Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer.

OBJECTIVE: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. METHODS: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. RESULTS: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. CONCLUSIONS: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.

Sources of anthropogenic lead in sediments from an artificial lake in Brasília-central Brazil.

Pb concentration and Pb isotopic composition are known to represent powerful tools to investigate the history of Pb pollution in water and sediments. In this paper, we present and discuss the results of a detailed study of sediments deposited in the Paranoá Lake, a 44-year-old artificial reservoir in Brasília, central Brazil. Pb concentration and isotopic composition of the sediments were obtained by ID-TIMS, on three different sample fractions: leachate, residue, and bulk sample. The leachate phase has proven to be most efficient to distinguish between anthropogenic and natural Pb inputs. In the Paranoá lake, important sources of contamination were recognized, producing higher Pb concentrations (max. 37.68 ppm) and significant variations in Pb isotopic composition, relative to the regional geogenic background. Contamination of the sediments due to anthropogenic activity produced less radiogenic Pb isotopic compositions (206Pb/207Pb=1.15-1.17), compared with the regional natural composition (206Pb/207Pb=1.19-1.25). 210Pb analyses along one bore hole which sampled the entire sediment section indicated a sedimentation rate of 8.2+/-1.8 mm/year. The combined use of the 210Pb ages and Pb isotopic compositions of these samples revealed three distinct periods in the lake history: (1) the period of the time formation of the lake in 1959 until ca. 1970 was characterized by the deposition of sediments displaying more radiogenic Pb isotopic signature, (2) the time interval from the start of the process of eutrophication at 1970, until 1995, was characterized by the deposition of sediments having less radiogenic average compositions, and (3) from 1995 until the present represents a period of recovery of water quality, after two sewage treatment stations started to operate.

Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice.

IL-17 is a proinflammatory cytokine, and its in vivo expression induces neutrophilia in mice. IL-17E is a recently described member of an emerging family of IL-17-related cytokines. IL-17E has been shown to bind IL-17Rh1, a protein distantly related to the IL-17R, suggesting that IL-17E probably possesses unique biological functions. In this study, we have identified the murine ortholog of IL-17E and developed transgenic mice to characterize its actions in vivo. Biological consequences of overexpression of murine (m)IL-17E, both unique to IL-17E and similar to IL-17, were revealed. Exposure to mIL-17E resulted in a Th2-biased response, characterized by eosinophilia, increased serum IgE and IgG1, and a Th2 cytokine profile including elevated serum levels of IL-13 and IL-5 and elevated gene expression of IL-4, IL-5, IL-10, and IL-13 was observed in many tissues. Increased gene expression of IFN-gamma in several tissues and elevated serum TNF-alpha were also noted. In addition, IL-17E induces G-CSF production in vitro and mIL-17E-transgenic mice had increased serum G-CSF and exhibit neutrophilia, a property shared by IL-17. Moreover, exposure to mIL-17E elicited pathological changes in multiple tissues, particularly liver, heart, and lungs, characterized by mixed inflammatory cell infiltration, epithelial hyperplasia, and hypertrophy. Taken together, these findings suggest that IL-17E is a unique pleiotropic cytokine and may be an important mediator of inflammatory and immune responses.

IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding.

The proinflammatory cytokine interleukin 17 (IL-17) is the founding member of a family of secreted proteins that elicit potent cellular responses. We report a novel human IL-17 homolog, IL-17F, and show that it is expressed by activated T cells, can stimulate production of other cytokines such as IL-6, IL-8 and granulocyte colony-stimulating factor, and can regulate cartilage matrix turnover. Unexpectedly, the crystal structure of IL-17F reveals that IL-17 family members adopt a monomer fold typical of cystine knot growth factors, despite lacking the disulfide responsible for defining the canonical "knot" structure. IL-17F dimerizes in a parallel manner like neurotrophins, and features an unusually large cavity on its surface. Remarkably, this cavity is located in precisely the same position where nerve growth factor binds its high affinity receptor, TrkA, suggesting further parallels between IL-17s and neurotrophins with respect to receptor recognition.

