Enhanced rectal absorption and reduced local irritation of the anti-inflammatory drug ethyl 4-biphenylylacetate in rats by complexation with water-soluble beta-cyclodextrin derivatives and formulation as oleaginous suppository.

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between air-plethysmographic venous function and clinical severity in primary varicose veins.

AIM: The role of air plethysmography (APG) in the diagnosis of chronic venous insufficiency has not been well established. The purpose of this study was to elucidate the relationship between APG parameters and clinical severity in patients with chronic venous insufficiency. METHODS: Two hundred and ninety-four limbs in 154 patients with primary varicose veins were evaluated by APG. Limbs were categorized according to the clinical classification of chronic venous disease suggested by the Ad Hoc Committee on Reporting Standards in Venous Disease of the North American Chapter of the Society for Vascular Surgery and International Society for Cardiovascular Surgery (SVS/ ISCVS). RESULTS: The venous filling index (VFI) was significantly higher in classes 2, 3, 4, and 5+6 than in class 0 or 1, and did not differ among classes 2, 3, 4, 5+6. The ejection fraction did not differ significantly among the 6 classes, and the residual volume fraction was significantly higher in classes 2, 3, 5+6 than in class 0. CONCLUSIONS: APG is a reasonable method for distinguishing the presence or absence of chronic venous insufficiency, but it cannot discriminate the clinical severity. Among APG parameters, the VFI is the most useful diagnostic parameter in the evaluation of chronic venous insufficiency.     

In vivo detection by microscopic chromocystoscopy of concurrent urothelial atypia in superficial bladder cancer.

Microendoscopic observation of methylene blue-stained urothelial surfaces, so-called microscopic chromocystoscopy (MCC), was undertaken in 65 patients with superficial bladder cancer (Ta and T1) and its effectiveness in detecting concurrent urothelial dysplasia or carcinoma in situ was studied. A total of 166 biopsy samples were taken from 75 stained and 91 non-stained portions. Of 75 methylene blue-stained areas, 21 were judged to be abnormal (MCC-positive) by microscopic observation. Fourteen of these 21 MCC-positive areas (67%) were proven to be abnormal histologically, while 7 of 54 MCC-negative portions (13%) were histologically abnormal. Only 4 of 91 biopsies (4%) from non-stained mucosa were proven to have urothelial atypia. In per patient figures, 1 or more concurrent field changes were detected in 15 of 65 cases (23%). MCC contributed to the diagnosis in 10 of these 15 patients.     

Apolipoprotein levels in preeclamptic pregnancies]

Lipoprotein is known to increase during pregnancy but the factors responsible for the change have not been established. In addition, the lipoprotein concentration in preeclamptic pregnancy is significantly higher than in normal pregnancy. The apolipoproteins are an important determinant of metabolism and the structure of plasma lipoproteins. In normal pregnancies, non pregnancies and preeclamptic pregnancies the levels of blood apolipoproteins AI, AII, B and E were determined by TIA methods. (1) In normal pregnancies, the concentrations of apolipoproteins AI, AII, B and E were 182.6 +/- 20.9 mg/dl (n = 12, mean +/- S.D.), 33.3 +/- 5.7 mg/dl, 128.6 +/- 20.8 mg/dl, and 6.8 +/- 1.9 mg/dl, respectively. (2) In the pregnancies, the concentrations of apolipoproteins AI, AII, B and E were 135.6 +/- 9.3 mg/dl (n = 5), 30.8 +/- 1.9 mg/dl, 76.0 +/- 19.7 mg/dl, and 4.4 +/- 0.7 mg/dl, respectively. (3) In the preeclamptic pregnancy, the concentrations of apolipoproteins AI, AII, B and E were 181.0 +/- 27.6 mg/dl (n = 22), 33.2 +/- 4.8 mg/dl, 145.7 +/- 41.6 mg/dl and 5.8 +/- 1.4 mg/dl, respectively. The concentration of apolipoprotein B in preeclamptic pregnancy was significantly higher (p less than 0.001) and apolipoprotein E was significantly lower (p less than 0.01) than in normal pregnancies. These data suggest that the measurement of apolipoprotein is useful for the evaluation of preeclamptic pregnancy.     

Maintenance of Androgen-, Glucocorticoid- or Estrogen-responsive Growth in Shionogi Carcinoma 115 Subline Sustained in Castrated Mice with High Dose of Estrogen for 30 Generations (3 Years)

Shionogi carcinoma 115 (SC115), an androgen-dependent mouse mammary tumor, rapidly loses its androgen responsiveness after androgen withdrawal. The growth of this tumor can also be stimulated by high doses of estrogen or glucocorticoid. In the present study, the maintenance of hormone-responsive growth of SC115 tumors with a high dose of estrogen was examined in castrated male mice using an SCI 15 subline obtained by serial transplantations of SCI 15 tumors in estrogen-treated castrated mice for 3 years (30 generations) (subline E₂). Seed tumors from both SC115 and subline E₂ could rapidly grow in castrated mice given daily injections of testosterone propionate (TP), 17β-estradiol (E₂), or dexamethasone (Dex) (100 μg/mouse/day) but not in those given vehicle alone. Although SCI 15 and subline-E₂ tumors grown with TP or Dex showed temporary regression after steroid withdrawal, the tumors grown with E₂ did not show such temporary regression. The TP-, E₂-, or Dex-induced growth of subline-E₂ tumors was almost the same as that of the original SCI 15 tumors. However, responsiveness to androgen, estrogen or glucocorticoid of both tumors disappeared within one passage in steroid-depleted castrated mice. The present findings demonstrate that the loss of responsiveness to androgen as well as to high doses of estrogen or glucocorticoid of SCI 15 tumors can be prevented in castrated mice not only with androgen but also with high doses of estrogen.     

Disinhibition of somatosensory evoked potential recovery in alcoholics

The pathogenesis of cognitive impairment in alcoholics remains unclear. Previous studies suggested that diffuse white matter atrophy is associated with cognitive impairment in alcoholics. To elucidate this issue, the present study evaluated alcoholics with cognitive impairment using the somatosensory evoked potential (SEP) recovery method, which is suitable for detecting subtle dysfunction at the cortical level. Subjects comprised 12 alcoholics with mild cognitive impairment [Mild group: Mini Mental State Examination Score (MMSE), ≥24; mean, 27.9 ± 1.6], 12 alcoholics with moderate to severe cognitive impairment (Moderate group: MMSE score, < 24; mean, 21.0 ± 2.5) and 12 normal subjects (Control group). SEP was recorded from the hand sensory area contralateral to the median nerve stimulated at the wrist. Single-pulse or paired-pulse stimuli at various interstimulus intervals (10–300 ms) were administered. Recovery functions of N9 (a peripheral nerve component), N20, N20-P25 and P25-N33 (cortical components) were studied. N20 recovery curves of both alcoholic groups were less suppressive than those of Controls, and P25-N33 recovery curves of the Moderate group were more excitatory than those of the Mild or Control groups. A disinhibited recovery pattern of N20 indicates subcortical dysfunction, and a disinhibited pattern of P25-N33 would be induced by cortical dysfunction. Therefore, subcortical dysfunction indicated by an abnormal N20 recovery pattern may contribute to the early cognitive impairment of alcoholics, whilst the cortical dysfunction indicated by an abnormal P25-N33 recovery pattern may contribute to the later cognitive impairment of alcoholics.