Nachio Akiyama

A new orally active antitumor 1R,2R-cyclohexanediamine-platinum(IV) complex: trans-(n-valerato)chloro(1R,2R-cyclohexanediamine) (oxalato)platinum(IV)

Purpose: The authors have previously reported that trans-bis(n-valerato)(1R,2R-cyclohexanediamine) (oxalato)platinum(IV) (C5-OHP), an oxaliplatin derivative, is an orally active antitumor agent in an intraperitoneal (i.p.) L1210 murine leukemia model. In this study, several oxaliplatin derivatives of the general formula trans-(carboxylato)chloro(1R,2R-cyclohexanediamine)(oxalato)platinum(IV) were synthesized in order to find new derivatives with greater oral activity than C5-OHP in a clinically predictive tumor model. In the formula, the carboxylate and chloride ligands are situated in axial positions. Methods: Four complexes with the axial carboxylate ligands n-butyrate, n-valerate, n-caproate or n-heptanoate were synthesized and designated C4-OHP-Cl, C5-OHP-Cl, C6-OHP-Cl and C7- OHP-Cl, respectively. The oral antitumor activity of the complexes was evaluated against the murine reticulosarcoma M5076 implanted subcutaneoulsy (s.c.) in to male BDF1 mice. The complexes were administered orally daily for 5 days in two cycles initiated on days 5 and 12 postimplantation. The physicochemical properties were examined by measuring the concentrations of the complexes in test solutions at intervals by HPLC. The pharmacokinetic behaviors of C5-OHP-Cl, C6-OHP-Cl and C5-OHP following a single oral administration were studied in non-tumor-bearing male BDF1 mice. Results: Of the complexes synthesized in this study, C5-OHP-Cl, which exhibited high activity in the i.p. L1210 model, was found to be orally active in the s.c. M5076 model while C5-OHP was not. The in vitro reduction of the complexes by ascorbate was much more rapid than that of C5-OHP, while the complexes were more stable than C5-OHP in HCl-acidic and alkaline solutions. Pharmacokinetic study showed that Cmax and AUC0–24h values of plasma total and filterable platinum of C5-OHP-Cl were four to six times greater than those of C5-OHP, indicating that C5-OHP-Cl was absorbed more than C5-OHP. Conclusion: C5-OHP-Cl was found to be a superior l-OHP derivative C5-OHP, exhibiting significant oral antitumor activity in the s.c. M5076 model. The enhanced activity of C5-OHP-Cl was considered to be due in part to increased susceptibility to reduction and increased gastrointestinal absorption. C5-OHP-Cl is a suitable candidate for further study as an oral cancer chemotherapy agent.

Significance of water solubility in the gastrointestinal absorption of trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)platinum(IV), an orally active antitumor platinum complex, and its analogs.

Trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)-platinum (IV) (C5-OHP) is an orally active platinum complex we prepared. The gastrointestinal absorption of C5-OHP was examined in rats and compared with those of C5-OHP analogs which have a general formula of trans-bis(n-OCOCnH2n+1 )(1R,2R-cyclohexanediamine)(oxalato)platinum (IV) as well as C5-OHP. The complexes did not show significant differences in pharmacokinetic behavior after i.v. injection. Plasma platinum level after a single oral administration at a dose was higher for a complex with higher water solubility. The intestinal absorption rate measured by an in situ recirculating perfusion technique was higher for a complex with higher lipophilicity. These results indicate that the water solubility is a more dominant factor than the lipophilicity in the gastrointestinal absorption of the complexes. Then, the effects of surfactants and x-cyclodextrin (x-CD) on the solubility of C5-OHP was studied. Among the agents tested, x-CD showed the highest effect in increasing the solubility. Administration of C5-OHP together with x-CD gave approximately three times higher plasma platinum levels than administration of C5-OHP alone. Water solubility was found to be a dominant factor in the gastrointestinal absorption of C5-OHP and its analogs.

