Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds.

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.

An efficient synthesis of (±)-narwedine and (±)-galanthamine by an improved phenolic oxidative coupling.

Old problems, new ideas! The biomimetic phenol coupling of norbelladine derivatives such as 1 (Bn = benzyl) to form galanthamine (2), a drug used in the treatment of Alzheimer's disease, has been greatly improved by the use of the hypervalent-iodine oxidation reagent phenyliodine(III) bis(trifluoroacetate) (PIFA).

A novel intramolecular through-space interaction between F and CN: a strategy for the conformational control of an acyclic system.

X-Ray crystallographic analyses of fluorocyanides anti-1 and 2 revealed a novel intramolecular through-space interaction between F and CN in an acyclic system, which was applied to a stereoselective protonation of acyclic fluorocyanides 2 having flexible conformation.

Metachronous carcinoma of the vulva and fallopian tube.

BACKGROUND: Metachronous carcinoma of the vulva and fallopian tube is an unusual co-occurrence of gynecological malignancies. A report of such a case that developed and recurred over a 7-year period is presented. CASE: A 53-year-old G3P3 female presented with a verrucous carcinoma of the vulva and a serous papillary adenocarcinoma of the left fallopian tube metachronously. To investigate a possible association between the co-occurrence of the rare neoplasms and factors associated with multiple gynecological malignancies, we analyzed the status of human papillomavirus infection and DNA mismatch repair deficiency as indicated by microsatellite instability. All samples analyzed were negative for these factors. CONCLUSION: The present results support the possibility that metachronous carcinomas of the vulva and fallopian tube involve unknown etiological factors or arise independently.

Synthesis and anti-influenza virus activity of novel pyrimidine derivatives.

Efficient synthetic routes of 2-amino-4-(omega-hydroxyalkylamino)pyrimidine derivatives were investigated in relation to the anti-influenza virus activity of these compounds. The derivatives in which cyclobutyl and cyclopentyl groups were introduced to the beta-position of the aminoalkyl group (especially the cyclobutyl group substituted by a phenylalkyl group at the 3'-position) resulted in improved antiviral potency: i.e. an average 50% effective concentration for inhibition of plaque formation (EC50, microM) of 0.1-0.01 microM for both types A and B influenza virus. The antiviral efficacies were in the order of amino group > hydroxyiminomethyl group > halogen substitution at the 5-position, and chlorine or methoxy group > hydrogen at the 6-position of the pyrimidine ring. The antiviral indices of these compounds were 2-6 with respect to the 50% inhibitory concentration for cell proliferation (IC50, microM) for growing cells, but > 500 to > 10(4) with respect to the IC50 for stationary cells, indicating that these compounds may be efficacious for the topical treatment of influenza virus infection.

[Phase I study of a combination chemotherapy of nedaplatin and cisplatin].

A new platinum complex, nedaplatin, has been reported to be effective for both ovarian and cervical cancers. We designated a phase I dose-escalation study of a combination chemotherapy of nedaplatin and cisplatin to investigate the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Six patients, including two with advanced cervical cancer, three with ovarian clear cell adenocarcinoma and one with endometrial clear cell adenocarcinoma, were enrolled in this study. The doses of the two agents were escalated alternatively, i.e., a tandem method, from 40 to 80 mg/m2 by 20 mg/m2. Nedaplatin and cisplatin were administrated by intravenous drip infusion and repeated after an interval of at least 4 weeks, as a rule. The major toxicity observed was hematotoxicity. One of the 6 patients dropped out of this study because of severe hematotoxicity after 80 mg/m2 of nedaplatin and 60 mg/m2 of cisplatin were administered. With a dose of 80 mg/m2 nedaplatin and 80 mg/m2 cisplatin, severe neutropenia was found in all 6 patients, and thrombocytopenia and anemia were found in 1 patient, respectively. A slight hearing loss was detected by audiometry in 5 patients, but no one was inconvenienced in daily life. Mild nausea and vomiting were also observed in all 6 patients. In conclusion, the DLT of this combination therapy was hematotoxicity and the MTD was 80 mg/m2 for nedaplatin and 60 mg/m2 for cisplatin, respectively. Thus, 60 mg/m2 of nedaplatin and 60 mg/m2 of cisplatin may be recommended for combined administration.

