution of betaAPP were disturbed in AD brains showing uneven decreases or increases of neuronal betaAPP expression in individual neurons and betaAPP accumulation in neurons, neuronal processes and abnormal structures including dystrophic neurites, senile plaques and neurofibrillary tangles.

Aged↗

PubMed2000

Renal carcinogenesis induced by ferric nitrilotriacetate in mice, and protection from it by Brazilian propolis and artepillin C.

The protective effect of Brazilian propolis and its extract Artepillin C against ferric nitrilotriacetate (Fe-NTA)-induced renal lipid peroxidation and carcinogenesis was studied in male ddY mice. Fe-NTA-induced renal lipid peroxidation leads to a high incidence of renal cell carcinoma (RCC) in mice. Administration of propolis by gastric intubation 2 h before or Artepillin C at either the same time, 2 h, or 5 h before the intraperitoneal injection of Fe-NTA (7 mg Fe/kg) effectively inhibited renal lipid peroxidation. This was evaluated from the measurement of renal thiobarbituric acid-reactive substances (TBARS) or histochemical findings of 4-hydroxy-2-nonenal (4-HNE)-modified proteins and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Repeated injection of Fe-NTA (10 mg Fe/kg per day, twice a week for a total of 16 times in 8 weeks) caused subacute nephrotoxicity as revealed by necrosis and pleomorphic large nuclear cells in the renal proximal tubules, and gave rise to RCC 12 months later. A protective effect from carcinogenicity was observed in mice given propolis or Artepillin C. Furthermore, the mice given Fe-NTA only developed multiple cysts composed of precancerous lesions with multilayered and proliferating large atypical cells. Mice treated with propolis and Artepillin C also had cysts, but these were dilated and composed of flat cells. These results suggest that propolis and Artepillin C prevent oxidative renal damage and the carcinogenesis induced by Fe-NTA in mice.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4(+) T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4(+) T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes. METHODS: Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity. RESULTS: The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18(+)CD68(+) macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. IL-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls. CONCLUSIONS: These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.

Cell Division↗

PubMed2000

Expression of mitochondrial thioredoxin-dependent antioxidant protein, SP-22, in normal human and inflammatory mouse placentae.

The aim of this study was to elucidate whether a novel mitochondrial antioxidant protein, SP-22, is localized in placenta and whether its expression is induced in placenta of lipopolysaccharide (LPS)-exposed mouse. Western blot analysis of normal human placenta indicated that the SP-22 protein was located in the mitochondrial fraction. Immunohistochemical analysis of SP-22 in normal placenta showed that immunoreactive SP-22 was distributed mostly in cytotrophoblastic cells but with almost no signal in syncytiotrophoblasts. The positive signals were also detected in the decidual cells and stromal cells in stem villi of normal placenta. We also examined LPS-mediated inflammatory placenta on day 13 of pregnancy at various time points after LPS injection (50 microg/kg, intraperitoneally). Western blot analysis indicated that LPS approximately quadrupled the expression of SP-22 in placenta of LPS-exposed mouse. When the SP-22 protein was localized immunohistochemically, the decidua and the diploid trophoblasts in the basal zone were intensively stained in placenta of LPS-exposed mouse compared to the control. The localization and inducible expression of SP-22 protein in placenta suggest a possible role in antioxidant system in mitochondria of normal and inflammatory placentae.

Animals↗

PubMed2000

Characteristics of collagen-induced Ca2+ mobilization in bovine platelets.

We characterized the collagen-induced increase in cytosolic Ca2+ ([Ca2+]i) of bovine platelets loaded with the Ca2+ indicator Fura-PE3/AM. Collagen (10 micrograms/ml)-induced increase in [Ca2+]i was only partially inhibited by aspirin, a cyclooxygenase inhibitor, or adenosine 3'-phosphate 5'-phosphosulfate (A3P5PS, a P2Y1 receptor antagonist), while in human platelets it was almost completely suppressed by aspirin. Collagen-induced increase in [Ca2+]i of bovine platelets was inhibited by U73122 (0.3-5 microM), a phospholipase C inhibitor. Collagen (10 micrograms/ml) increased production of inositol 1,4,5-trisphosphate, which was prevented by pretreatment with U73122 (5 microM). Collagen (10 micrograms/ml) accelerated Mn2+ entry, since the rate of Fura-PE3 quenching by Mn2+ was enhanced by 13-fold following stimulation with collagen. U73122 inhibited the acceleration of Mn2+ entry induced by collagen. PGE1 (2.5 microM) partially inhibited the collagen (50 micrograms/ml)-induced increase in [Ca2+]i in bovine platelets but not in human platelets. The data suggest that collagen-induced Ca2+ mobilization in bovine platelets is mediated by phospholipase C. The Ca2+ mobilization in bovine platelets is different from that in human ones as to the dependency on arachidonic acid metabolites and sensitivity to PGE1.

Adenosine Diphosphate↗

PubMed2000

Reversible dimerization of 20 kilodalton human growth hormone (hGH).