Pilot study for preoperative administration of 1-OHP to patients with advanced scirrhous type gastric cancer

A new DACH platinum complex, l-OHP, was developed by Kidani as an anticancer agent. A clinical trial took place in Europe which demonstrated its therapeutic efficacy for colorectal cancer. An effective treatment, especially chemotherapy for patients with a advanced scirrhous type gastric cancer, has not yet been established. An in vitro study showed that l-HOP inhibited cell growth in human gastric cancer cell lines. Our pilot study determined the efficacy of preoperative administration of l-OHP, 67 mg/m2 to 100 mg/m2, every 2-3 weeks, for two to three cycles, in five patients with this disease (Stage III and IV) roentogenoscopically and histologically. The platinum concentration in the tissues was also measured. By X-ray examination of the stomach at the time of pre- and post-administration of l-OHP, extension of the lesional gastric wall was observed. Histologically three Grade 2 responses and two Grade 1a responses were obtained according to the criteria presented by Japanese Research Society for Gastric Cancer. The mean platinum concentrations in the lesional tissues were 0.98 ppm and 0.5 ppm in the patients administered l-OHP for three and two cycles respectively. There was no toxicity that prevented surgery. These preliminary results showed the possibility that 1-OHP would be effective for patients with advanced scirrhous type gastric cancer as a neoadjuvant therapy.

An orally active antitumor cyclohexanediamine-Pt(IV) complex: trans,cis,cis-bis(n-valerato) (oxalato)(1R,2R-cyclohexanediamine)Pt(IV)

In order to develop orally active antitumor platinum complexes, several cyclohexanedlamine-Pt(IV) complexes of a general formula trans,cis,cis-[Pt(IV) (OCOCnHn+1)2 (oxalato)(1R,2R-cyclohexanediamine)] were synthesized by derivatizing oxaliplatin [Pt(III)(oxalato)(1R,2R-cyclohexanediamine), I-OHP], which is a potent antitumor cyclohexanedlamine-Pt(II) complex we have prepared and now undergoing clinical trials. The I-OHP derivatives were found to be stable, lipophilic and reduced to yield I-OHP, an active species, quantitatively by ascorbate in vitro. All the derivatives were antitumor active against mouse lymphocytic leukemia L1210 when given i.p. In particular, trans-bis-valerato-oxalato-1R,2R-dach-Pt(IV), C5-OHP, showed markedly high activity. C5-OHP also exhibited significant antitumor activity against L1210 when orally administered. C5-OHP was considered to be a suitable candidate for the oral cancer chemotherapy agent to be developed.

Surgery in patients with HIV infection : indications and outcome

We reviewed the records of 12 patients with HIV infection (one stage I, three stage II, two stage III, six stage IV) who received 15 surgical procedures under general or lumbar/epidural anesthesia. We discussed surgical indications, their poor wound healing and precautions for preventing the risk of transmission of HIV to health care workers. Six emergency and nine elective operations were performed. Postoperative complications developed after three emergency and three elective operations. Ten patients showed delay of wound healing which was not directly correlated with the CD4+ cell count. No operative deaths occurred. In any stage of HIV infection, not only palliative but also curative operations can be performed as long as HIV infection, opportunistic infections and HIV-related neoplasms can be controlled. Late stage wound healing is poor, but the wound will heal without keloid formation, although it takes two to three times longer than usual. For operating on patients with HIV infection precautions for preventing needle sticks, sharp injuries and blood exposure should be learned and used by health care workers. As a result, surgical staff members will be able to perform operations safely on HIV-infected patients to improve both quality of life and the prognosis of their disease.

Orally Active DACH-Pt (IV) Compounds

Since the discovery of the antitumor activity of cisplatin by Rosenberg, et al.1 in 1969, many attempts have been made to prepare highly antitumor active Pt complexes without severe toxicities. The authors discovered a simple preparative separation method of 1,2-diaminocyclohexane (dach) geometrical isomers, cis and trans2, by Nickel complex formation and trans isomers were resolved into d and l optical isomers by the conventional method.

Diagnosis of peripapillary carcinoma: endoscopic findings

During the period 1982-1988, 8 patients were admitted with peripapillary carcinoma. Pancreatico-duodenectomy (PD) was successfully carried out on 7 occasions but only 3 patients are alive today. Early diagnosis of this disease is therefore mandatory. Endoscopic sphincterotomy is particularly useful for the diagnosis of the non-exposed type of carcinoma in the peripapillary region.