Mariko Nagata

Computational consideration of cisplatin hydrolysis and acid dissociation in aqueous media: effect of total drug concentrations

Cisplatin (cis-DDP) is subject to nucleophilic displacement of chloride in water, forming aquated species, subsequently liberating hydrogen ion(s) with increasing pH. This study intends to theoretically analyze the hydrolysis and polyprotic dissociation behavior of cis-DDP in various aqueous media. A mathematical model was expressed by nonlinear simultaneous equations in terms of the total drug concentration, pH and pCl based on the hydrolysis and acid dissociation constants already published. Some of the interesting simulation results include that (1) in water, cis-DDP behaves in a very complicated manner, highly depending on the total drug concentration, pH and pCl, (2) in normal saline, about 3% of the total concentration is a positively charged chloro-aqua that may be very reactive, (3) in assumed blood (pH 7.4, [Cl(-)]=0.11 mol/l, mu=0.15), the drug is stabilized at the level of 85% and the remnants are the chloro-hydroxo (11%) and the chloro-aqua (4%), (4) in assumed intracellular conditions (pH 7.1, [Cl(-)]=0.01 mol/l, mu=0.15), the drug is converted to a large extent to various species including the parent species (44%), the chloro-hydroxo (30%), hydroxo-aqua (2%), chloro-aqua (24%) diaqua (less than 1%) and dihydroxo (null). The results of this analysis may provide a useful preliminary knowledge of existing species in a system concerned and a rationale for re-evaluating the reactions between cis-DDP and various nucleophilic substances already reported while there are somewhat conflicting interpretations of some cis-DDP reactions.

Chemotherapy Targeting Regional Lymph Nodes by Gastric Submucosal Injection of Liposomal Adriamycin in Patients with Gastric Carcinoma

We investigated the delivery of adriamycin (ADR) to the regional lymph nodes of the stomach following the gastric submucosal injection of liposomal adriamycin (Lipo‐ADR) in 34 gastric carcinoma patients, as well as following intravenous administration of free ADR (F‐ADR) in another 18 patients. Prior to radical gastrectomy, Lipo‐ADR was endoscopically injected into the gastric submucosa adjacent to the primary tumor via a needle‐tipped catheter. After Lipo‐ADR injection, the ADR concentration in the primary and secondary drainage lymph nodes was higher than in the other regional lymph nodes. Thus, the regional nodes more susceptible to metastasis showed higher levels of ADR. In contrast, the intravenous administration of F‐ADR produced a similar and far lower ADR concentration in all the nodes. Delivery of ADR to the primary drainage lymph nodes following injection of 5 ml of Lipo‐ADR was compared with delivery to the left gastric artery lymph nodes after intravenous administration of an equal dose of F‐ADR. The ADR levels (μg/g) after gastric submucosal injection were 15.1±8.30 on day 1 (n = 4); and 11.9±4.80 on day 4 (n = 6). Those after intravenous administration were 0.29±0.10 on day 1 (n = 4); and 0.36±0.0 on day 4 (n = 2). The differences between the two groups were significant (P<0.05). The ADR levels after the gastric submucosal injection were far higher than those after intravenous administration. These findings indicate that the gastric submucosal injection of Lipo‐ADR can specifically deliver ADR to the regional lymph nodes at high concentrations. Such preoperative adjuvant chemotherapy targeting the regional lymph nodes may be useful for preventing the lymph node recurrence of gastric carcinoma.

Coagulation recovery after warfarin‐induced hypoprothrombinaemia by oral administration of liposomally‐associated vitamin K1 to rabbits

The effect of liposomally-associated vitamin K1, administered orally, was investigated using rabbits with warfarin-induced hypoprothrombinaemia, and evaluated in comparison with other dosage forms of the vitamin, including a vitamin K1 emulsion, the physical mixture of the emulsion with empty liposomes, polyoxyethylene hydrogenated castor oil (HCO-60)-stabilized emulsion and the vitamin solubilized by HCO-60. The effect on blood coagulation recovery of each preparation was estimated as the time required for the prothrombin complex activity to return to 60% (TPCA60). The coagulation recovery time of the liposomal preparation was much faster than that of the other preparations and it was compared with the response to intravenous administration in which the vitamin was considered to be 100% available. The TPCA60 for the intravenous administration was 1.9 h, that for the oral liposomal preparation was 6.2 h, HCO-60 solubilized vitamin 13.6 h, HCO-60 stabilized emulsion 19.6 h, the physical mixture 17.8 h and plain emulsion 18.2 h. The vitamin K1 dose was maintained at 12 mg kg-1 in each instance.

Solubilization of Vitamin K1 by Bile Salts and Phosphatidylcholine‐Bile Salts Mixed Micelles

Abstract— The solubilization of vitamin K1 by bile salts (sodium deoxycholate, sodium cholate and their corresponding glycine conjugates) and phosphatidylcholine (egg)‐bile salt mixed micelles has been investigated. The solubilization curves were not always linear with increasing bile salts, but the vitamin was appreciably solubilized in the region below their CMCs. In the bile salt solutions (20 mM, phosphate buffered saline, pH 7.5, ions strength 0.2), the solubilized vitamin ranged from 0.3 to 0.9 mM. With increasing phosphatidylcholine, the amount of vitamin solubilized was dramatically increased; at the molar ratio of 1:1 (both 20 mM), the amount of vitamin solubilized was about 25–30 times more than by the corresponding bile salts alone. There is a possibility that exogeneous phospholipid given orally as liposomal forms assists the solubilization of vitamin K1, in the intestine. This characteristic is suggested as being responsible, in part, for the enhanced recovery of blood coagulation after oral administration of liposomal vitamin K1 to warfarin‐treated rabbits.

Lymph Node — Targeting Delivery of Adriamycin by Liposomal Administration into Gastric Submucosa in Rabbits

We studied tissue distribution of adriamycin for up to 7 days after gastric submucosal injection of Liposomal adriamycin (Lipo-ADR) (0.4 mg/kg) and i.v. of an equal dose of free adriamycin (F-ADR) in rabbits. The AUC of the regional lymph nodes was 85.4 μg-day/g after the submucosal injection and 8.44 μg day/g after the i.v. The targeting index of the regional lymph nodes, defined as the ratio of the AUC after the submucosal injection to the i.v., was 10.1, and of the bone marrow was 0.25. Gastric submucosal injection of Lipo-ADR enhanced lymph node-specific delivery of ADR.

Prognostic Comparison of Hepatic Resection of Liver Metastases and Chemotherapy via the Portal Vein with Liposome-Entrapped Adriamycin for Unresectable Liver Metastases on Gastric Cancer

The prognoses of hepatic resection of the liver metastases on the gastric cancer were compared with those by chemotherapy via the portal vein with liposome-entrapped adriamycin for unresectable liver metastases. Seven cases of hepatic resection in liver metastases were operated from 1988 to 1992. Postoperative mean survival times were 15.6 months in Hr0(L), 12.7 months in Hr1(L) and 35.4 months in Hr2(AP). To date, 7 cases of unresectable liver metastases have been evaluated via the potal vein with Lipo-ADM(20–30mg/every 2 weeks/body). There were no side effects via the portal vein with Lipo-ADM. As compared with survival time of hepatic resection and unresectable cases with Lipo-ADM for liver metastases, statistically there were no differences between hepatic resection and unresectable cases in the survival time.