A noncovalent dimer of the 22 kilodalton human growth hormone (22 K-hGH) is known to have diminished somatogenic activity compared with monomeric 22 K-hGH. In the present study, we examined the biological activity and physicochemical behaviour of a noncovalent dimer of the 20 kilodalton human growth hormone (20 K-hGH), an isoform of 22 K-hGH. Analysis of the equilibrium between monomeric and associated forms revealed that the associated 20 K-hGH was present in the dimeric form in aqueous solution. The kinetics of dimerization in rat plasma followed the theory of dissociation-association equilibrium, and more than 99% of 20 K-hGH molecules existed as a monomer in the equilibrium state at the physiological hGH concentration. Analysis of the pharmacokinetics showed that the ratio of the administrated dimer in rat circulation decreased from 43% to less than 4% in 2 h. A preparation of noncovalent dimeric 20 K-hGH had essentially the same degree of biological potency as that of a monomer in both in vitro and in vivo bioassays. In conclusion, dimerization of 20 K-hGH is reversible both in vitro and in vivo and a noncovalent dimer can function as a pharmaceutically active component of a 20 K-hGH preparation, in contrast to a 22 K-hGH preparation.

Animals↗

PubMed2000

A novel bioassay based on human growth hormone (hGH) receptor mediated cell proliferation: measurement of 20K-hGH and its modified forms.

Previously we introduced the full-length hGH receptor (hGHR) into the mouse pro-B cell line, Ba/F3, and obtained stable transfectant (Ba/F3-hGHR), which could grow in response to 20K- and 22K-hGH in a dose-dependent manner(1). In the present study, we established a new bioassay system based on the proliferation of the Ba/F3-hGHR in combination with the eluted stain assay (ESTA). The Ba/F3-hGHR assay is completed in 18 h and requires only 10(-6)-fold amount of GH sample (1.8 ng) as compared with the rat weight gain assay. The validation study shows that the Ba/F3-hGHR assay is specific for hGH, precise (RSD = 1.1-19.7%) and ultrasensitive (lower limit of working range = 18.7 pg/mL). Four modified forms of recombinant 20K-hGH (oxidized, deamidated, des-Phe(1)and cleaved form) all of which are newly identified were measured by the Ba/F3-hGHR assay and the rat weight gain assay with our in-house recombinant 20K-hGH as standard. The oxidized and deamidated 20K-hGH were fully active, however the des-Phe(1)and cleaved 20K-hGH had significantly reduced activities in both assays. These findings suggest that the Ba/F3-hGHR assay is useful as an alternative to the rat weight gain assay.

Amino Acid Sequence↗

PubMed2000

Endothelial cell response to different mechanical forces.

PURPOSE: Endothelial cells (ECs) are subjected to the physical forces induced by blood flow. The aim of this study was to directly compare the EC signaling pathway in response to cyclic strain and shear stress in cultured bovine aortic ECs. MATERIALS AND METHODS: The ECs were seeded on flexible collagen I-coated silicone membranes to examine the effect of cyclic strain. The membranes were deformed with a 150-mm Hg vacuum at a rate of 60 cycle/min for up to 120 minutes. For a comparison of the effect of shear stress, ECs from the same batch as used in the strain experiments were seeded on collagen I-coated silicone sheets. The ECs were then subjected to 10 dyne/cm(2) shear with the use of a parallel flow chamber for up to 120 minutes. Activation of the mitogen- activated protein kinases was assessed by determining phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 with immunoblotting. RESULTS: ERK, JNK, and p38 were activated by both cyclic strain and shear stress. Both cyclic strain and shear stress activated JNK with a similar temporal pattern and magnitude and a peak at 30 minutes. However, shear stress induced a more robust and rapid activation of ERK and p38, compared with cyclic strain. CONCLUSIONS: Our results indicate that different mechanical forces induced differential activation of mitogen-activated protein kinases. This suggests that there may be different mechanoreceptors in ECs to detect the different forces or alternative coupling pathways from a single receptor.

Animals↗

PubMed2000

Function after early radial head resection for fracture: a retrospective evaluation of 15 patients followed for 3-18 years.

We reviewed the results of early radial head resection in 15 patients after fracture of the radial head or neck: 4 Mason's type II fractures and 11 Mason's type III fractures. The average age at operation was 41 years and the patients were reexamined after mean 10 (3-18) years. Only 5 patients had no pain and all patients had reduced elbow power, in several of them a substantial loss.

Adult↗

PubMed2000

The skin permeation mechanism of ketotifen: evaluation of permeation pathways and barrier components in the stratum corneum.

To evaluate the pathways and barrier components in the stratum corneum (SC) for the permeation of ketotifen, the effect of delipidization on the permeation and partition was examined under several donor pHs. Assuming that ionized ketotifen (KTH+) and un-ionized ketotifen (KT) contribute independently in both permeation and partition, the intrinsic permeability coefficients and SC/water partition coefficients of both species were estimated. Delipidization enlarged the permeability of KTH+ 100 times. This suggested that the lipid phase functions as the barrier against KTH+. KT has an intrinsic permeability 100 times larger than that of KTH+. Delipidization did not result in a significant change in permeability of KT. This suggested that the permeability of KT through the lipid phase is comparable to that through the aqueous phase in delipidized SC; that is, the lipid phase functions as a highly permeable pathway for KT. On the other hand, the permeability coefficient of KT through delipidized SC was 1/34 of that through the pure aqueous layer, which had a thickness equivalent to SC. Since this suggests that the permeability of KT through the proteinaceous phase is much lower than that through the aqueous phase, the proteinaceous phase can be assumed to function as a barrier against the permeation of KT. From these results, it is concluded that the predominant permeation pathway for KT is through the lipid phase. The SC/water partition coefficient of KT was cut in half by delipidization, but the value was still more than 100. These results show that the proteinaceous phase functions not only as the barrier, but also as the depot for KT. The knowledge obtained here will be useful for formulation design and for the selection of enhancers in a transdermal therapeutic system of ketotifen.

Algorithms↗