Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors.

BACKGROUND: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. PATIENTS AND METHODS: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). RESULTS: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). CONCLUSIONS: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.

Magnetic relaxations of antiferromagnetic nanoparticles in magnetic fields.

We reexamine anomalous magnetic relaxations of ferritin in magnetic fields, the presence of which has been regarded as evidence suggesting the existence of thermally assisted macroscopic quantum tunneling in antiferromagnetic nanoparticles. In the present study, relaxation curves of ferritin are examined using an approach that is free from assumptions regarding distributions of various parameters of polydispersive particles. The results are not anomalous. In other words, the relaxation is accelerated by the field, as expected for classical superparamagnetic fluctuations.

[Diagnosis of prostate capsular invasion by pelvic magnetic resonance imaging and serum level of prostate specific antigen].

Transrectal ultrasonography (TRUS), computed tomography (CT), and magnetic resonance imaging (MRI) are employed to diagnose the clinical stage of prostate cancer. However, several cases are diagnosed as pathological stage pT3 after total prostatectomy. We investigated the accuracy of the evaluation of pathologic capsular penetration by preoperative pelvic MRI and preoperative serum PSA level and capsular penetration. The diagnostic accuracy of capsular penetration by MRI was 63.3%. On the other hand, the diagnostic accuracy of capsular penetration by preoperative PSA was 89.7% when its cut off value was 17 ng/ml. We conclude that preoperative serum PSA level could be more useful to diagnose accurately stage of prostate cancer than pelvic MRI.

Phase transitions of iron-nitride magnetic fluids.

Phase transitions of magnetic fluids in the zero field were studied from the viewpoint of static susceptibility and typical relaxation time in order to distinguish between the transitions and the blocking phenomena. We used iron-nitride magnetic fluids containing nearly uniform particles so as to remove the effects of particle-size distribution. In the densest sample, we observed the growth of ferromagnetic fluctuations and, in the diluted samples, a temperature-induced first-order phase transition.

Induction of Extra Claws on the Chelipeds of a Crayfish, Procambarus clarkii.

In a crayfish, Procambarus clarkii, growth of an extra claw was induced by making a V-shaped wound in the proximal end of the propodus of the second and third chelipeds. Two nerve bundles were damaged by the wounding. Some type of extra growth developed on the propodi of 13 of the damaged chelipeds: a pair of extra claws (2 chelipeds), a pair of extra dactyls (1 cheliped), a single extra dactyl (2 chelipeds), and a single slight projection (8 chelipeds). The extra claws and dactyls developed from the peripheral side of the propodus away from the wound site. One of a pair of extra dactyls and the single extra dactyls could be moved only slightly, either manually or by the crayfish. The other extra dactyls could be moved by the crayfish. Muscles were associated with each of the extra and primary claws. The muscles attached to the double extra claw or dactyl were innervated by nerve bundles that were branches from the primary thick nerve bundles. One possible explanation for these findings is that the severed nerve fibers in the thick nerve bundles regenerate, elongate into aberrant roots, and form extra claws or dactyls.

Suppression of allograft responses induced by interleukin-6, which selectively modulates interferon-gamma but not interleukin-2 production.

BACKGROUND: Interferon (IFN)-gamma produced by activated T cells represents an important effector cytokine in mediating an inflammatory response. METHODS: The present study investigated the modulation of allograft responses by inhibiting IFN-gamma production. C57BL/6 (B6) lymph node cells were stimulated with class II H2-disparate B6-C-H-2bm12 (bm12) spleen cells. RESULTS: Addition of interleukin (IL)-6 to the primary B6 anti-bm12 mixed lymphocyte reaction (MLR) inhibited neither proliferative responses nor IL-2 production. However, IL-6 induced a dose-dependent suppression of IFN-gamma production in the same MLR cultures. B6 mice were engrafted with bm12 skin grafts, and IL-6 was given to bm12 skin graft recipients every other day. T cells from these recipient mice produced significantly less IFN-gamma in secondary B6 anti-bm12 MLR than those from bm12 skin graft recipients that had not received IL-6 injections. IFN-gamma production by these T cells was suppressed more strongly when the secondary MLR was conducted in the presence of IL-6. In addition to suppression of IFN-gamma expression, IL-6 injections resulted in prolongation of bm12 skin graft survival. The critical involvement of IFN-gamma in anti-bm12 rejection responses was substantiated by evidence that administration of anti-IFN-gamma monoclonal antibody strikingly prolonged bm12 skin graft survival. The prolongation of graft survival by in vivo treatment with either IL-6 or anti-IFN-gamma monoclonal antibody was found to be induced without blocking cellular infiltration of the grafts. CONCLUSIONS: These results indicate that IFN-gamma acts as a key cytokine in a B6 anti-bm12 allograft response and that IL-6 may down-regulate this response by inhibiting IFN-gamma production of alloreactive T cells.