[Incidence of synchronous or metachronous multiple primary cancers and aggregation of cancers in families of patients with endometrial cancer].

We evaluated the incidence of synchronous or metachronous multiple primary cancer, hereditary or familial cancer, and the familial aggregation of cancer in 142 patients who were treated for endometrial cancer at Tsukuba University Hospital in the period 1977 to 1995. Synchronous multiple primary cancers were identified in 6 of the 142 patients (4.2%). Eleven patients (7.7%) had a history of extraendometrial cancer. Patients with endometrial cancer had a significantly high incidence of a history of breast cancer. Endometrial cancer was diagnosed in two patients who were screened before menopause. Four patients with endometrial cancer (2.8%) subsequently developed extraendometrial forms of cancer. One patient (0.7%) was considered to have a hereditary form of cancer, and 5 patients (3.5%) had familial forms of cancer. A total of 86 cases of cancer were found among 53 kindred (37.3%). More detailed studies are needed to elucidate the aggregation of cancers in the families of patients with endometrial cancer in Japan. Patients with a history of breast cancer should be screened for the presence of endometrial cancer.

[An immunohistological study on expression of glutathione S-transferase pi (form) in human endometrial carcinoma].

Ninety-five specimens from patients with endometrial carcinoma (82 of endometrial type, 6 of adenoacanthoma, 4 of adenosquamous carcinoma, 3 of atypical endometrial hyperplasia) and 13 with ovarian endometrioid carcinoma were stained immunohistochemically with a rabbit polyclonal antibody prepared against the placental form of the enzyme glutathione S-transferase pi (GST-pi). Histological studies showed that the degree of staining decreased as the tumor lost its differentiation in endometrial carcinoma, but the degree of staining was independent of the differentiation in the case of ovarian endometrioid carcinoma. A comparison between the grade of staining of GST-pi in 82 cases of the endometrial type of endometrial carcinoma and 13 cases of ovarian endometrioid carcinoma revealed a stronger stain for the endometrial carcinoma than for ovarian endometrioid carcinoma (p < 0.01, Mann-Whitney's U test). Therefore, the GST-pi value for endometrial carcinoma was different from that for endometrioid carcinoma. In general, as compared with ovarian endometrioid carcinoma, endometrial carcinoma is considered to be resistant to chemotherapeutic agents. In conclusion, these results suggest that there is an apparent correlation between the GST-pi value and chemoresistance of the tumor.

[Adjuvant chemotherapy with cyclophosphamide, adriamycin, and CDDP (CAP) for high risk endometrial cancer after complete surgery].

One hundred and six patients with endometrial cancer were treated at Tsukuba University Hospital between 1983 and 1992. Sixteen patients who underwent complete resection were at high risk for recurrence and were given adjuvant platinum-based, multiagent chemotherapy instead of adjuvant radiotherapy. Eligibility criteria included outer-third myometrial invasion (group 1; n = 5), pelvic lymph node metastasis (group 2; n = 3) or both myometrial invasion and lymph node metastasis (group 3; n = 8). Of these three groups at high risk for recurrence, each patient in groups 1 and 2 developed recurrence and died. In group 3 two patients developed recurrence and one patient has died. There was one treatment death due to neutropenic sepsis in group 3. The recurrence sites in all four patients were local and no distant recurrence was noted. In other words, of 15 patients (excluding one treatment death) at high risk for recurrence, three of 12 patients (25%) with deep myometrial invasion and three of 10 patients (30%) with positive pelvic lymph nodes developed recurrence and died. The other 12 patients (include one patient with recurrence; 100 months) have survived for a long interval (range, 45-131 months). The survival rates for stage I, II, III, and IV are 92.6, 89.5, 60.0%, respectively. Patients with stage I in this study had a better survival than those with stage I in the 1984 annual report of the Japan Society of Obstetrics and Gynecology (p < 0.05). The findings of this prospective clinical trial supported those of the randomized trial comparing adjuvant CAP with radiation therapy.

[An immunohistological study on expression of glutathione S-transferase pi (form) in human ovarian carcinoma].

