A series of benzofuran derivatives were prepared to study their antagonistic activities to the A sub(2A) receptor. Replacement of the ester group of the lead compound 1 with phenyl ring improved the ...PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds 13c, 13f, and 24a showed good potency in vitro and were identified as novel A sub(2A) receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.
Novel benzofuran derivatives as potent and selective adenosine A
2A inhibitors were synthesized and evaluated.
A series of benzofuran derivatives were prepared to study their antagonistic activities ...to the A
2A receptor. Replacement of the ester group of the lead compound
1 with phenyl ring improved the PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds
13c,
13f, and
24a showed good potency in vitro and were identified as novel A
2A receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.
Lipid abnormalities are associated with various disorders ranging from generalized atherosclerosis to renal diseases, including lipoprotein glomerulopathy that is characterized by glomerular ...lipoprotein thrombi and causes type III hyperlipoproteinemia, proteinuria, and renal failure. This study examines lipoprotein glomerulopathy, which recurred in a transplanted kidney. Molecular biologic analysis of the patient's apolipoprotein (apo) E gene demonstrated E2/E5 type variants. Immunohistochemical analysis of the diseased kidney demonstrated various lipid peroxidation-specific protein adducts, suggesting a potential role of oxidative stress in this disorder. Recurrence in the transplanted kidney suggested a pathogenic role of extraglomerular humoral component(s) resulting from abnormal lipoprotein metabolism, presumably linked to apo E and other genetic or acquired factor(s). Furthermore, the finding that the patient showed pathologic abnormalities in the transplanted kidney with no clinical signs or symptoms of renal disease indicated that lipoprotein glomerular damage progresses early before any clinical manifestations.
Abstract 4655
Umbilical cord blood from unrelated donors has been successfully used as an alternative hematopoietic stem cell source to treat hematologic malignancies in patients lacking HLA-matched ...donors. However, umbilical cord blood transplantation (UCBT) is associated with a higher risk of engraftment failure and more delayed immunological recovery than bone marrow transplantation and peripheral blood stem cell transplantation (PBSCT). Recently, human herpesvirus-6 (HHV-6) has been recognized as an important pathogen in allogeneic hematopoietic stem cell transplantation (HSCT). In particular, HHV-6 reactivation often causes limbic encephalitis with a dismal prognosis. We conducted a prospective, multicenter study to assess the safety and efficacy of preemptive therapy with foscarnet sodium (PFA) to prevent HHV-6 encephalitis after HSCT.
Eligible patients were aged from 16 to 75 years with hematologic disorders refractory to conventional therapy and considered to require UCBT or HLA 1-haplotype mismatched HSCT (haplo HSCT) due to the unavailability of an HLA-identical relatives or a suitable unrelated donor. Informed consent was obtained from all subjects according to the Declaration of Helsinki, and this study protocol was approved by the institutional ethical committee. The amount of plasma HHV-6 DNA was measured 3 times per week between day 7 and day 36 after UCBT or PBSCT from HLA-haploidentical relative donors. PFA, 90 mg/kg/day, was given when the amount of HHV-6 DNA exceeded 5 ×102 copies/ml.
Of 20 cases registered between September 2007 and January 2009, 12 of 15 UCBT recipients (80%) became positive for HHV-6 DNAemia, and 7 cases exceeded 5×102 copies/ml, while none of the 5 patients who received haplo HSCT became positive (UCBT vs. haplo HSCT; p<0.004). HHV-6 reactivation occurred earlier in patients who eventually required PFA due to an increase in the HHV-6 DNA copy number greater than 5×102 copies/ml than in patients who did not require PFA treatment (median date of developing HHV-6 DNAemia, day 17 vs. day 22 after HSCT, p<0.02). PFA was given to 7 patients whose HHV-6 DNA copy number exceeded 5×102 copies/ml on day 15 to day 20 (median, day 17) after UCBT. The amount of HHV-6 DNA in the plasma decreased the day after PFA administration in 4 of 7 patients, while the other 3 patients required 3-4 days until the copy number decreased. Two patients showed an increase in HHV-6 DNA copy number greater than 1×104 /ml prior to the initiation of PFA without accompanying symptoms suggestive of encephalitis. One patient developed limbic encephalitis with mild symptoms just after initial PFA administration, but the encephalitis resolved without any neurologic sequelae. Mild and transient adverse effects were associated with PFA in only 2 of 8 patients.