beta-estradiol 3-benzoate affects spermatogenesis in the adult mouse.

beta-estradiol 3-benzoate (E(2)B) (10, 16, 20, 40, 80 and 160 microg/kg body weight) was administered daily to experimental groups of adult mice for the following periods; 2, 3 days, 1, 2, 4, and 8 weeks. Morphological changes in the testes were observed by both light and electron microscopy. Exfoliation of the germ cells was observed in the lumen of the seminiferous tubule. The spermatogenic cycle, especially stage XII, was disordered. Spermatids older than step 6 were severely affected. Detected abnormalities in the spermatids were deformation of the nucleus and acrosome. Partial deletion in the Sertoli-spermatid ectoplasmic specialization was also observed. Germ cells younger than step 7 spermatids were not affected morphologically. These abnormalities were not detected in the mice treated with the chemical at less than 16 microg/kg body weight. It is concluded that the chemical seems to affect round spermatids metabolically, but the morphological effect can be detected only from the spermatids older than step 6. The effects of the chemical on adult mice were reversible.

The impact of a 4 cm. cutoff point for stratification of T1N0M0 renal cell carcinoma after radical nephrectomy.

PURPOSE: The 1997 TNM classification defines T1 tumors as those smaller than 7 cm. Recently, a cutoff point of 4 cm. has been proposed to create a subclass of T1 tumors. We evaluated the validity of this cutoff point by assessing the pathological findings and prognoses of patients with T1N0M0 renal cell carcinoma following radical nephrectomy. MATERIALS AND METHODS: We reviewed the hospital charts of 333 patients with T1N0M0 tumors, followed as long as 282 months (median 63) after radical nephrectomy. The validity of tumor size cutoff point for predicting survival outcome was tested in relation to other prognostic factors, including patient age, tumor position, nuclear grade, tumor histopathology and degree of microscopic venous invasion. RESULTS: During followup 32 patients (9.6%) had tumor recurrence and 21 (6.3%) died of renal cell carcinoma. A 5 cm. cutoff point maximized the differences in cancer specific survival rates and a 4 cm. cutoff point maximized the differences in disease-free survival rates. Tumor size was directly related to microscopic venous invasion and nuclear grade, which are significant prognostic factors, and a 4 cm. cutoff point enhanced these relationships. CONCLUSIONS: Tumor size is an important prognostic factor for patients with T1N0M0 renal cell carcinoma. A cutoff point of 4 cm. is practical for dividing the T1N0M0 classification into T1a and T1b subclasses.

Lactulose-L-rhamnose intestinal permeability test in patients with liver cirrhosis.

A lactulose-L-rhamnose intestinal permeability test was conducted on 35 patients with liver cirrhosis and six normal controls. Gas chromatography was used to measure lactulose and L-rhamnose concentrations in blood and urine specimens. The excretion of each molecule was expressed as the percentage of the orally administrated dose and the lactulose-L-rhamnose ratio as the ratio of the percentage of each probe molecule excreted. The mean 8-h lactulose excretion ratios were 0.56 and 0.16% in patients with liver cirrhosis and the control subjects, respectively (P<0.05), whereas the corresponding excretion ratios for L-rhamnose were 4.40 and 3.49%. The mean lactulose-L-rhamnose excretion ratios in patients with liver cirrhosis and the control subjects were 0.124 and 0.049, respectively (P<0.05). The lactulose-L-rhamnose excretion ratio increased in patients with liver cirrhosis complicated by large intestinal vascular ectasia of the large intestine or rectal varices, which were used as parameters for evaluating the effects of portal hypertension on the lower digestive tract. These results suggest that an increase in lactulose intestinal permeability in patients with liver cirrhosis proves the effects of portal hypertension extending to the lower digestive tract.

Acinar cells of the pancreas are a target of interleukin-22.