Enzymatic hydrolysis of the conjugate of vitamin D and related compounds.

The monoglucuronides of vitamin D, 25-hydroxyvitamin D and the corresponding pro-forms were subjected to enzymatic hydrolysis using beta-glucuronidase, and substrate specificities were found in the examined enzymes originating from different sources, which were determined using reversed-phase high-performance liquid chromatography with UV detection. The enzymatic hydrolysis of the corresponding monosulfates was also examined using the same system.

Characterization of monoglucuronides of vitamin D2 and 25-hydroxyvitamin D2 in rat bile using high-performance liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

The characterization of vitamin D2 3-glucuronide, 25-hydroxyvitamin D2 3-glucuronide and 25-hydroxyvitamin D2 25-glucuronide, biliary metabolites obtained from rats dosed with vitamin D2 and 25-hydroxyvitamin D2 per os, was carried out using HPLC-atmospheric pressure chemical ionization (APCI)-MS. The glucuronide obtained from bile specimens was identified by comparison of its chromatographic behaviour with an authentic sample using HPLC-APCI-MS operating in the negative-ion mode. Methylation of the respective fraction with diazomethane gave the methyl ester, which was also confirmed by HPLC-APCI-MS operating in the positive-ion mode. The (M-H)- and (M + NH4)+ ions were monitored in the selected-ion monitoring mode.

Separation and characterization of monoglucuronides of vitamin D(3) and25-hydroxyvitamin D(3) in rat bile by high-performance liquid chromatography.

The separation and characterization of vitamin D(3)- and 25-hydroxyvitamin D(3)-monoglucuronides, biliary metabolites obtained from rats dosed with D(3) and 25-hydroxyvitamin D(3) per os, respectively, were carried out by HPLC. The glucuronide fractions were obtained from bile specimens by the combined use of a Bond Elut C18 cartridge, for solid phase extraction, and a lipophilic gel (piperidinohydroxypropyl Sephadex LH-20), for ion-exchange chromatography. Each glucuronide was identified by comparison with an authentic sample in three ways: its chromatographic behavior, that of its fluorescent labeled derivative using 4-[4-(6-methoxy-2-benzoxazolyl)phenyl]-1,2,4-triazoline-3,5- dione and data obtained following enzymatic hydrolysis using beta-glucuronidase.

Cardiopulmonary bypass and cellular immunity: changes in lymphocyte subsets and natural killer cell activity.

To investigate whether cell-mediated immunity responses are suppressed or activated by the effect of cardiopulmonary bypass (CPB), we studied peripheral blood lymphocyte subsets and antibody-dependent cell-mediated cytotoxicity in 52 adult patients who had undergone open heart operations. Lymphocyte function also was studied with regard to mixed lymphocyte reaction, which indicates the amount of DNA synthesis of lymphocytes, and natural killer (NK) cytotoxicity, which represents the killing activity of NK cells on the tumor cells (K-562), in 11 patients. The total T lymphocyte (OKT3+ and OKT11+) number showed no significant change during CPB. Suppressor/cytotoxic T cell (OKT8+) and NK cell (Leu7+ and Leu11+) numbers were found to be remarkably increased. However, helper/inducer T cell (OKT4+) and B cell (Leu12+) numbers were decreased during CPB. Antibody-dependent cell-mediated cytotoxicity was elevated during CPB. All of these changes were almost returned to the preoperative levels by the seventh day after operation. Mixed lymphocyte reaction and NK cytotoxicity were also activated during CPB. The results show that heart operations in which cardiopulmonary bypass is used are associated with activation of cytotoxic cell-mediated immunity.