Role of P-Glycoprotein in Ocular Clearance of Rhodamine 123 in Rabbits

Pharmaceutical Research -     

The Influence of the Product Liability Act, Governmental Regulation, and Medical Economics on Medical Devices and Their Clinical Applications

Abstract: The advancement of medical technology constantly demands the introduction of safer and more efficient medical instruments and devices. Recent litigation and rulings against the manufacturers of breast implants and the subsequent refusal of major plastic companies to supply materials to them are seriously threatening the production and development of other permanent implants such as ventricular assist devices and even disposable catheters. In addition, government overregulation also discourages and hinders production and clinical applications of new instruments. Current trends such as cost effectiveness measures and economic restraints imposed by government agencies and managed care systems are endangering investments from the medical and industrial communities to exploit more expensive and sophisticated instrument technologies. The resultant lack of grant money and pressure from animal rights advocates also suppress experimentation on primates and domestic laboratory animals.     

Differential Sensitivity to the Effects of Psychotropic Drugs: Psychotics vs Normals; Asian vs Western Populations

Abstract: The effects and side-effects of psychotropic drugs are determined by many variables, and the host factor is one of the most important. A lower sensitivity of schizophrenics than normals to the sedative effect of chlorpro-mazine and of manic depressives to imipramine were demonstrated quantitatively by a higher percent time of waking EEG following medication. The mean therapeutic dose of chlorpromazine for the manic state was found to be much lower in Japanese than in Western populations in a controlled study comparing the antimanic efficacy of carbamazepine and chlorpromazine. A lower therapeutic dose in Asian populations has been reported also on other antipsychotic drugs, lithium, and tricyclic antidepressants. The lower therapeutic dose level was discussed from the standpoint of transcultural psy-chopharmacology.     

Effect of 7-Bromo-5-(2-pyridyl)-3H-l, 4-benzodiazepine-2(1H)-one, Bromazepam (Ro 5–3350), a New Minor Tranquilizer, on Psychoneurosis with Special Reference to the Obsessive-Compulsive Symptoms

Clinical application of a minor tranquilizer bromazepam, 7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(lH)-one (Ro 5–3350) was made on 18 cases of obsessive-compulsive neurosis, 10 of anxiety neurosis, 6 hypochondriasis, 4 hysteria and 3 of phobia of bodily odor.

• 1) In 18 cases of obsessive-compulsive neurosis, bromazepam was found markedly effective in 6, effective in 3, fairly effective in 5, ineffective in 2, and aggravated in 2 cases. The effective cases were those with obsessive thinking and manifest anxiety. In other kind of neurosis, bromazepam was markedly effective in 5 and effective in 2 of 10 anxiety neurotic cases, whereas it was almost ineffective in the cases of hypochondriasis, hysteria and phobia of bodily odor.
• 3) The maximum daily dose of bromazepam was 10 to 20 mg in many cases, and 20 to 30 mg in some other cases. The durg is quick-acting to such an extent that it took 2 to 5 days for its action to become manifest in markedly effective cases.
• 4) Various laboratory tests revealed no appreciable abnormality in most cases where bromazepam was employed. Physical side effects such as slight hypotension, dizziness, and sleepiness were observed in a few cases, and mental side effects such as loquaciousness and restlessness in about 20 cases.
• 5) The target symptoms of bromazepam were suggested to be anxiety, tension, and irritation like previously reported other benzodiazepines. The fact that its action of relieving anxiety and tension and of elevating mood was found to be more potent than those of other benzodiazepines and that it was effective on some obsessive-compulsive neurosis that showed little response to other benzodiazepines, suggested that bromazepam is a potent and characteristic new minor tranquilizer of clinical value.

     

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.     

