Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies.

BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. PATIENTS AND METHODS: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. RESULTS: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure. CONCLUSION: OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored. CLINICALTRIALSGOV IDENTIFIER: NCT01184807.

Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene.

The xeroderma pigmentosum variant (XP-V) is one of the most common forms of this cancer-prone syndrome. XP groups A through G are characterized by defective nucleotide excision repair, whereas the XP-V phenotype is proficient in this pathway. The XPV gene encodes DNA polymerase eta, which catalyzes an accurate translesion synthesis, indicating that the XPV gene contributes tumor suppression in normal individuals. Here we describe the genomic structure and chromosomal localization of the XPV gene, which includes 11 exons covering the entire coding sequence, lacks a TATA sequence in the upstream region of the transcription-initiation, and is located at the chromosome band 6p21.1-6p12. Analyses of patient-derived XP-V cell lines strongly suggested that three of four cell lines carried homozygous mutations in the XPV gene. The fourth cell line, XP1RO, carried heterozygous point mutations in the XPV gene, one of which was located at the splice acceptor site of exon 2, resulting in the omission of exon 2 from the mature mRNA. These findings provide a basis for diagnosis and therapy of XP-V patients.

The entrapment of kojic oleate in bilayer vesicles.

The entrapment of kojic acid and its newly synthesized ester (kojic oleate) has been evaluated. Kojic oleate was synthesized by DCC (N,N'-dicyclohexylcarbodiimide, DCC)/(4-(N,N-dimethylamino)pyridine, DMAP) esterification method and identified by FAB-MS and 1H NMR. The synthesized product was mainly 7-O-kojic oleate with more than 80% yield. It was entrapped in vesicular membrane prepared from 9.5:9.5:1.0 molar ratio of amphiphiles (Span 60, Tween 61 or DPPC), cholesterol and dicetyl phosphate. Kojic acid was encapsulated in the water compartment of these vesicles in order to confirm the vesicle formation. The morphology and particle size of the vesicles were characterized by an optical microscope and transmission electron microscope (TEM). The entrapment efficiencies of kojic acid and kojic oleate in the vesicles were investigated by dialysis and column chromatography, respectively. The contents of the entrapped kojic acid and kojic oleate were assayed by HPLC. The entrapment efficiency of kojic acid was 0.01-0.04 mol, whereas kojic oleate gave higher entrapment efficiency of 0.25-0.35 mol/mol of the total compositions of amphiphile/cholesterol/dicetyl phosphate. Structural modification of kojic acid improved its entrapment in the vesicles. Tween 61 vesicles could entrap kojic oleate more than did Span 60 vesicles. The pi-A isotherms revealed the lower area per molecule of Span 60, which formed a more rigid pack of its molecule on air/water interface than that of Tween 61. This implied the high rigidity of vesicular membrane prepared with Span 60 led to the lower amount of kojic oleate entrapped in the vesicles. From the release study of kojic acid through the dialysis membrane, it indicated that the intercalation of kojic oleate in the vesicular membranes did not significantly affect the release of kojic acid from the vesicles.

A drug formulation using an alginate hydrogel matrix for efficient oral delivery of the manganese porphyrin-based superoxide dismutase mimic.

In order for patients to avail of the therapeutic benefits of antioxidant drugs efficiently and conveniently, a robust oral delivery system needs to be developed. However, a common problem in oral drug delivery is ensuring that the drug remains functionally intact even after it has passed through the acidic environment of the gastrointestinal (GI) tract. To protect drugs within the GI environment, we formulated a design based on encapsulating liposomal drugs by using an alginate matrix as a carrier. The liposomal drug was composed of manganese porphyrin (Mn-por), which has been developed as a mimic of superoxide dismutase (SOD), as the therapeutic agent based on the antioxidative effect, namely superoxide (O2˙(-)) inhibitory activity. A cytochrome c assay revealed that the O2˙(-) inhibitory activity of Mn-por could be maintained even after treatment with simulated gastric and intestinal fluids. We demonstrated that oral administration of the formulated drug significantly inhibited the growth of transplanted tumors in mice. The drug formulation presented in this study would be a good candidate for orally available systems, which can effectively deliver SOD mimics.

