In vitro metabolism of fenthion and fenthion sulfoxide by liver preparations of sea bream, goldfish, and rats.

The in vitro metabolism of fenthion and its sulfoxide (fenthion sulfoxide) in sea bream (Pagrus major) and goldfish (Carassius auratus) was investigated and compared with that in rats. Fenthion was oxidized to fenthion sulfoxide and the oxon derivative, but not to its sulfone, in the presence of NADPH by liver microsomes of sea bream, goldfish, and rats. These liver microsomal activities of the fish were lower than those of rats but were of the same order of magnitude. The NADPH-linked oxon- and sulfoxide-forming activities of liver microsomes of the fish and rats were inhibited by SKF 525-A, metyrapone, alpha-naphthoflavone, and carbon monoxide. The oxidizing activity to fenthion sulfoxide was also inhibited by alpha-naphthylthiourea. Several cytochrome P450 isoforms and flavin-containing monooxygenase 1 exhibited these oxidase activities. Fenthion sulfoxide was reduced to fenthion with liver cytosol of the fish and rats upon addition of 2-hydroxypyrimidine, N(1)-methylnicotinamide, or butyraldehyde, each of which is an electron donor of aldehyde oxidase, under anaerobic conditions. The activity was inhibited by menadione, beta-estradiol, and chlorpromazine, which are inhibitors of aldehyde oxidase. The activities in the fish livers were similar to those of rat liver. Aldehyde oxidase purified from the livers of sea bream and rats exhibited the reducing activity. Thus, fenthion and fenthion sulfoxide are interconvertible in fish and rats through the activities of cytochrome P450, flavin-containing monooxygenase, and aldehyde oxidase.     

Development of stereotactic irradiation system of body tumors under respiratory gating

Stereotactic radiosurgery for body tumors is hampered by the difficulties in body fixation and respiratory motions of the tumor. We have developed a Microton-based system for the stereotactic irradiation of body tumors, which delivers radiation at a predetermined respiratory phase. The patients are fixed non-invasively in the custom-made bed, and CT images are obtained. The isocentor is calculated with reference to those images and is marked onto the patient's skin and the custom-made bed. The patient lying on the bed is transferred to the treatment couch of the Microtoron. After reproducing the isocenter, actual treatment is started. The treatment couch as well as the gantry move automatically around the isocenter according to the treatment planning. The circular collimator moves by computer control to reduce geometrical errors to less than 0.5 mm, which is evoked by gantry movement. Respiratory movement of the abdominal wall is measured by laser displacement monitor. The Microtron delivers X-rays at a predetermined respiratory phase with a lag time of 20 msec after the on-signal from the monitor.     

Primary Sjögren's syndrome initially manifested by optic neuritis: MRI findings

We herein describe the MRI findings in a patient clinically diagnosed with primary Sj?gren's syndrome (SjS) initially manifested by retrobulbar optic neuritis. A 63-year-old woman suddenly had left ocular pain and progressive visual disturbance. MR T2-weighted images revealed hyperintensity in the left optic nerve, with swelling. Contrast-enhanced T1-weighted images showed no abnormal enhancement. Follow-up MRI 6 months after admission revealed no significant changes in the affected optic nerve. To our knowledge, optic neuritis as a complication of SjS has been reported in ten patients [1, 2, 3, 4, 5, 6] and MRI findings in only one of them [6]. We thought MR images were useful for visualizing optic nerve involvement in SjS and observing its course.     

Four highly oxygenated isopimarane-type diterpenes of Orthosiphon stamineus

Four highly oxygenated isopimarane-type diterpenes, named orthosiphols O, P and Q and nororthosiphonolide A, have been isolated from the aerial parts of Orthosiphon stamineus from Myanmar, together with three known diterpenes, orthosiphols D and E and orthosiphonone A. Their structures were determined on the basis of extensive spectral analysis. All the isolated compounds displayed mild antiproliferative activities against highly liver metastatic colon 26-L5 carcinoma and human HT-1080 fibrosarcoma cell lines.     

Development of transdermal formulation of tulobuterol for the treatment of bronchial asthma

beta 2-Adrenergic agonists have been widely used to treat patients with asthma. Usually, oral dosage forms of beta 2-agonists have been used, but side effects such as palpitation and tremor have been reported because of excessive serum levels around Tmax. It is said that circadian variations exist in the manifestation of asthma with maximum incidence of asthma attacks in early morning at around 4 a.m., the so-called morning dip. Chronotherapy for asthma based on circadian rhythm should be more efficient and have a lower frequency of side effects. Accordingly we developed a transdermal delivery system of the beta 2-agonist tulobuterol adapted to the circadian rhythm. The system is designed to administer the appropriate dose of the drug at an optimal time using the so-called Crystal Reservoir System. The superiority of the transdermal formulation of tulobuterol over the current therapy using oral formulations of beta 2-stimulants was indicated by its excellent pharmacokinetic profile, and confirmed by the results of clinical trials. This formulation is the first transdermal chrono-delivery system reported anywhere in the world, and is expected to provide more effective and safe treatment of asthma and related diseases not only in adults, but also especially in children.     

A case report of both CAF and docetaxel-resistant breast cancer responding to paclitaxel weekly therapy

A 58-year-old woman underwent CAF and docetaxel therapy for lung, liver and bone metastases from breast cancer operated on 14 years ago. Because of progressive disease due to secondary resistance to CAF and docetaxel, the patient was given three courses of paclitaxel therapy (60 mg/m2, day 1, 8, 15, repeated every 4 weeks). The paclitaxel weekly therapy brought about no adverse effects and remarkable effects against lung and liver metastases (PR). Although the duration of the response to the paclitaxel therapy was limited to about two months due to the progression of skull bone metastasis, paclitaxel weekly therapy may be effective against both CAF and docetaxel-resistant breast cancer.     

