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).

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.

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.

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.

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.

Degradation kinetics and mechanism of aminocephalosporins in aqueous solution: cefadroxil.

The degradation kinetics and mechanism of a new, orally effective cephalosporin derivative, cefadroxil, in aqueous solution were investigated at pH 2.51-11.5 at 35 degrees and ionic strength 0.5. The degradation rates were determined by high=pressure liquid chromatography. At constant pH and temperature, the degradation followed first-order kinetics and a log k-pH profile was presented. The shape of the rate-pH profile resembled that for cephalexin or cephradine under the same conditions. Citrate and phosphate buffers enhanced general acid and base catalysis of the degradation. In aqueous solution, cefadroxil was shown to degrade by three parallel reactions: (a) intramolecular aminolysis by the C-7 side-chain amino group on the beta-lactam moiety, (b) water-catalyzed or spontaneous hydrolysis, and (c) beta-lactam cleavage by the nucleophilic attack of hydroxide ion. In neutral and weak alkaline solutions, the main degradation products were two piperazine-2, 5-diones and 3-hydroxy-4-methyl-2(5H)-thiophenone, the former being formed from Reaction a, while the latter arose via the degradation pathways of Reaction b and/or c.

Physiologically based pharmacokinetic model for beta-lactam antibiotics I: Tissue distribution and elimination in rats.

The disposition characteristics of beta-lactam antibiotics in rats were investigated, and a physiologically based pharmacokinetic model capable of predicting the tissue distribution and elimination kinetics of these drugs was developed. Protein-binding parameters in rat serum were determined by equilibrium dialysis. Linear binding was found for penicillin G, methicillin, dicloxacillin, and ampicillin; however, nonlinear binding was observed for penicillin V and cefazolin. After intravenous bolus dosing, cefazolin was recovered almost completely in urine and bile, while for the penicillins, penicilloic acid was found to be the major metabolite. Biliary excretion of cefazolin followed Michaelis-Menten kinetics, and no significant inhibition of urinary secretion was observed after probenecid administration. The renal clearance of unbound drug was 0.82 ml/min with a reabsorption ratio (R) of 0.22. Tubular secretion was inhibited for the penicillins by probenecid plasma concentrations of 50 micrograms/ml, resulting in an R-value of 0.32. Erythrocyte uptake, serum protein binding, and tissue-to-plasma partition coefficient (Kp) were measured. Theoretical Kp values were calculated and found to be in good agreement with the Kp values for three of the antibiotics. Plasma and tissue concentrations (lung, heart, muscle, skin, gut, bone, liver, and kidney) were measured as a function of time at various doses for inulin and cefazolin in rats after an intravenous bolus dose, and were found to be in reasonable agreement with concentrations predicted by the model. These correlations demonstrate that the proposed model can accurately describe the plasma and tissue contributions of inulin and cefazolin in the rat and suggest that this model could have utility in predicting drug distribution in humans.

[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.

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.

[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.

[Right-sided traumatic diaphragmatic hernia following blunt trauma].

The mechanism of right-sided traumatic diaphragmatic hernia following blunt trauma was examined. In 13 cases of Traumatic diaphragmatic hernia admitted to the Department of Traumatology Osaka University Hospital, 3 cases were on the right. All cases were associated with severe injuries in the chest, abdomen and pelvis. Rib fractures, hemothorax, and liver injury were seen in the same site of the ruptured diaphragm. So it seemed that there were some differences in the force itself caused diaphragmatic rupture between right-sided and left. We reviewed 40 cases of right-sided traumatic diaphragmatic hernia reported in Japan. The following results were obtained. Main force which caused right-sided diaphragmatic rupture was the blunt impact to the right thoracic wall. In the right-sided diaphragmatic hernia, the most frequently herniated organ was the right lobe of the liver and there was high-frequency of G-I tract herniation in delayed types. Herniation of the abdominal organs seemed to be varied as the time passed.