Non-decay type fast-setting calcium phosphate cement: setting behaviour in calf serum and its tissue response.

Non-decay type fast-setting calcium phosphate cement (nd-FSCPC) was evaluated in terms of its setting behaviour in calf serum and its tissue response to investigate the feasibility of its clinical use in surgical applications. Non-decay type cements were prepared by adding various amounts of sodium alginate to the liquid phase of base cements, fast-setting calcium phosphate cement (FSCPC) and conventional calcium phosphate cement (c-CPC). Cement pastes were immersed in serum at 37 degrees C immediately after mixing, and decay behaviour, setting time and mechanical strength were measured to evaluate the possibility of their use in surgical applications. Also, nd-FSCPC was implanted into rat subcutaneous tissue for the initial evaluation of biocompatibility of this potential bioactive cement. nd-FSCPC set in approximately 6-7 min in serum, even when the cement paste was immersed in the serum immediately after mixing, whereas c-CPC and FSCPC decayed completely upon immersion. nd-FSCPC transforms to hydroxyapatite (HA) within 24 h and shows a diametral tensile strength of approximately 4-5 MPa. As a result of transformation to HA, nd-FSCPC showed excellent tissue response when implanted subcutaneously in rats. We conclude that nd-FSCPC has good potential value for use in orthopaedics, plastic and reconstructive surgery, and oral and maxillofacial surgery, where the cement is exposed to blood.

The inhibitory effect of vitamin E on K-ras mutation at an early stage of lung carcinogenesis in mice.

In this study, we investigated the effect of vitamin E on the activation of the K-ras oncogene with a 61st codon A-->T mutation at an early stage of urethane-induced lung carcinogenesis in mice. Thirty days after urethane injection, the K-ras mutation was detected in 64% of lung samples tested by mutant-allele-specific amplification. The consumption of a supplemented diet with about 20-times more vitamin E than the control diet, only during the promotion phase or during both the initiation and promotion phases of lung carcinogenesis, reduced the frequency of the mutation to 36 and 18%, respectively. Also, vitamin E suppressed the level of proliferating cell nuclear antigen as a marker of cell proliferation in the lungs of mice treated with urethane. These results support the notion that vitamin E is a useful chemopreventive agent against lung cancer.

Iron depletion prevents adenine nucleotide decomposition and an increase of xanthine oxidase activity in the liver of the Long Evans Cinnamon (LEC) rat, an animal model of Wilson's disease.

The Long Evans Cinnamon (LEC) rat, which accumulates excess Cu in the liver as in patients with Wilson's disease, is a mutant strain displaying spontaneous hepatitis. It was reported that Fe, like Cu, increases in the liver and that the severity of hepatitis is modified by Fe in the diet. In this experiment, oxidative stress increased by Fe was investigated before the onset of hepatitis. To examine the effect of Fe on the progress into hepatitis, LEC female rats were fed an Fe-regular (Fe 214 microg/g; Fe(+) group) or an Fe-restricted (Fe 14 microg/g; Fe(-) group) diet from 53 days of age for 35 days. Fischer rats were also fed as control animals. Adenine nucleotide decomposition was determined as an index of oxidative stress based on xanthine oxidase activity. The size of the hepatic pool of adenine nucleotides (ATP+ADP+AMP) was significantly smaller in LEC rats than Fischer rats. The energy charge (ATP+0.5ADP)/(ATP+ADP+AMP) was smaller in Fe(+) groups than in Fe(-) groups. In the LEC rat liver, the Fe concentration in the Fe(+) group was 160% of that in Fe(-) group and the correlation coefficient between the hepatic Fe concentration and the energy charge was significant. In this strain, an increase of xanthine oxidase activity resulted in an increase of xanthine, an oxidized metabolite of hypoxanthine in the liver. The results suggest the involvement of the Fe in the progression into hepatitis in the LEC rat, even if the dietary Fe concentration is similar to that of commercial diet.

The repetitive activation of extracellular signal-regulated kinase is required for renal regeneration in rat.

