In this review, rhythmic variations, including circadian and circannual ones, were demonstrated in the pharmacokinetics and pharmacodynamics of many drugs, These suggest that the consideration of the timing of drug administration improve a rational drug therapy, increasing drug efficacy and safety. Rhythmic variation in the dose-response relationship is caused by change in the dose-concentration and/or concentration-response relationship. Therefore, to investigate chronopharmacological study from viewpoints of dose-concentration-response relationship becomes an important clue for dosage adjustment. Controlled drug delivery systems are of great importance for the pharmacotherapy of disease, A drug delivery system (DDS) enabling a constant-rate administration is attractive from the clinical point of view, namely such a system could minimize the peak and trough variation in plasma drug concentration after dosing so as to avoid toxicity associated with drug levels exceeding the upper limit of therapeutic range and lack of effect with drug levels dropping below the lower limit of the range, However, pulsatile administration is preferred for peptides and hormone pharmacotherapy. For chronopharmacotherapy, a pattern of input at different release rates is also preferred to that at a constant rate. Finally, we emphasized the need to consider chronopharmacology in DDS design.

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The objective of this study is to investigate the potential use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) as a biocompatible solubilizer for a lipophilic absorption enhancer, 1-[2-(decylthio)-ethyl] azacyclopentane-2-one (HPE-101) involved in the nasal preparation of insulin. The solubility of HPE-101 in water increased in a linear fashion as a function of HP-β-CyD concentration : the apparent stability constant of the complex was estimated to be 4300 M^-1 at 25°C. When bovine insulin was administered nasally to rats, a simultaneous use of HPE-101 solubilized in HP-β-CyD showed a prominent increase in serum immunoreactive insulin levels and a marked hypoglycemia. The proteolysis of insulin in rat nasal homogenates was slightly inhibited by the solubilized HPE-101, and appeared to be of minor importance of the nasal absorption enhancement. HPE-101 enhanced the nasal permeability, as indicated by the transport of inulin, an inert and membrane impermeable marker from the nasal cavity into systemic circulation. This enhancing effect was potentiated by the solubilization of HPE-101 in HP-β-CyD, probably through the facilitated transfer of HPE-101 into the nasal mucosa. These results suggest that a combination of HPE-101 and HP-β-CyD is useful for designing the nasal delivery systems of peptide and protein drugs.

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Chemoembolization is a useful cancer treatment which combines chemotherapy and tumor devascularization using an anticancer drug and transcatheter embolization of the arteries running to the tumor. TNP-470 is a new type of anticancer durg which prevents tumor neovascularization thereby blocking nutrient supply. We expected that the chemoembolization using microspheres containing this angiogenesis inhibitor would produce strong anticancer activity attributed to sitespecific inhibition of the tumor neovascularization, especially the development of collateral circulation. We examined the anticancer effects of chemoembolization using TNP-470 microspheres prepared with poly(DL-lactic/glycolic acid) in rabbits bearing VX-2 carcinoma. It is assumed that microspheres of 53-125 μm in diameter persistently embolized the arterial capillaries surrounding the tumor for 2∼3weeks and released the drug over 5 days. When TNP-470 was injected s. c. 5 times at a dose of 5 mg at 2-or 3-day intervals, tumor growth was found to be significantly inhibited after the 3rd injection(P<0.05). A single i. a. injection of 1 mg of TNP-470 aqueous solution or 50 mg of placebo microspheres provided slight suppression of tumor growth, but microspheres containing the same dose of TNP-470 caused striking regression of the tumor for 9 days, and this effect was dose-dependent. Chemoembolization should offer promising and reliable therapy using angiogenesis inhibitors with less systemic side effects.

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The product of oncogene erb B-2 is a transmembrane type glycoprotein (Mr 185000) and has tyrosin kinase activity. It has amino acid sequence homology with EGF receptor, suggesting that p185^erbB-2 is a growth factor receptor. Monoclonal antibodies(MoAbs) were prepared to c-erb B-2 gene transfected NIH-3T3 cells (SV22) and characterized. The molecular weight of the antigen recognized with MoAbs was 180 K dalton. According to the reactivity to deletion mutants, the epitope of MoAbs was existed within No. 292 to 370 amino acids in extracellular domain of erb B-2 molecule. The distribution of erb B-2 antigen was limited and very few in normal tissues in immunohistology, while adenocarcinoma tissues expressed erb B-2 antigen. Double determinant immunoassay with two distinct anti-erb B-2 MoAbs showed that shedding erb B-2 antigen was detected in only low percentage of patient sera with malignant diseases. Furthermore, anti-erb B-2 MoAb was accumulated more in tumors than in normal organs in vivo. These results suggest that anti-erb B-2 MoAbs are of use for passive immunotherapy.

