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Lipophilic ion-pair complexes of 3-dl-alpha-tocopherylcarbonyl-1-n-alkyl-pyridinium-cromolyn (TAP-CG) were designed to enhance the percutaneous absorption of cromolyn (CG), and the effect of n-alkyl chainlength of the ion-pair complexes on the CG permeation through hairless mouse skin was evaluated in vitro. The permeation rates of CG were examined in isopropyl myristate (IPM) suspension using static Keshany-Chien type diffusion cells at 32 degrees C. The permeation parameters, steady-state flux, diffusion coefficient, partition coefficient between skin and IPM, and permeability coefficient were determined. Steady-state fluxes of CG increased linearly with the increasing n-alkyl chain-length of TAP-CG, and 3-dl-alpha-tocopherylcarbonyl-1-n-hexyl-pyridinium-cromolyn (THP-CG) produced the highest CG flux (0.62 +/- 0.11 nmol.cm-2.h-1), which was 14-fold greater than that of CG.Na in IPM suspension and more than 480-fold greater than that of CG.Na in aqueous solution due to increasing lipophilicity. In the case of TAP-CG with longer n-alkyl chainlength than THP-CG, however, the steady-state fluxes of CG decreased due to the high molecular weight and/or the high lipophilicity of the ion-pair complexes. It is suggested that lipophilic ion-pair complexes, especially THP-CG, are effective in absorption of cromoglicate through the skin. The results would be useful for studies on the role of each counterion in the lipophilic ion-pair complexes.

The raw material of tocopherol succinate was tested for the preparation of the "Tocopherol Succinate Reference Standard (Control 021)". Analytical data obtained were as follows: infrared spectrum, same as that of the Tocopherol Succinate Reference Standard (Control 981); specific absorbance, E1% 1 cm (286 nm) = 40.7; thin-layer chromatography, no impurities were detected until 50.0 micrograms; high-performance liquid chromatography (HPLC), four impurities were detected and the amount of tocopherol succinate was estimated to be 99.0%; loss on drying, 0.11%. Based on the above results, the raw material was authorized as the Japanese Pharmacopoeia Reference Standard (Control 021).

Purpose: To confirm the intraocular dynamics of 1% deuterium (D)-labeled alpha-tocopherol acetate (VEA) solution., Methods: The concentrations of D3-VEA and D3-alpha-tocopherol (VE) derived from D3-VEA in the aqueous humor and lens were measured after instilling 1% D3-VEA continuously into the cul-de-sac of rat eyes for one and three weeks. D3-VEA and D3-VE concentrations were determined by gas chromatograph/mass spectrometry., Results: D3-VEA and D3-VE concentrations in the aqueous humor after one and three weeks of continuous administration were 93.1 and 498.9, and 9.4 and 21.5 ng/ml, respectively. The concentrations in the lens were 15.0 and 6.1, and 9.8 and 4.8 ng/g, respectively., Conclusion: The penetration of VEA into the aqueous humor and lens by eyedrop application was confirmed.

alpha-Tocopherol (alpha-Toc), a lipophilic phenolic antioxidant that is localized mainly in the biomembrane, protects cells against oxidation-associated cytotoxicity by prevention of membrane lipid peroxidation, maintenance of the redox balance intracellular thiols and stabilization of the membrane structure. We investigated the age-related changes in redox dynamics of alpha-Toc in plasma and erythrocyte membrane of an elderly (66 weeks old) and young group (10 weeks old). Total, alpha-, beta + gamma-, delta-Toc and alpha-tocopherolquinone (alpha-TocQ) in plasma and erythrocyte membrane were determined by high-performance liquid chromatography (HPLC) with a series of multiple coulometric working electrodes (CWE). Rat venous blood sample was divided into plasma and erythrocyte layers by centrifugation, and then erythrocyte membrane sample was prepared according to the method of Dodge et al. under a stream of nitrogen. In plasma, total and alpha-Toc concentrations were increased, and beta + gamma-, delta-Toc and alpha-TocQ concentrations were decreased age-dependently. In the erythrocyte membrane, total, alpha-TocQ concentrations and three fractions of tocopherols decreased age-dependently. Also, a decrease in the alpha-TocQ/alpha-Toc ratio in erythrocyte membrane was observed in the elderly group. These findings suggest that the alpha-Toc uptake in erythrocyte membrane and utilization rate of alpha-Toc in erythrocyte membrane decline age-dependently. This decline may promote membrane lipid peroxidation. alpha-Toc redox dynamics in erythrocyte membrane were useful to investigate the pathophysiology of aging mechanisms related to oxidative stress.

The raw material of tocopherol succinate was tested for preparation of the "Tocopherol Succinate Reference Standard (Control 981)". The analytical data obtained were: infrared spectrum same as that of the Tocopherol Succinate Reference Standard (Control 8510); specific absorbance, E(1%)1 cm (286 nm) = 40.7; thin-layer chromatography, no impurities detected until 50.0 microgram; high-performance liquid chromatography (HPLC),three impurities detected and amount of tocopherol succinate estimated to be 98.2%, loss on drying, 0.19%, assay by HPLC, 101.7%. Based on the above results, the raw material was authorized as the Japanese Pharmacopoeia Reference Standard (Control 981).