In this study, we investigated the activation of p42 extracellular signal-regulated kinase (ERK2) during renal regeneration after HgCl2-induced acute renal failure (ARF) in rat. ERK2 activation was observed at 5 and 29 hr after HgCl2 injection, respectively. The tyrosine phosphorylation of hepatocyte growth factor receptor (c-MET) occurred between 2.5 and 5 hr after the treatment. On the other hand, the phosphorylation of epidermal growth factor receptor (EGFR) was transiently observed at 29 hr after the injection. The peak of ornithine decarboxylase activity as a marker of G1 phase was at 10 hr, and subsequently the labeling index of proliferating cell nuclear antigen as a marker of S phase increased at 53 hr. These results indicate that the repetitive activation of ERK2 related to the phosphorylation of c-MET and EGFR is required for the renal regeneration in HgCl2-induced ARF of rat.

Activation of extracellular signal-regulated kinase in lung tissues of mice treated with carcinogen.

The activation of extracellular signal-regulated kinase (ERK) in lung tissues of mice, as determined by the appearance of phosphorylated form, was observed on day 30 after urethane injection, and the activation also occurred in urethane-induced lung tumors. Immunohistochemical analysis using anti-phosphorylated ERK antibody indicated that the active form of ERK localized in alveolar epithelial cells. Furthermore, we confirmed by immunoprecipitation and immunoblot analysis that other essential components of the ERK cascade, that is, Ras, Raf and MEK (known as ERK kinase) were activated. These results indicate that the activation of the ERK signal in alveolar epithelial cells at the early stage of urethane-induced lung carcinogenesis is an important factor to develop lung tumors.

Association of mast cells with vaginal trichomoniasis in endocervical smears.

In endocervical smears obtained from 40 women with Trichomonas vaginalis infection, 25 women with infections other than T. vaginalis and 35 cytologically normal women, inflammatory cells consistent with mast cells (tissue basophils) were examined. Mast cells were present predominantly in the smears of patients infected with T. vaginalis but were infrequent in those of patients with other infections and in those of the normal, control group. The numbers of mast cells in endocervical smears and the white blood cell counts in vaginal discharges showed a positive correlation with the degree of T. vaginalis infection. Our data seem to indicate that the presence of mast cells in the uterine cervix may be an immunologic response, possibly of an allergic nature, to T. vaginalis.

Cytologic evaluation of atypical cells in cervicovaginal smears from women with tubal pregnancies.

Cytologic changes in the cervicovaginal smears of 28 women with tubal pregnancies are described. Eleven cervicovaginal smears showed atypical cells, including two cellular patterns: glandular type and naked-nuclei type. About 60% of the cases with atypical cells included the naked-nuclei type of cell, which showed wide variations in nuclear size. Polyploid Feulgen DNA distributions were noted for both types of cells, which probably originate with the Arias-Stella reaction of the endometrium. The cytologic observation of atypical Arias-Stella cells in cervicovaginal smears may be useful in the early diagnosis of ectopic pregnancy, especially if both cell types are present.

The presence of mast cells in IUD smears. A preliminary report.

PIP: A study on IUD-induced cytologic changes is reported, and new preliminary findings of large numbers of mast cells (tissue basophils) in addition to macrophage development are emphasized. 20 Ota rings were removed within 10 days after menstruation; the devices had been in place from 1-7 years. Touch preparations were made from the IUDs and from 20 controls without inflammatory changes. In the IUD smears, the mean number of mast cells per 2 slides was 311; whereas in control smears, the mean was only 49. No correlation between the number of mast cells and the period the IUDs were in situ was found. Histologically, the IUDs were associated with marked leukocyte infiltrate. Others have noted the changes in immunoglobulin concentration resulting from IUD use. Since mast cells are known to have receptors for immunoglobulin E, these results suggest that mast cells may have an important role in the antifertility action or foreign body reactions of IUDs.^ieng

The cells from intrauterine contraceptive devices: with special reference to the occurrence of mast cells.

