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.     

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.     

Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice

It is well accepted that bacterial and virus infections elevate the levels of cytokines in serum and cerebrospinal fluids. Such high levels of cytokines might alter the integrity of the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB), subsequently affecting brain penetration of drugs. However, few reports have addressed this issue. Thus, we investigated brain penetration of cyclooxygenase (COX) inhibitors, commonly used as antipyretics, in mice treated with Shiga-like toxin II (SLT-II) derived from E. coli O157:H7, which significantly elevates cytokine levels. As antipyretics, we used diclofenac, mefenamic acid, and acetaminophen. We found that SLT-II significantly increased the brain-to-plasma concentration ratio (Kp) of diclofenac and mefenamic acid, but not of acetaminophen. Moreover, the Kp of diclofenac and mefenamic acid was increased by probenecid, an anionic compound. These results suggest that efflux anion transporters might be involved in the transport of diclofenac and mefenamic acid. Western blot analysis revealed that SLT-II decreased the expression of organic anion transporter-3, an efflux transporter located on the BBB and/or BCSFB. Taken together, these results suggest that SLT-II and/or SLT-II-stimulated cytokines might change brain penetration of drugs and could possibly increase the risk of their side-effects by altering the expression of transporters.     

Parapapillary choledochoduodenal fistula associated with cholangiocarcinoma

Parapapillary choledochoduodenal fistula is a rare disorder. We herein report a case of parapapillary choledochoduodenal fistula associated with cholangiocarcinoma. A 61-year-old woman was admitted to our hospital for further examination of a liver tumor. She had no clinical symptoms, but computed tomography scans showed an irregularly contoured liver tumor which was histologically confirmed to be adenocarcinoma, by a needle biopsy examination. Duodenal fiberscopy revealed a fistula orifice 1.0cm proximal to the orifice of the papilla of Vater, and endoscopic retrograde cholangiography through the fistula showed a communication to the common bile duct. Hypotonic duodenography demonstrated reflux of contrast material into the choledochoduodenal fistula. The bile sample collected from the common bile duct showed extremely high levels of pancreatic enzymes, including amylase, phospholipase-A2, and elastase-I. Furthermore, Helicobacter DNA was detected in bile by polymerase chain reaction (PCR) analysis. This experience suggests to us that parapapillary choledochoduodenal fistula may be a risk factor for biliary tract carcinoma, and surgical management is the treatment of choice for this rare condition, even when the patient has no significant clinical symptoms.