Anti-Manic and Prophylactic Effects of Carbamazepine (Tegretol) on Manic Depressive Psychosis A Preliminary Report

• 1). The anti-manic, anti-depressive and prophylactic effects of carbamazepine (CAZP, Tegretol-Ciba Geigy) on the endogenous mani-depressive psychosis (MDP) were investigated on 50 MDP cases. The dosage of the drug ranged from 200 to 1,200 mg daily (usually 400 to 600 mg).
• 2). The effect of CAZP on 33 manic states was: “markedly effective” seven (23%), “effective” six (19%), “slightly effective” five (16%), “ineffective” 13 (42%), whereas the effect on six depressive states was: “markedly effective” one and “ineffective” five. No definite relationship was found between the kinds of drugs in combination use and the effect of CAZP. No significant difference of the CAZP effect was found in the four patient groups with different age of onset of the illness, nor among the “continuous,”“frequent” and “periodic” type cases.
• 3). The prophylactic effect of CAZP on 27 cases in which the assessment of the effect on the manic episode was possible was: “markedly effective” 13 (48%), “effective” seven (26%) and “ineffective” seven (26%), whereas that for depressive episode was: 12 (45%), two (7%) and 13 (48%), and the result of the general assessment on each patient was 14 (43%), 10 (30%) and nine (27%), respectively. The kinds of drugs in combination use, age of onset and type of course of the illness did not have any influence on the prophylactic effect of CAZP.
• 4). The prophylactic effect on MDP of CAZP did not parallel that of lithium salt, but CAZP may be effective on cases which did not respond to lithium and vice versa.
• 5). Side-effects such as ataxia, dizziness, exanthema, drowsiness and headache were observed in five of the cases, and the CAZP was discontinued in four of them.
• 6). The mechanism of effectiveness of the CAZP on MDP was discussed.

     

Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer

The number of published studies on peritoneal dissemination of scirrhous gastric carcinoma is very small as a result of the unavailability of highly reproducible animal models. Orthotopic implantation of HSC-44PE and HSC-58 (scirrhous gastric carcinoma-derived cell lines) cells into nude mice led to dissemination of the tumor cells to the greater omentum, mesenterium, peritoneum and so on, and caused ascites in a small number of animals. Cycles of isolation of the ascitic tumor cells and orthotopic inoculation of these cells were repeated in turn to animals. This was to isolate highly metastatic cell lines with a strong capability of inducing the formation of ascites (44As3 from HSC-44PE; 58As1 and 58As9 from HSC-58). All three cell lines induced tumor formation at the site of orthotopic injection, and caused fatal cancerous peritonitis and bloody ascites in 90-100% of the animals approximately 3-5 weeks after the inoculation. When the parent cells were implanted, the animals became moribund in approximately 12-18 weeks, however, none of the animals developed ascites. Complementary DNA microarray and immunohistochemical analyses revealed differences in the expression levels of genes coding for the matrix proteinase, cell adhesion, motility, angiogenesis and proliferation between the highly metastatic- and parent-cell lines. The usefulness of this model for the evaluation of drugs was assessed by analyzing the stability of the metastatic potential of the cells and the reproducibility. Animals intravenously treated with CPT-11 and GEM showed suppressed tumor growth and significantly prolonged survival. The metastatic cell lines and the in vivo model established in the present study are expected to serve as a model of cancerous peritonitis developing from primary lesions, and as a useful means of clarifying the pathophysiology of peritoneal dissemination of scirrhous gastric carcinoma and the development of drugs for its treatment.     

Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats

Recently, we found that potent P-glycoprotein (P-gp) inhibitors, such as verapamil and cyclosporin A, markedly modulated the pharmacokinetics of digoxin in rats, whereas they did not affect beta-methyldigoxin pharmacokinetics significantly. Digoxin is also a substrate of rat organic anion transporting polypeptide 2 (Oatp2). Here, we compared the magnitude of Oatp2-mediated drug interaction of digoxin and beta-methyldigoxin using amiodarone as an Oatp2 inhibitor in rats. Amiodarone (20 mg/kg) given intravenously significantly increased plasma levels and decreased biliary excretion, liver distribution, and intestinal distribution of digoxin administered intravenously at a dose of 10 mug/kg. Amiodarone also significantly decreased biliary excretion and liver distribution of beta-methyldigoxin, but the change in plasma levels of beta-methyldigoxin was quite small. These findings may give a clue in selecting these cardiac glycosides in clinical pharmacotherapy for patients receiving multiple drugs towards escape from Oatp2-mediated drug interactions.