A study of cytologic smears from 26 women using intrauterine contraceptive devices (IUDs) confirmed our previous findings for mast cells and further defined the averages, proportions and types of cells in IUD smears. The average number of cells was found to be 65.5 x 10(4), with a range of 1.3 x 10(4) to 280 x 10(4). The cellular proportions found were 49.0% macrophages, 42.7% polymorphonuclear leukocytes, 4.0% endometrial glandular cells, 1.3% mast cells and 3.0% other cells. Total nucleated-cell counts showed one group with a large number of cells (greater than 5 x 10(5) cells) and another group with a smaller number of cells (less than or equal to 5 x 10(5) cells). These groups showed significant differences in cell types, with a predominance of polymorphonuclear leukocytes in the former and macrophages in the latter. The mast cell counts were similar in both groups. The data suggest that mast cells have a role in IUD functioning. It may be based on an immunologic mechanism.

Cytologic findings in postpartum and postabortal smears.

A study was undertaken to evaluate the cytologic features of pregnancy-induced cell patterns (PIP) observed in postpartum and postabortal cervicovaginal smears. A total of 3,000 PIP were evaluated and studied by an indirect immunofluorescent technique using human chorionic gonadotropin (HCG). Three characteristic types of PIP were demonstrated. In type I PIP, the cells had a sheetlike arrangement with a fine chromatin pattern and were thought to be of decidual origin. Type II PIP were shed in clumps and had round nuclei, cytoplasmic vacuoles and coarse chromatin. They were thought to originate in the endometrium with the Arias-Stella reaction. Type III PIP were large and had large nuclei with marked atypism. They were thought to be cytotrophoblasts. Almost all of the type III PIP were positive with the anti-HCG stain. It is concluded that this classification and analysis is significant and could reduce the number of false-positive cytology reports on postpartum and postabortal smears.

Biliary excretion of copper, manganese, and horseradish peroxidase in Eisai hyperbilirubinemic mutant rats (EHBRs) with defective biliary excretion of glutathione.

A mixture of copper (Cu) (0.38 mg/kg), manganese (Mn (0.038 mg/kg), and horseradish peroxidase (HRP) (5.0 mg/kg) was injected intravenously (i.v.) into mature Eisai hyperbilirubinemic rats (EHBRs) and Sprague-Dawley rats (SDRs). Bile was collected at 10-min intervals before and after the injection, under anesthesia. The liver, kidneys, and blood were removed 40 min after the injection. The serum conjugated bilirubin concentration was 0.85 mg/dL in the EHBRs, but was below detection limits in the SDRs. The bile-reduced glutathione (GSH) concentration was much lower in the EHBRs (0.04 mg/mL) than in the SDRs (1.30 mg/mL). However, the hepatic GSH concentration was about 1.6 times higher in EHBRs (2.26 mg/g liver) than in SDRs (1.43 mg/g liver). The low excretion of biliary GSH was not caused by the activity of GGT in the liver, since there was no significant difference in the activity between the two groups (5.8 +/- 3.4 and 4.6 +/- 2.4 mumol p-nitroaniline/g protein/30 min in SDR and EHBR groups, respectively). There was a delay of initial biliary excretion of Cu in EHBRs compared to SDRs. The biliary concentration of Mn was slightly lower in EHBRs than in SDRs. Forty min after the injection of metals, however, there was no difference between hepatic concentrations of the two metals in the two groups. Our results suggest that abnormal deposition of the two metals is not observed naturally in EHBRs. Injected HRP was excreted rapidly and notably in the EHBRs compared to SDRs. Furthermore, the biliary concentration of beta-N-acetyl-D-glucosaminidase (beta-NAG) was significantly higher in EHBRs than in SDRs, Rapid biliary excretion of Cu, but not of Mn, may be related to the hepatobiliary transport of GSH, but the transport and lysosomal function do not originally regulate the biliary excretion of Cu.

Bronchial atresia: three-dimensional CT bronchography using volume rendering technique.

We report a case of asymptomatic bronchial atresia of the anterobasal and laterobasal segments of the right lower lobe. Because of the absence of typical bronchial mucocele on chest radiograph, it was difficult to base the diagnosis on chest radiography alone. Helical CT images demonstrated the characteristic appearance of bronchial atresia, and three-dimensional (3D) CT bronchography using the volume rendering technique helped us to comprehend the spatial relationship between the dilated bronchus distal to the atresia and the more proximal bronchus.