Specimens from 102 cases of ovarian cancer were stained immunohistochemically with a rabbit polyclonal antibody prepared against the placental form of the enzyme glutathione S-transferase (GST-pi). All 28 cases of mucinous adenocarcinoma, 19 of clear cell carcinoma and 4 of malignant transformed dermoid cysts were stained positively with the GST-pi antibody. These tumors are considered to be resistant to chemotherapeutic agents as compared with other epithelial tumors. With regard to the histological grade, the degree of staining was reduced according to the loss of differentiation. An investigation of the relationship between GST-pi stain and the prognosis of the 50 patients with stage 2,3 or 4, according to the Kaplan-Meier method, revealed that the prognosis improved as the staining decreased. In conclusion, results suggested that immunohistochemical staining of GST-pi is correlated with the chemoresistance of the tumor, and may predict the outcome in patients with ovarian cancer.

Cytomorphologic, cytometric and histomorphologic observations after laser therapy for cervical lesions.

To analyze the healing process after laser therapy for cervical lesions, the clinical, cytologic, histologic and colposcopic features in 109 cases were studied chronologically. The healing process of the cervical epithelium usually began from both the squamous and columnar epithelial borders, starting around the 10th day after laser therapy; the process covered the whole tissue defect with multilayered epithelium within seven weeks. Inflammatory changes also usually abated within that time. Cytomorphologically, laser therapy resulted in the occurrence of (mostly degenerated) "fiber-type" and orangeophilic cells in smears taken during the first two weeks after treatment. Tissue repair cells were seen in smears collected from the first posttherapy day through the fourth week after laser therapy. Using computer-assisted image cytometry, the reparative cells in samples taken shortly after treatment (roughly, the first to fifth days) exhibited more hyperchromatic (3-4N) nuclei than did those in later samples; however, the mean DNA content of the early reparative cells was generally concentrated around that of the 2N reference cells. These findings suggest that follow-up, including cytologic and colposcopic examination, for the early detection of residual or recurrent lesions should start in the eighth week and continue periodically for at least one year.

[Key points and problems concerning chemosensitivity tests, with special reference to MTT assay].

Recently, the semiautomated tetrazolium-based MTT colorimetric assay have been used to measure chemosensitivity. We also have been used this assay for 4 ovarian clear cell carcinoma cell lines to investigate the chemosensitivity of this tumor. In this study, several problems have been faced to be solved. In this paper, we pointed out these problems and indicated solutions.

Age-related change in tissue-to-plasma partition coefficient of cefazolin for noneliminating organs in the rat.

Age-related changes in tissue distribution characteristics of cefazolin, a cephalosporin antibiotic, were examined for noneliminating organs of rats. The in vivo tissue-to-plasma partition coefficients (Kp,vivo) varied markedly among different ages and organs. In particular, muscle and skin acted as reservoirs for cefazolin distribution. There were also marked differences in interstitial fluid space (IS), determined using [14C]inulin, among different ages and organs. For muscle and bone, the magnitude of the age-related changes in Kp,vivo of cefazolin and IS was in the order of 1-week-old greater than 7-week-old = 100-week-old greater than 50-week-old rats. This is well correlated with the age-related changes in the volume of distribution at the steady state of cefazolin per body weight (Vdss/BW) and the extracellular fluid volume per body weight (Vecw/BW) determined previously using [14C]inulin. The predicted Kp value (Kp,pred) was estimated by incorporating the serum protein binding parameters of cefazolin, the IS values, and an interstitial-to-plasma albumin concentration ratio (AR) into equations derived from an extracellular fluid model. The Kp,pred values exhibited a fairly good correspondence with the Kp,vivo values determined for various organs, except gut, in rats of all four ages. These results suggest that the determinant of the age-related change in Vdss/BW is the difference in the IS value of muscle and bone, while the age-related change in serum protein binding plays only a modest role.

Tracheobronchial rupture caused by blunt chest trauma: acute respiratory management.

The clinical management of 12 patients with major intrathoracic tracheobronchial rupture (complete, 3; incomplete, 9) due to blunt trauma has been reviewed and compared with that of two groups of patients with chest injuries not involving the tracheobronchial tree, 17 patients with multiple rib fractures and 17 with chest injuries requiring thoracotomy for control of pneumothorax and hemothorax. The effect of injury on ventilatory function was significantly greater in the patients with tracheobronchial injury in whom an elevated PCO2 at the time of admission was associated with a poor prognosis. Conventional ventilatory management with endotracheal intubation and positive pressure ventilation causing increased air leakage produced further deterioration of pulmonary function in four of the patients with tracheobronchial disruption. The use of a double-lumen endobronchial tube in two patients with tracheobronchial rupture facilitated ventilatory support and subsequent operative management.