The raw material of tocopherol acetate was examined for the preparation of the "Tocopherol Acetate Reference Standard (Control 971)". Analytical data obtained were as follows: infrared spectrum, the same as that of the Tocopherol Acetate Reference Standard (Control 941); specific absorbance, E1 cm 1% (284 nm) = 43.0; thin-layer chromatography, no impurities were detected until 50.0 micrograms of the loaded raw material; high-performance liquid chromatography (HPLC), one impurity was detected and the amount was estimated to be about 0.68%; assay by HPLC, 100.2%. Based on the above results, the raw material was authorized as the Tocopherol Acetate Reference Standard (Control 971) of National Institute of Health Sciences.

Temporary vessel occlusion (TO) for aneurysmal clipping is an effective technique to facilitate dissection between aneurysm and parent vessels, and to place a permanent clip at the aneurysmal neck precisely. However, several unsolved problems remain regarding the overall safety and risk resulting from this technique. The authors examined a series of patients in whom mannitol 500 ml, tocopherol acetate 500 mg, and phenytoin 500 mg were administered intravenously as ischemic protection during TO for the aneurysmal clipping. The study comprises a nonconcurrent retrospective analysis of 144 consecutive aneurysm clippings performed with the aid of intentional TO at the Hiroshima Prefectural Hospital from 1985 to 1995. To identify technical and patient-specific risk factors for perioperative stroke, factors studied included duration, location of the temporary clip application, number of occlusive episodes, patient sex, age, and preoperative neurological status, timing of operation, as well as postoperative, temporary or permanent, neurological deficits (ND) due to TO were used. Overall frequency of postoperative ND due to TO manifested clinically and radiologically were 9.0% and 9.7%, respectively. In both univariate and multivariate analysis there were no significant factors relevant to the ND. However, duration of the temporary occlusion time over 20 minutes was the factor most influential on the ND due to TO. Duration of the temporary occlusion time was shown to have no link with outcome. Based on our findings the authors conclude that temporary vessel occlusion within 20 minutes with anti-ischemic drugs is a relatively safe adjunct to aneurysmal surgery.

The myocardial protective effect of phosphate diester linkage of vitamin E and vitamin C (EPC-K1), a new hydroxyl radical scavenger, was investigated in an isolated working rat heart model. Initially, 0.25-3.0 micrograms/ml of EPC-K1 was given to non-ischemic heart to examine the effect of EPC-K1. Cardiac function did not change until 3.0 micrograms/ml EPC-K1 administration, however percent change of aortic flow prior to treatment (%AF) decreased significantly with 3.0 micrograms/ml and hearts were arrested with 5.0 micrograms/ml. Creatine kinase (CK) leakage did not change until 0.5 microgram/ml, however significantly increased over 1.0 microgram/ml. In the second protocol, EPC-K1 was applied before 15 min of ischemia at 37 degrees C. The %AF recovered significantly with 0.5 and 1.0 microgram/ml (81.2 +/- 3.1% and 75.2 +/- 4.1% vs. 57.2 +/- 3.1% in the control group), but hearts did not start to beat with 2.0 micrograms/ml. CK leakage was suppressed with 0.5 microgram/ml, although not significantly. In the third protocol, 0.5 microgram/ml of EPC-K1, which had the best protective effect before ischemia, was administered during reperfusion after 15 min of ischemia at 37 degrees C. The %AF (64.7 +/- 5.1%) was significantly higher than in the control group (57.2 +/- 3.1%), but was significantly less than in the pre-ischemic EPC-K1 group (81.2 +/- 3.0%). Thus, EPC-K1 had a myocardial protective effect at an appropriate dose, especially when given before ischemia. However, EPC-K1 showed myocardial toxicity at a high dose, therefore use of the correct dose will be important.

We report the effect of vitamin E succinate (VE succinate) on the proliferation of cultured bovine choroidal endothelial cells (BCECs). BCECs were incubated with a medium containing vitamin E (VE) or one of the VE derivatives gamma-tocopherol, VE phosphate, VE succinate, VE nicotinate, VE acetate, or trolox, at a concentration of 10 microM. The proliferation of BCECs was assessed by 3H-thymidine uptake and cell counting. Especially in VE and VE succinate, the proliferation assay was performed on BCECs at two different stages, that is, the proliferating stage and the quiescent stage. The effect of protein kinase C (PKC) stimulator phorbol ester (PMA) on the VE succinate-induced inhibition of BCEC proliferation was also examined. VE succinate was found to significantly inhibit BCEC proliferation at a concentration of 10 microM or greater both by 3H-thymidine uptake assay and by cell counting. This inhibitory effect was not noted in other VE derivatives. The inhibitory effect was the most prominent in the proliferating BCECs and co culture of PMA. VE succinate inhibits the proliferation of cultured BCECs and PKC is involved in this action at least in part.