Interleukin-22 (IL-22) (also reported as IL-10-related T cell-derived inducible factor, IL-TIF) is a recently identified cytokine found to signal through a receptor comprising the class II cytokine receptor family members IL-10Rbeta/CRF2-4 and IL-22R. Previous work has established that IL-10Rbeta, also a component of the IL10R complex, exhibits a broad distribution of mRNA expression. Here, we observe that IL-22R exhibits a restricted expression pattern, with highest levels of mRNA expression in pancreas and detectable expression in multiple other tissues, particularly liver, small intestine, colon, and kidney. We find that isolated primary pancreatic acinar cells and the acinar cell line 266-6 respond to IL-22 with activation of Stat3 and changes in gene transcription. IL-22 mediates robust induction of mRNA for pancreatitis-associated protein (PAP1)/Reg2 and osteopontin (OPN). PAP1 is a secreted protein related to the Reg family of trophic factors and was initially characterized as a protein elevated in pancreatitis. In vivo injection of IL-22 resulted in rapid induction of PAP1 in pancreas, a response not observed in mice deficient in IL-10Rbeta. These results support the conclusion that IL-10Rbeta is a required common component of both the IL-10 and IL-22 receptors and suggest that IL-22 may play a role in the immune response in pancreas.

IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1.

We report identification of interleukin (IL)-17E, a novel member of the IL-17 family of cytokines. IL-17E is a ligand for the recently identified protein termed EVI27/IL-17BR, which we term IL-17 receptor homolog 1 (IL-17Rh1) in light of the multiple reported ligand-receptor relationships. Murine EVI27 was identified through its location at a common site of retroviral integration in BXH2 murine myeloid leukemias. IL-17Rh1 shows highest level expression in kidney with moderate expression in multiple other organs, whereas IL-17E mRNA was detected at very low levels in several peripheral tissues. IL-17E induces activation of NF-kappaB and stimulates production of the proinflammatory chemokine IL-8.

[Case report of a long-term home parenteral nutrition patient].

We experienced a patient who received long-term home parenteral nutrition. A 55-year-old woman underwent left adrenalectomy in June, 1992. The histopathological diagnosis was aldosteronism. Abdominal pain and ileus appeared in July, 1993, and an adhesiotomy was conducted. Due to poor appetite and weight loss, fluid was sometimes injected peripherally. After abdominal pain in November, 1996 and April, 1997, the ileus reappeared in July, 1997. A Groshong catheter with a port was then inserted through the subclavian vein to the superior vena cava/right atrial junction. Using this catheter, home parenteral nutrition started. Some time later oral nutrition became possible, but now high calorie parenteral nutrition is continued. The only complications were pain and red skin at the port. A Groshong catheter with port is thus useful for home parenteral nutrition.

Nucleotide sequence and infectivity of a full-length cDNA clone of panicum mosaic virus.

The sequence of an infectious cDNA clone of panicum mosaic virus (PMV) showed that the single-stranded RNA genome is 4326 nucleotides (nt) and a single highly abundant subgenomic (sg) RNA of 1475 nt was synthesized during PMV infection of pearl millet plants and protoplasts. Computer comparisons revealed strong similarities between the predicted amino acid sequences of the p48 and p112 open reading frames (ORFs) and replicase proteins of members of the Tombusviridae. The sgRNA has the potential to encode five proteins. Three small ORFs, p8, p8-FS, and/or p6.6 have similarity to ORFs of carmo-, necro-, and machlomoviruses thought to be involved in virus spread in plants. The sgRNA also has the potential to encode a 26-kDa capsid protein and a 15-kDa nested gene (p15) of unknown function. PMV transcripts also supported replication and movement of SPMV, the satellite virus. Genome organization, physicochemical properties, and biological features indicate that PMV is a member of the Tombusviridae family. However, PMV differs sufficiently from previously described members to warrant its placement in a new genus provisionally designated Panicovirus.

[Histopathological effect of neoadjuvant chemohormonal therapy for prostatic cancer].

