The understanding of periodic and predictable changes in drug effects is a goal of chronopharmacology. To better understand chronopharmacologic rhythms, chronopharmacokinetics, chronesthesy (chronopharmacodynamics) and chronergy are the essential concepts. Both chronopharmacokinetic and chronopharmacodynamic circadian changes are known in many drugs. The role of circadian changes in hepatic cytochrome P-450 isozymes and activities were explained as one of the important chronopharmacodynamic mechanism. The other example of chronesthesy was circadian variation of blood pressure in a patient after subarachnoid hemorrhage. The desynchronization of blood pressure circadian rhythm observed in this patient suggested the importrance of synchronization in the treatment of severely affected neurological disorders, and thus the importance of chronotherapy. Rational chronotherapy for the optimization of drug administration timing is possible when considering all these basic concepts. The programmable-in-time pumps as device for clocking intravenous infusion and the sustained-release drug form would be useful from the practical point of view. Further widespread diffusion of chronopharmacological knowledge in clinical medicine is indispensable for optimization of drug administration timing.

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In order to speculate the disposition of cetylmannoside-modified liposomes (Man-MLV) in human, interactions between Man-MLV and plasma were investigated in this study. Man-MLV was rapidly destabilized in human fresh plasma, as same as in rat fresh plasma. On the other hand, liposomes without the surface modification of cetylannoside(PC-MLV)was not destabilized in human fresh plasma, altough PC-MLV was destabilized in rat fresh plasma. Furthermore, the instability of Man-MLV in human fresh plasma was induced by the activation of the classical pathway of complement, but that in rat fresh plasma was induced by the activation of the alternative complement pathway. These results suggested that there was the possibility of species differences on dispositions of liposomes in vivo. The present study is considered to be useful for clinical application of liposomes as drug carrier.

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Lysozyme(Mw : 14, 300) was derivatized by chemical modification with caproic anhydride to the N-terminal of lysine residue. The product observed to be more lipophilic than parent lysozyme by high-performance liquid chromatography. The activity and modified percentage of amino groups of caproyl derivative were 76.5% and 40% of parent lysozyme, respectively. Intestinal absorption of lysozyme and caproyl derivative was examined by in situ closed small intestinal loops of rats. A significant increase in cumulative amount of lymph fluid of caproyl derivative was found in comparison with that of parent lysozyme. However both compounds were not detected in plasma. Lysozyme and caproyl derivative were observed to be almost stable in phosphate buffered saline or lymph fluid in vitro. These findings suggested that acylation of lysozyme such as caproylation might be a useful approach for improving the lymphatic transport of enzyme with high molecular weight.

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Lactose carrying polystyrene (PVLA) had been shown to be a good matrix for hepatocyte culture due to specific interaction between the galactose residue and asialoglycoprotein receptors on hepatocyte. In this study, we investigated the possible applicability of this specific interaction and the ability of PVLA to form super molecular structures, which could serve as a drug carrier, in targeted delivery of drugs. Spectrophotometric observations indicated that the super molecular structure, resulting from the amphiphilic property of PVLA interacted strongly with ANS (8-anilino-1-naphthalenesulfonic acid), our hydrophilic drug models, and DPH (1, 6-diphenyl-1, 3, 5-hexatriene) or NBD (7-benyyl-4-nitrobenz-2-oxa-1, 3-diazole), our hydrophobic drug models, to form inclusion complexes of drugs and PVLA. When hepatocytes were incubated with the PVLA-NBD inclusion complex, high amount of NBD was transferred into hepatocytes. These results suggest that PVLA could be used as hepatocyte targeting drug carrier.

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Tissue distributions of adriamycin-oxidized dextran conjugate (ADM-OXD) in tumor-bearing rats were studied using two kinds of ADM-OXD preparations which were labelled with ¹⁴C on glycine bound to dextran chain(¹⁴C-GLY) or adriamycin (¹⁴C-ADM) moieties. Rats intramuscularly implanted with Walker carcinosarcoma 256 into the hind legs were intravenously injected with ADM-OXD preparations labelled with ¹⁴C-GLY or ¹⁴C-ADM. On excretions to urine, radioactivities derived from both ADM-OXD preparations reached almost half of their doses within 6 hours. Incorporation of radioactivity from both radioactive preparations was highest in the kidney, followed by the reticuloendothelial tissues such as the liver and spleen. In the respective tissues, radioactive concentrations from ¹⁴C-GLY was around 30% less than those from ¹⁴C-ADM, the ratios of which were kept almost constant during the experiment period. Accumulation of radioactivity in the tumor from both preparations was 7 to 8 higher than that in the muscle 3 hours after injection. This study provides evidence that most of ADM-OXD will be circulating in blood as conjugate form and incorporated into respective tissues and organs.