A case of nontraumatic clostridial gas gangrene occurring in a patient with colon adenocarcinoma, liver cirrhosis, and diabetes mellitus.

An autopsy case of clostridial gas gangrene occurring in a 54-year-old man with colon adenocarcinoma, liver cirrhosis, and diabetes mellitus is reported. The patient died 4 days after the onset of symptoms with episodes of vomiting and abdominal pain. Gangrene of both hips and perineum, hemolysis, renal failure, and disseminated intravascular coagulation were the dominant clinical features. Clostridium septicum was isolated from the subcutaneous tissue fluid. Adenocarcinoma of the ascending colon with ulceration found at autopsy was supposed to be an entry of the organism. Histologically, lesions of subcutaneous tissue and muscles were characterized by the absence of inflammatory infiltrates in spite of extensive necrosis. A summary of 35 cases of gas gangrene hospitalized to the Osaka University Hospital for the past 16 years indicates that clostridial gas gangrene patients with underlying diseases such as malignant neoplasm, diabetes, liver cirrhosis or immunodeficiency have a relatively poor prognosis.

Age-related change of cefazolin binding to rat serum proteins and its relation to the molar ratio of free fatty acid to serum albumin.

The binding of cefazolin to rat sera has been studied as a function of age. A significant difference was observed in the cefazolin binding to serum protein among 1-, 2-, 3-, 5-, 7-, 50- and 100-week-old rats. There was a good correlation between the dissociation constants of cefazolin binding and the molar ratio of free fatty acid to albumin concentration in sera. This suggests that both changes of concentration of albumin and free fatty acid, which could be a major endogenous inhibitor of cefazolin binding, play an important role in the age-related changes of the serum protein binding. Removal of free fatty acid in 1- and 2-week-old rat sera showed marked increases of the cefazolin binding. On the contrary, addition of oleic acid to 7-week-old rat serum produced significant reduction of cefazolin binding to rat serum protein. Accordingly, free fatty acid could effectively inhibit the cefazolin binding in the physiological concentration range with increasing age, and the age-related changes of cefazolin binding to rat serum protein appear to be due to the fluctuation of the molar ratios of free fatty acid to albumin concentration in sera.

Physiologically based pharmacokinetic model for cefazolin in rabbits and its preliminary extrapolation to man.

In the present study, the physiologically based pharmacokinetic model, which succeeded previously in predicting the pharmacokinetics of beta-lactam antibiotics in rats [A. Tsuji, T. Yoshikawa, K. Nishide, H. Minami, M. Kimura, E. Nakashima, T. Terasaki, E. Miyamoto, C.H. Nightingale, and T. Yamana: Physiologically based pharmacokinetic model for beta-lactam antibiotics. I: tissue distribution and elimination in rats. J. Pharm. Sci. 72, 1239-1252 (1983)], was applied to cefazolin pharmacokinetics in rabbits and man. After iv bolus dosing in normal rabbits, the time courses of cefazolin concentration in plasma and various tissues (lung, heart, muscle, skin, bone, gut, liver, and kidney) were found to be very similar to those in rats. The values of physiological parameters (tissue plasma flows, tissue volumes, tissue/plasma albumin ratio) and biochemical parameters determined in this study (for nonlinear plasma protein binding, intrinsic renal clearance of active secretion and reabsorption) were incorporated into mass balance equations derived from the model. There was reasonable agreement between the model predictions and the observed data for cefazolin and inulin in rabbits. The model was also successful in the prediction of cefazolin disposition in rabbits with renal failure. Using available information reported for cefazolin in man, a preliminary extrapolation from the present model was attempted, and the overall predicted results after iv administration of 1 g cefazolin in man were compared with the serum and bone tissue data. The length of the effective antibacterial period for the drug is also discussed in terms of its predicted concentration unbound with proteins in various tissue interstitial fluids in man.