To improve the therapeutic results in prostatic cancer, radical prostatectomy or total cystoprostatectomy were performed with chemohormonal therapy before operation. Radical prostatectomies were conducted in eight patients with localized prostatic cancer and total cystoprostatectomies in ten patients with severe cystic infiltration. The administration schedule of chemohormonal therapy was as follows: prior to operation, 30-60 mg/sqm/day of etoposide was administered for 7 days every 3 weeks, 250-500 mg/day of diethylbestrol diphosphate for 30 days, and 3.6 mg of LH-RH agonist was also administered. Sixteen of the subjects survived, and were socially rehabilitated (14 cases of NED, 1 case of NC and 1 case of PD) and 2 of the subjects died of cancer. Histopathological findings showed 9 cases of poorly differentiated adenocarcinoma, 4 cases of well differentiated adenocarcinoma and 5 cases of moderately differentiated adenocarcinoma. Histopathological effect of neoadjuvant chemohormonal therapy in surgical specimen showed that 2 of the subjects had grade 0a effect, grade 0b in 7 cases, grade 1 in 5 cases and grade 2 in 4 cases.

[Continuous subcutaneous injection therapy with interferon-alpha for renal cell carcinoma patients with bone metastasis].

Thirteen patients with renal cell carcinoma who had proven bony metastases were treated with multimodal treatment including surgery, radiotherapy and immunotherapy in the form of subcutaneous continuous injection of by natural type interferon-alpha (INF). The mode of administration of IFN was as follows: IFN, 2,5000 x 10(4) unit dissolved in 60 ml saline, was continuously injected (0.5 ml/hr) via a subcutaneous route as one course of the treatment and was given two courses in two weeks preoperatively. Postoperatively, IFN was given every week and the number of courses totally amounted to 15. In some cases IFN was given thereafter either every week or every other week. In four patients whose serum concentration of IFN was measured during and after administration of continuous IFN, the concentration of IFN rose after injection and showed 40.5 IU/ml in average 24 hours later. The concentration was kept measurable in six to eight days long and the maximum concentration was 167 IU/ml. In IFN-treated patients nine survived including two CRs, two NCs, five PDs and four deaths. The five year survival rate was 53%. Continuous subcutaneous injection of IFN in combination with surgery and/or radiotherapy is effective in the treatment of bony metastasis from renal cell carcinoma.

[Surgical neoadjuvant chemo-hormonal therapy for advanced prostatic carcinoma].

To improve the therapeutic results as well as the patient's quality of life (QOL) in advanced prostatic carcinoma, total cystprostatectomy or pelvic exenteration was performed in combination with chemo-hormonal therapy before and after operation on twelve patients with stage D2 prostatic carcinoma who had infiltration in the periprostatic organs including urinary bladder and large intestine and showed strong bladder irritation, gross hematuria and ileus symptoms. Eight patients with severe cystic infiltration underwent total cystprostatectomy, urinary division and lymph node dissection, and four with ileus symptoms had pelvic exenteration, urinary division, proctostomy and lymph node dissection. As a rule of dosing schedule for chemo-hormonal therapy, 30-60mg/sq m of etoposide was continuously administered for 5 days before operation in addition to 250-500 mg of diethylbestrol diphosphate given for 30 days after operation. Furthermore, 2-3 courses of 30-60 mg/sq m of etoposide was administered for successive days, at 3-week intervals and then 30-60 mg/sq m of etoposide at 6-to-8-week intervals for 2 years together with 75-100 mg of chrolmadinone acetate as maintenance treatment. Nine of the 12 patients survived, including 4 patients with complete response, 3 patients with partial response and 2 patients with no change. These findings, suggested that the combination of surgical treatment and chemo-hormonal therapy is of use not only for providing an effective therapeutic means but also for improving the QOL in patients with advanced prostatic carcinoma.

[Verrucous carcinoma of the penis: a case report and MRI findings].