Beneficial Effects of Immediate Enteral Nutrition After Esophageal Cancer Surgery

This study was conducted to determine the effects of immediate enteral nutrition (EN) on nutritional status, immunological competence, and the suppression of excessive inflammatory responses in patients following esophageal cancer surgery. Twenty-four patients who underwent the same elective operation for thoracic esophageal carcinoma were randomized into an immediate enteral nutrition (IEN) group who received EN from postoperative day (POD) 1 and a parenteral nutrition (PAN) group. Both groups received comparable volumes and calories on the same POD. Laboratory studies were carried out preoperatively and on PODs 1–7. Other nutritional and immunological assessments were repeated on PODs 1 and 7. Plasma concentrations of nitrate and nitrite were also measured. All of the patients in the IEN group tolerated enteral feeding well. There were no significant differences in the results of nutritional assessments, lymphocyte function, or plasma nitrate and nitrite levels between the two groups. The IEN group showed a significantly earlier recovery of the total lymphocyte count. The serum levels of total bilirubin and C-reactive protein were significantly attenuated in the IEN group. These results indicate that immediate EN may have beneficial effects on immunological competence and the suppression of excessive inflammatory responses in patients following esophagectomy. Patients undergoing radical esophageal surgery who are subjected to severe surgical stress might benefit the most from early EN. Received: November 13, 2000 / Accepted: May 15, 2001     

Perioperative management of a patient with systemic lupus erythematosus, myasthenia gravis, and pemphigus foliaceous]

A 38-year-old female with systemic lupus erythematosus (SLE), myasthenia gravis (MG), and pemphigus foliaceous (PF) was scheduled to undergo total hysterectomy and lymphadenectomy. Preanesthetic examination revealed anemia, a prolonged activated partial thromboplastin time, and a reduced percent vital capacity. Antiphospholipid antibody was not positive. After treating the bullous lesions of PF and the muscle weakness due to MG (noted on admission for surgery) with oral prednisolone, the patient was scheduled for surgery. To avoid the use of a muscle relaxant and the potential complications of the airway manipulation involved in using a laryngeal mask or endotracheal tube, since the patient had MG and PF, a regional anesthetic technique was selected. This involved continuous epidural anesthesia, achieved using 1% or 2% mepivacaine, with sedation by a combination of propofol infusion (3 mg.kg-1.hr-1) and nitrous oxide (60% in oxygen). The patient breathed spontaneously under the mask throughout the 3.5-hr operation. The intraoperative surgical and anesthetic course was uneventful. After a benign postoperative course, the patient was discharged on the 16th postoperative day.     

Three-color flow cytometric study on lymphocytes derived from thymic diseases.

BACKGROUND: Anterior mediastinal masses derive from a variety of diseases. Thymomas have been shown to commonly hold CD4(+)CD8(+) double-positive (DP) lymphocytes, and identification of this subset by two-color flow cytometric study was suggested to help diagnosis of thymoma. Several other thymic diseases, however, possibly hold CD4(+)CD8(+) DP lymphocytes. In this study, we utilized the three-color flow cytometric method for further examination of the phenotypes of lymphocytes in the thymic diseases. MATERIALS AND METHODS: One hundred eight specimens (77 primary and 10 metastatic thymomas, 10 thymic carcinomas, 2 thymic carcinoids, 4 malignant lymphomas, 2 seminomas, an inflammatory pseudotumor, and 2 nonneoplastic thymic hyperplasias) were subjected to the study. The expressions of CD3, CD4, and CD8 on tumor-associated lymphocytes were evaluated by three-color flow cytometric study. RESULTS: The proportion of the CD4(+)CD8(+) DP subset was more than 30% in all 78 lymphocyte-rich thymomas, in 2 malignant lymphomas, and in both thymic hyperplasias. CD3 expression of the CD4(+)CD8(+) DP subset ranged from a negative to a high level in thymomas and thymic hyperplasias, while it was restricted to a particular level in CD4(+)CD8(+) DP-type malignant lymphomas. The proportion of CD3(+) cells in the CD4(+)CD8(-) single-positive subset was consistently less than 90% in the lymphocyte-rich thymomas, while it was more than 90% in the thymic hyperplasias. CONCLUSION: Although identification of the CD4(+)CD8(+) DP subset in the tumor-associated lymphocytes does not necessarily indicate thymoma, a further characterization of thymic neoplasms possessing the CD4(+)CD8(+) DP subset was enabled by three-color flow cytometric study, suggesting the utility of this method as an ancillary tool for differential diagnosis of these diseases.     

Pharmaceutical and Biomedical Differences between Micellar Doxorubicin (NK911) and Liposomal Doxorubicin (Doxil)

The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of DXR inside micelles or liposomes in an aqueous solution is known to be strongly quenched by the outer shells of the micellar or liposomal formation. Thus, by measuring the fluorescence intensity of DXR released from NK911 or Doxil, we could determine the stability of the micellar or liposomal DXR formation. Furthermore, NK911 was found to be less stable than Doxil in saline solution. In drug distribution experiments using an in vitro solid tumor model, when spheroids formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the spheroids, including their center. On the other hand, when the spheroids were exposed to Doxil, DXR was distributed only to the surface of the spheroids. It has been suggested that Doxil can deliver DXR to a solid tumor more efficiently than NK911 via the EPR (enhanced permeability and retention) effect, because Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in NK911 may be distributed by diffusion to cancer cells distant from the tumor vessel, because NK911 can leak out of the tumor vessel and may be able to release free DXR more easily than Doxil. It has been suggested that drug carrier systems such as liposomes and micelles should be selected appropriately bearing in mind the characteristics of the tumor vasculature and the tumor interstitium.