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Tetragastrin (TG) has a potent pharmacological activity as gastrin. However, the oral bioavailability of TG is extremely low(about 3%) because of its high hydrophilicity and extensive hydrolysis in the gastrointestinal mucosa. in order to improve intestinal absorption of TG, we synthesized a new lipophilic derivative of TG by chemical modification of the peptide with caproic acid, and caproyl-TG (Cap-TG) was obtained. Cap-TG was confirmed to be more lipophilic than TG by high performance liquid chromatography. Intravenous injection of Cap-TG showed 1.7 fold higher activity than TG. The gastric acid secretion activities of these compounds were measured in rats after intestinal administration. When Cap-TG was administered into large intestinal loop, a marked increase in gastric acid secretion was observed in comparison with TG, while we found no significant effect following the small intestinal administration of Cap-TG. These results indicated that chemical modification of TG with caproic acid might be a useful approach for improving the large intestinal absorption of TG.

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Hydrophilic nylon microcapsules containing concanavalin A and succinyl-amidophenyl-glucopyranoside insulin (SAPG-insulin), whose average diameter was 70 γm were prepared to achieve a self-regulating insulin delivery system. The microcapsules were enclosed in polymer membranes for in vitro assessment and the release of SAPG-insulin was evaluated under a flow condition of glucose solution. The amount and the rate of SAPG-insulin released from this pouch were dependent upon the external glucose concentration around the pouch. Also, SAPG-insulin was quickly released from a pouch in response to the change of the external glucose concentration. In addition, to optimize this self regulating insulin delivery system, we studied the kinetics of solute permeation through a membrane separating two compartments : donor and receiver under the condition that the receiver compartment was continuously eluted.

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The promoting effect of sodium guaiazulene-3-sulfonate (AZ) on nasal absorption of insulin and calcitonin was studied in rats. The promoting effect of AZ was compared with two established nasal absorption promoters i. e. sodium caprate(Na Cap) and glycyrrhetinic acid 3-O-monohemiphthalate disodium (GA-MHPh 2Na). The nasal absorption of insulin was estimated from plasma immunoreactive insulin and changes in glucose levels. Plasma glucose level was decreased by intranasal administration of 10 U/kg insulin with 1% AZ, The extent of total decrement of glucose level to control was 51% and comparable to that with 1% Na Cap. The addition of 1% AZ to the nasal formulations enhanced insulin bioavailability from 3.7% to 27.6%. The nasal absorption of salmon calcitonin was evaluated from serum calcitonin and changes in calcium levels. Serum calcium levels were de-creased by intranasal administration of 10 U/kg salmon calcitonin in the presence of two already known promoters as effectively as intramuscular administration of the same dose, The addition of 1% AZ also showed the same extent of decrease as these ; the extent of total decrement of serum calcium level to control was 26.6%. The optimum concentration of AZ was about 1%. Intranasal administration of 1% AZ alone hardly changed plasma glucose level and serum calcium level from control. Hence, promoting effect of AZ on nasal absorption of insulin and calcitonin was proved. These findings indicate that AZ can be safe and effective nasal absorption promoter of peptides.

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Four ester derivatives of 2′, 3′-dideoxyinosine (DDI), acetate (C2-DDI), octanoate (C8-DDI), benzoate (Bz-DDI), and hemisuccinate (Suc-DDI), were synthesized from deoxyinosine, and evaluated as a prodrug of DDI, The esters were proved to quantitativery regenerate DDI in the presence of human plasma. Absolute bioavailability was evaluated by an oral administration to rats by using water or olive oil as a solvent. Hydrophobic prodrugs, C8-DDI and Bz-DDI, showed higher bioavailavility when administered as a water suspension than as an oil solution, though hydrophilic prodrugs, C2-DDI and Suc-DDI, showed higher bioavailability with an oil suspension than with a solution in water.

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Hippocrates described the use of seton to cure fistula in ano. The first surgical lay open of anal fistula was performed in 1337. The routine surgical treatment employed today is fistulectomy and fistulotomy. Thus, in principle the surgical treatment of fistula in ano has remained the same without much improvement. The need of prolonged hospitalization, chances of recurrence and anal incontinence in some of the cases of high level fistula have encouraged us to try out a new indigenous ambulatory treatment of fistula in ano. Treatment of 221 cases of anal fistula by application of Kshara sutra, one of the Ayurvedic treatment were performed in our clinic from July 1985 to March 1991 in Japan. Kshara sutra used in this series were prepared by Dr. Upali Pilipitiya in Sri Lanka and were cotton surgical thread impregnated with latex of Euphorbia antiquorum powder of rhizomes of Curcuma longa and alkaline powder of Achyranthes aspera. Of the 182 cases over 1 year follow-up, the youngest patient was 1 year old and the oldest was 83 years of age. The fistulous tract was cut through between 1∼5 week in average depending upon the initial length of tracts. The average of cutting was 11 mm. every week. There have been 9 patients (4.9%) of recurrence, 7 patients of pus pocket formation and a patient of slight anal deformity in the follow-up so far. Clinical experience with the 182 patients indicates that fistula in ano can be safely treated by this technique of biochemical curette with excellent results. Furthermore the recurrences and morbidity are practically negligible. Our uniformly good results suggest that biochemical medicated caustics of Kshara sutra may be responsible for the drug delivery system of chemical fistulectomy. This treatment can also be employed to severely ill patients of hypertension, diabetes and heart disease.

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