A 54-year-old male visited our cancer center with the chief complaint of penile tumor in May, 1992. Magnetic resonance imaging (MRI) demonstrated a penile tumor and showed that this tumor invaded the submucosa but neither corpora cavernosa nor corpus spongiosum. Partial penectomy was performed in June, 1992. Histopathological examination of the resected tumor showed verrucous carcinoma. MRI was useful to investigate the degree of invasion of the penile tumor.

An autopsy case of purulent mycobacterial meningitis in AIDS.

The patient was a 46-year-old male hemophiliac who died of acute mycobacterial meningitis associated with AIDS (acquired immune deficiency syndrome). Autopsy revealed severe basal meningitis which was characterized by an infiltration of numerous polymorphonuclear leukocytes. Severe mural inflammation of the subarachnoid arteries was noted, and innumerable acid-fast bacilli were demonstrated. Epithelioid cell granulomas were not found in the meningeal lesion. The lungs, liver, spleen, and bone marrow contained many epithelioid cell granulomas with caseous necrosis. Massive proliferation of swollen histiocytes could not be identified in any organ. The absence of epithelioid cell granulomas in the meningeal lesion indicate a severe impairment of cell-mediated immunity in the patient; this anergic type of lesion is one of the characteristics of tuberculosis occurring in association with terminal AIDS.

[A case of cytomegalovirus infection that caused gastrointestinal perforation after surgery for cancer of the bladder].

A 78-year-old man visited our department for macroscopic hematuria in June, 1989. On the basis of the diagnosis of tumor of the bladder and right afunctional kidney, total right nephro-uretero-cystectomy and skin grafting of the left ureter were performed on August 2. The patient continued to have fever of unknown origin postoperatively. Repeat laparotomy, which was performed for rectal fistula on August 25, revealed that the abdominal wall, colon, small intestine and mesenterium adhered to one another, producing a mass and that two sites in the rectum were perforated. A part of the small intestine was excised, the perforated sites were sutured, and an artificial anus was created at the transverse colon. Since the patient had intermittent fever and continued to complain of abdominal pain after creation of the artificial anus, nosotropic therapy was continued. However, the patient died from cardiac insufficiency on October 10. Erosion and ulcer were histologically observed over a wide range in the excised small intestine. In addition there was a defect in one area of the small intestine, penetrating the tunca muscularis propria, in which many cytomegalovirus (CMV) inclusion bodies were observed. CMV inclusion bodies were also detected in the bladder with re-examination of specimens from the excised bladder. From these findings, it appears that endogenetic CMV may have been reactivated in the present case.

[Clinical study of bilateral metachronous testicular tumors with different histological findings].

Seventy-seven patients with primary malignant testicular tumors were treated in our hospital. Twenty-five of them were given antineoplastic agents containing cis diamine dichloro platinum (CDDP). In three long-term survivors, new malignant testicular tumors developed meta-chronously and had different histological findings from those of the initial tumors. Case 1. A 28-year-old patient with a yolk sac tumor of the left testicle, stage IIO, developed metastasis to the supraclavicular lymph nodes five years after radiation. Chemotherapy containing of VP-16 (837 mg), CDDP (1050 mg), vincristine (32 mg), bleomycin (480 mg), and actinomycin-D (16 mg) achieved complete remission. Four years 11 months later a seminoma of the contralateral testicle, stage I, was disclosed and he died of cancer 11 years and four months after the onset of the initial disease. Case 2. A 30-year-old patient with testicular teratoma, stage IIIA, on the right side gained complete remission after a CDDP containing chemotherapy. One year and four months after the beginning of the CDDP use (1,300 mg totally as CDDP) a seminoma on the contralateral side, stage I, was detected. He died of cancer eight years and two months after his initial tumor was detected. Case 3. A 37-year-old patient with combined tumor of seminoma and yolk sac tumor of the right testicle, stage IIIO, was free from disease for six years and five months under chemotherapy. At this point a seminoma, stage I, of the contralateral testicle was newly found and treated by radiation.(ABSTRACT TRUNCATED AT 250 WORDS)