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Liposomes were investigated as a carrier for the delivery of therapeutic agents to target brain tumors. We have developed the coating of liposomes with pullulan and 1-aminolactose pullulan, and compared with conventional neutral liposome. When pullulan-coated liposome labeled with ¹⁴C was intracarotidly administrated into the 9L cells immlanted brain tumor rats, brain tumor uptake of radioactivity increased 4.5 times and spleen uptake decrease compared with the neutral liposome. The cytotoxity of cisplatin against 9L-glioma cells was not inhibited by encapsulation of pullulan-coated liposmes. The quantity of platinum of 1-aminolactose pullulan-coated liposome-encapsulated cisplatin into the brain tumor was about 4 times as great as that of pullulan-coated liposome-encapsulated cisplatin. Considering that polysaccharide-coated liposomes become more stable, both physiochemically and biochemically, than conventional liposomes, 1-aminolactose pullulan-coated liposomes may be useful in targeting brain tumors.

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Tissue distribution of anticancer agents was compared in combination with or without L-623 in S. 180 bearing mice and the pharmacokinetics of ¹⁴C-L-623 were studied in S. 180 and Ehrlich carcinoma bearing mice. (1) The concentration of peplomycin, 5-fluorouracil and adriamycin in tumor tissues increased selectively in combination with L-623. (2) Above effects were observed by before or simultaneous administration of L-623. (3) The blood level curves of ¹⁴C-L-623 showed a relatively short α-phase and a very long γ-phase. (4) ¹⁴C-L-623 distributed highly in the liver and spleen and moderately in the heart, lung, stomach and kidney for a long time. Into tumor tissues, it distributed slowly and reached a considerably high level at 7 to 24 hours after administration and persisted for a week. By multiple daily doses, ¹⁴C-L-623 showed accumulation in normal and tumor tissues.

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A structural change in the stratum corneum of hairless rat skin by subcutaneous enhancers and its enhancing effect on indomethacin permeation through the full-thickness skin was examind. The stratum corneum was characterized in terms of a bound water content and a extraction by an enhancer. Enhanced permeation of indomethacin was observed by particular treatments, which lowered a bound water content and showed some extraction. This result suggests that the exchange of bound water in polar lipids by enhancer molecules showed the solubilization and extraction of some lipids from the stratum corneum to cause a reconstructed structure of lipids with the enhancer molecules for accerelating the indomethacin permeation. On the contrary, some treatments which showed an increase in bound water content in the stratum cornuem exhibited a suppressive effect on the permeation. This result suggests that such natural moisturing factors penetrate the hydrated layers of intracellular lipid layers to increase the barrier property of the stratum cormeum. Thus, it is concluded that such a characterization of the stratum corneum can be a useful method on evaluating structural changes in skin and predicting the enhancing properties of several subcutaneous enhancers on drug permeation.

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Effects of strict glycemic control on insulin secretion and insulin action were studied in non-insulin dependent diabetics who had acute deterioration of glycemic control. Strict glycemic control was assessed with one-day operation of artificial endocrine pancreas followed by multiple insulin injections. Insulin doses for maintaining perfect daily glycemic control was comparble to these which was given before achievement of strict glycemic control. Oral glucose tolerance test showed an improvement in insulin secretion after strict glycemic control. Euglycemic hyperinsulinemic clamp test elucidated an recovery of insulin resistance after strict glycemic control. These results indicated that strict glycemic control could improve both insulin secretory ability and insulin sensitivity in acutely-deteriorated noninsulin dependent diabetics.

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An application of curdlan, a natural β-1, 3-glucan, to controlled drug delivery was investigated in a form of oral dosage form. Theophylline was chosen as a model drug to be incorporated with curdlan in a tablet. It was found that the drug release rate from the tablets prepared from spray-dried particles of curdlan/theophylline was constant up to 8 hr in vitro studies. Since theophylline release was not influenced by pH or various ions, curdlan tablets could control the drug release in physiological fluids after oral administration. Drug release was estimated to be diffusion controlled by applying the release data to Higuchi's equation. The theophylline release profile from the curdlan tablets was compared with those from 5 kinds of commercially obtained sustained release tablets in pH 1.2 medium for 2 hrs followed by in pH 6.8 medium for 6 hrs at 37°C. In addition to theophylline, release profiles of acetaminophen, propranolol hydrochloride and salbutamol sulfate were also obtained from their curdlan tablets. Although the release rates were influenced by their solubilities, each drug release was sustained greatly compared with corresponding drug powder. Adjustment of drug content in the tablets and of tablet surface area allows formulation of the desired preparation.

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The mechanisms of beneficial action of steroids on peritumoral brain edema (BE) remain controversial. Steroids, although effective in reducing peritumoral BE when administered systemically, are limited by many systemic complications. To determine if topical dexamethasone (Dx) by osmotic pump to brain tumor beds would not only control peritumoral BE, but also lead to suppression of tumor growth, we studied experimental brain tumors produced in 102 rabbits by implanted VX2 carcinoma cells, Animals were separated into three groups : (1) untreated group, (2) systemic Dx treated group, (3) topical Dx treated group. Systemic or topical Dx did not control tumor growth and peritumoral brain edema, however both groups resulted in a significant increase in survival relation to the untreated group.

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