Automated synthesis of [11C]choline, a positron-emitting tracer for tumor imaging.

(beta-Hydroxyethyl)tri([11C]methyl)ammonium ([11C]choline) is a tracer very effective in imaging various human tumors using positron emission tomography (PET). We have constructed a computer-controlled [11C]choline synthetic apparatus which carries out the whole process of synthesis and product purification automatically. The setup is simple and the process quick. In 20 min, 11 GBq of [11C]choline (chloride) is obtainable from 26 GBq of [11C]CO2. The final product is a sterile and pyrogen-free [11C]choline "injection".

Nursing in Japan: caregivers of elderly family members with dementia.

1. The difficulties that caregivers of elderly family members suffering from dementia confronted are divided into five categories: incomprehensible situations, strange behavior, deterioration of dementia, trouble or inconvenience caused by demented behavior, and remarks vis-a-vis support network. 2. The considerable differences among caregivers of elderly persons suffering from dementia, in terms of problems faced and methods of coping, existed in beginning and awakening stages. 3. Nurses must assess which stages of the developmental process families are going through to implement effective nursing interventions that vary between the two stages.

[Clinical evaluation of pivmecillinam in the maintenance therapy of chronic urinary tract infection (author's transl)].

In order to evaluate the efficacy and safety of pivmecillinam (melysin tablet, PMPC), PMPC was administered to 78 chronic UTI cases in the field of obstetrics and gynecology (posthysterectomy infection, chronic cystitis, chronic pyelonephritis and etc.). In principle, daily 400 mg of PMPC was administered for 2 weeks. (1) Overall clinical efficacy judged by doctor was evaluated in 78 cases and the result was; excellent in 17, good in 37, fair in 10, poor in 13 and unknown in 1 case with the effectiveness rate of 69.2%. (2) Overall clinical efficacy judged by 'criteria for clinical evaluation in complicated UTI' recommended by UTI study member was evaluated in 54 cases and the result was; excellent in 15, good in 20 and poor in 19 cases with the overall efficacy rate of 64.8%, the result of which was similar to that of doctor's judgement. (3) Efficacy on pyuria was evaluated in 72 cases and it was cleared in 27, decreased in 25, unchanged in 20 and unknown in 6 cases. Efficacy on bacteriuria was evaluated in 72 cases and it was eliminated in 44, decreased in 9, replaced in 8, unchanged in 8 and unknown in 9 cases. (4) Side effect, considered by doctors to be caused by PMPC administration, was noticed in 3 out of 78 cases (3.8%), all of which was mild gastrointestinal disturbance and the administration of PMPC was continued. Abnormal change of laboratory finding considered by doctors to be caused by PMPC administration was noticed in 1 out of 78 cases, which was slight elevation of GOT and GPT values. It is therefore considered that PMPC appear to be useful drug for the maintenance therapy of chronic UTI in the field of obstetrics and gynecology.

[Laboratory and clinical studies on latamoxef in the field of obstetrics and gynecology].

Latamoxef (LMOX) is a new antibiotic synthesized by Shionogi Research Laboratory. Chemically LMOX is especially unique with a sulfur atom replacing the oxygen atom in the 1 position of the conventional cephalosporin nucleus, and in addition, this antibiotic has a cephamycin-like structure. The antibacterial activity of LMOX shows high potency against Gram-negative bacteria, but tends to be weak against Gram-positive bacteria. The tissue levels of LMOX in humans after intravenous injection of 1 g were examined. The levels in uterine and adnexa uteri tissue at 1 hour after administration were 25.4 and 27.4 micrograms/g respectively. LMOX was administered to 147 cases in infections of obstetric and gynecological field. The clinical effect according to disease was 94.6% for intrauterine infections, 95.0% for adnexitis, 87.0% intrapelvic infections, and 100% for external genital organ infections, making a total of 92.5%. The rate of occurrence of side effects or abnormal laboratory findings was similar to or slightly less than that seen with other beta-lactam antibiotics.