Ophthalmic Preservatives as Absorption Promoters for Ocular Drug Delivery

The effects of ophthalmic preservatives on the drug permeability through isolated ocular membranes of albino rabbits were investigated using a two-chamber glass diffusion cell. Tilisolol and fluorescein isothiocyanate (FITC)-dextrans (average molecular weights 4400 and 9400 Da; FD-4 and FD-10, respectively) were used as model penetrants of ophthalmic β-blockers and peptide drugs. Preservatives significantly enhanced the corneal penetration of not only tilisolol but also FITC-dextrans. Especially, benzalkonium chloride increased the corneal permeability of FD-4 and FD-10 by 28·8 and 37·1 times, respectively. These results indicate the usefulness of ophthalmic preservatives as absorption promoters for the ocular delivery of β-blockers and hydrophilic macromolecules. Preservatives also enhanced the conjunctival permeability of tilisolol, FD-4 and FD-10. The promoting effect of preservatives on the conjunctival drug penetration was smaller than that on the corneal one. Preservative increased the ratio of corneal to conjunctival permeability of tilisolol, FD-4 and FD-10. The different responses of corneal and conjunctival drug penetrations to ophthalmic preservatives may be useful to control the extent and pathway for the ocular and systemic absorptions of instilled drugs.     

NEUTRAL ENDOPEPTIDASE 3.4.24.11 INHIBITION POTENTIATES THE INHIBITORY EFFECTS OF TYPE-C NATRIURETIC PEPTIDE ON LEUKOTRIENE D4-INDUCED AIRWAY CHANGES

1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type-C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4 -induced airway microvascular leakage and bronchocon-striction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor. 2. Anaesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 μg/kg LTD₄ and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage. 3. Intravenous administration of CNP (100, 300 and 1000 μg/kg) significantly inhibited the LTD₄-induced microvascular leakage and bronchoconstriction in a dose-dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP. 4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.     

Reassessment of quantitative thallium-201 brain SPECT for miscellaneous brain tumors

In order to reassess the value of quantitative thallium-201 brain SPECT in the differentiation of miscellaneous brain tumors, we studied a total of 89 patients—35 pre-operative patients suspected of having a brain tumor and 54 post-operative patients with a brain tumor. We came to the conclusion that quantitative Tl-201 brain SPECT was very useful in discriminating cerebral radiation necrosis from recurrent tumor, estimating residual tumor burden, and detecting tumor regrowth earlier in postoperative patients. In preoperative patients, however, Tl-201 SPECT cannot be used effectively to differentiate glioma from other intracranial tumors, although intense uptake of Tl-201 may provide evidence of glioblastoma or a hypervascular lesion.     

Comparative analysis of CD80 and CD86 on human Langerhans cells: expression and function

Abstract Although both CD80 (B7–1) and CD86 (B7–2/B70) have been recently identified in cultured human Langerhans cells (LC), little is known of the role and regulatory properties of CD80 and CD86 on human LC. We present here the results of a study comparing the expression and function of CD80 and CD86 in human LC using the T-helper type-1 cytokines IL-2 and interferon γ (IFN)-γ, and the T-helper type-2 cytokines IL-10, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). Freshly isolated human LC expressed little CD80 and CD86 in vitro, but the expression of both molecules was rapidly induced during a 72-h incubation with cytokines and the expression of CD86 occurred much earlier and more strongly than that of CD80. The expression of both CD80 and CD86 was upregulated by GM-CSF and downregulated by IL-10, and the expression of CD86, but not that of CD80, was upregulated by both IL-4 and IFN-γ. Finally, pretreatment of LC with GM-CSF and IFN-γ, but not with IL-4, enhanced the alloreactive T-cell proliferation induced by the LC, and IL-10 pretreatment of LC decreased their capacity for alloreaction. These results indicate that the expression of both CD80 and CD86 on human LC may be regulated by these cytokines (IL-2, IL-4, GM-CSF, IFN-γ and IL-10) secreted from helper T cells infiltrating into the inflammatory microenvironment. Received: 4 December 1997     

GENERALIZED TUBERCULOSIS AFTER BCG VACCINATION –REPORT OF AN AUTOPSY CASE–

An autopsy case of generalized tuberculosis after BCG vaccination was reported. The patient, a boy BCG-vaccinated at the age of three, developed regional lymphadenitis, which was followed by subcutaneous abscesses in the chest wall. At the age of eleven, chest X-ray examination revealed an infiltrative shadow in the upper field. He died at thirteen years of age in poor condition with diarrhea and severe attacks of general convulsions. Autopsy disclosed generalized tuberculosis, especially in the skin, lymph nodes, lung, small intestine and brain. Microscopically, there was little tendency to develop tuberculous granulation tissue. Myriads of acid-fast bacilli were found in these ill-defined foci. The acid-fast bacilli were indistinguishable from BCG by bacteriological investigations. No definite causative factor could be traced. Complications induced by BCG vaccination were briefly discussed. ACTA PATH JAP. 19: 395˜407 1969.     

Growth factor-mediated interaction between tumor cells and stromal fibroblasts in an experimental model of human small-cell lung cancer

Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of beta-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.     

A polymorphism in the 5'-flanking region of the CYP2E1 gene and elevated lung adenocarcinoma risk in a Japanese population

Cytochrome P450 2E1 (CYP2E1) catalyzes the metabolic activation of the procarcinogen, N-nitrosodimethylamine, and cytotoxic carbon tetrachloride compounds. A tandem repeat polymorphism in the 5'-flanking region of the CYP2E1 gene was investigated in non-small cell lung carcinoma (NSCLC) patients to clarify the relationship between CYP2E1 gene polymorphism and lung cancer susceptibility. Blood samples were taken from 236 healthy control subjects (192 males and 44 females) and 111 patients (78 males and 33 females) who underwent surgery for NSCLC in Japan. DNA was isolated from these samples and the 5'-flanking region of the CYP2E1 gene was amplified by polymerase chain reaction and examined for tandem repeat polymorphisms using DNA fragment analysis. Sequence analysis confirmed the presence of three alleles, A2, A3, and A4 (361, 367, and 457 bp, respectively), with four genotypes observed in the lung cancer group and five genotypes in the control group. There was a statistically significant difference in genotype distribution between the lung adenocarcinoma and control group (P=0.0088, A4/A4 vs. non-A4/A4). In the lung adenocarcinoma group, the univariate risk estimates for the A4/A4 subgroup compared to the most common subgroup (A2/A2) was 4.300 (95% confidence interval = 1.358-13.618, P=0.0131). We conclude that the A4/A4 genotype of the 5'-flanking region of CYP2E1 was significantly more frequent in lung adenocarcinoma cases than in healthy controls and, therefore, may be involved in the development of lung adenocarcinoma.