The raw material of tocopherol acetate was tested for the preparation of the "Tocopherol Acetate Reference Standard (Control 941)". Analytical data obtained were as follows: infrared spectrum, the same as that of the Tocopherol Acetate Reference Standard (Control 919); specific absorbance, E1(1%)cm (284nm) = 44.5; thin-layer chromatography, no impurities were detected until 50.0 micrograms; high-performance liquid chromatography (HPLC), 2-3 impurities were detected and the amount was estimated to be about 1%; assay by HPLC, 100.8%. Based on the above results, the raw material was authorized as the Japanese Pharmacopoeia Reference Standard (Control 941).

A compound having structures of both vitamins E and C, L-ascorbic acid dl-alpha-tocopherol phosphoric acid diester potassium salt (EPC-K), which was proven to have both anti-oxidative3%!d moisturizing effects, has been formulated in the quasi drug hair growing products to mainly prevent dandruff and itching which may be one of the causes for the hair loss. Stabilities of EPC-K in 75% ethanolic solutions with various pHs (2-10) were examined extensively by storing them at 50 degrees C for 30 d and by sunlight exposure for 30 d. Decomposition of EPC-K was only observed under pH 2 at a level of 50% and under sunlight exposure at 25% level. A main decomposition product was identified as tocopheryl phosphate (EP), suggesting that a decomposition route was through hydrolysis. EPC-K was found to decompose by as much as 20% under 30 d storage at 50 degrees C when the concentration of the aqueous ethanolic solution was 0-30%. 1H, 13C and 31P-NMR studies in addition to a micelle formation test using pyrene fluorescent probe revealed that EPC-K formed a micelle at such low concentration of ethanol, which was assumed to be a cause for unstableness of EPC-K in that range. Hydrolytic decomposition of EPC-K was found by the reaction rate study to be a pseudo first order reaction with activation energy of 16.98 kcal/mol.

Tocopherol succinate was tested for the preparation of "Tocopherol Succinate Reference Standard (Control 881)". Analytical data obtained were as follows: infrared spectrum, same as Tocopherol Succinate Reference Standard (Control 851); absorbance, E1cm1% (286 nm) = 40.5; thin-layer chromatography, contaminants were not detected until 50 micrograms; high-performance liquid chromatography, three contaminants were detected; loss on drying, 0.09%; assay, 100.0%. On the basis of the above results, this material was authorized as the Japanese Pharmacopoeia Standard (Control 881).

The present study was performed in order to determine protective effect of dl-alpha-tocopheryl nictonate (EN) and dl-alpha-tocopheryl acetate (EA) on pulmonary edema induced by epinephrine (Epi) in mice. The tocopheryl esters were orally administered once a day for 10 days. Epi was then infused to induce pulmonary edema 3 hr after the final dosing. One or three min infusion of 0.01% Epi at a rate of 0.1 ml/min provoked toxic syndromes as pilorection, exophthalmos and salivation. Some animals died of respiratory failure. The lung weight either wet or dry increased after the EPi infusion and diffuse hemorrhage into alveoles was microscopically recognized in untreated animals. However, these findings were of lesser degree in animals receiving NE (20, 50 and 100 mg/kg/day) and Ea (corresponding doses with EN in molecular weight basis). When comparing the effect of EN with that of EA on the increase of lung weight and death from the Epi infusion, EN was more protective than EA. Although the mechanism of protecting action of these tocopheryl esters remains obscure, the interpretation is that these compounds did not affect the pressor response to Epi.

Tocopherol acetate was tested for the preparation of "Tocopherol Acetate Reference Standard (Control 881)". Analytical data obtained were as follows: infrared spectrum, same as Tocopherol Acetate Reference Standard (Control 851); absorbance, E1%1cm (284 nm) = 43.7; thin-layer chromatography, contaminants were not detected; high-performance liquid chromatography, one contaminant was detected; assay, 100.0%. On the basis of those results, this material was authorized as the Japanese Pharmacopoeia Standard (Control 881).

Antihypertensive action of TF-80, an alpha-tocopheryl ester of fusaric acid (FA), was studied in normotensive and hypertensive rats. Oral doses of TF-80 up to 100 mg/kg did not affect systolic blood pressure in Wistar rats, whereas 50 and 100 mg/kg doses produced a significant reduction in systolic blood pressure in both spontaneously hypertensive rats (SHR) and DOCA-salt hypertensive rats (DSR) without significant changes in heart rate. Although maximal reduction in systolic blood pressure at single oral dosing of TF-80 (50, 100 mg/kg) and FA (15, 30 mg/kg) was approximately the same extent, respectively, the antihypertensive action of TF-80 was longer-lasting than that of FA. TF-80 at a chronic administration of 1 to 100 mg/kg/day for 6-9 weeks was preventive to the generation of hypertension in young SHR and DSR, but FA did not prevent the generation of hypertension. Hypotensive doses of TF-80 did not interfere in the rise in blood pressure produced by vasoactive substances such as norepinephrine, prostaglandin F2 alpha and angiotensin II in SHR, and it also failed to inhibit plasma renin. TF-80 was also found not to have a diuretic effect. These results show that TF-80 has a mild and long-lasting antihypertensive action that is different from FA. However, the antihypertensive mechanism of TF-80 remains to be solved.