PFA administration guided by the HHV-6 copy number in the early posttransplant period is safe and may reduce the risk of severe limbic encephalitis.
Nakao:Alexion: Research Funding.
Epidermotropic metastatic malignant melanoma (EMMM) is a form of metastatic malignant melanoma that has dermal cell nests with epidermotropism and specific histopathological features. We report a ...patient with eight nodular lesions of the scalp with histopathological findings compatible with EMMM. The tumors developed one year before consultation and increased in size simultaneously. The histopathological findings of all eight tumors were very similar. The tumor cells were located mainly in the dermis and partly in the basal layer of the epidermis. They contained melanin pigments and were positive for anti‐HMB45 antibody. The tumors did not respond to combination chemotherapy with dacarbazine, nimustine, vincristine, and interferon‐beta. Therefore, all the tumors were surgically removed. No local relapse, distant metastasis or re‐elevation of plasma 5‐S‐cysteinyldopa was identified during nine months of follow‐up. Histopathologically, all eight tumors lacked apparent vascular invasion, which may be related to a slow clinical course of the present case.
Leiomyoma originating in the greater omentum Shukunami, Ken-ichi; Kurokawa, Tetsuji; Nishijima, Koji ...
European journal of obstetrics & gynecology and reproductive biology,
04/2005, Letnik:
119, Številka:
2
Journal Article
Abnormalities in dopaminergic and serotonergic neurotransmission in the forebrain are believed to be involved in the underlying mechanism of schizophrenia; therefore, the direct blockade of the ...receptors associated with these systems is a central strategy for schizophrenia treatment, even though this strategy concurrently produces adverse effects like extrapyramidal effects. Kappa opioid receptors exist extensively in the brain and recent reports have suggested that these receptors are involved in modulating the release of several neurotransmitters including dopamine and serotonin. In the present study, we investigated the effect of TRK-820, (E)-N-17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphinan-6 b-yl-3-( fura n-3-yl)-N-methylprop-2-enamide monohydrochloride, a selective kappa opioid receptor agonist, on phencyclidine-induced rat behavioral changes and on biochemical changes in the prefrontal cortex. First, TRK-820 dose-dependently inhibited phencyclidine-induced rat hyperlocomotion, which is one of the abnormal behaviors recognized as a rodent schizophrenia model. The inhibitory effect was completely antagonized with nor-BNI (nor-binaltorphimine hydrochloride), a selective kappa opioid receptor antagonist. Second, TRK-820 dose-dependently inhibited phencyclidine-induced stereotyped behaviors including head-weaving, which is considered a behavioral syndrome based on the impairment of the serotonergic system. Third, in an in vivo microdialysis study, TRK-820 dose-dependently attenuated the biochemical changes of both dopamine and serotonin in the prefrontal cortex of rats treated with phencyclidine without affecting their basal levels in normal rats. The initial findings that TRK-820 potentially modulates such monoamine changes and ameliorates abnormal behaviors related to their changes may suggest its therapeutic potential against the symptoms of schizophrenia.
•Allo-HSCT using either an HLA-matched related donor or an alternative donor can provide durable remission for CMML.•The higher TRM and lower engraftment rate after allo-HSCT using alternative donor ...are serious issues.•The disease status of CMML is also an important prognostic factor for post-transplantation outcomes.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio HR, 2.05; 95% confidence interval CI, 1.21 to 3.48; P = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P < .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P < .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.
Growth factors for rat primary glial cells were identified in conditioned medium of a human glioma-derived cell line. The
factors, designated glia-activating factors (GAFs), were purified to ...homogeneity by a combination of heparin affinity chromatography,
gel filtration, and high performance liquid chromatography on a heparin affinity column and a C4 reversed-phase column. GAFs
could be resolved into three peaks by C4 column chromatography. The M(r) values of these three proteins were estimated to
be 30,000, 29,000, and 25,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. These
M(r) values were in good agreement with the value of 26,000 +/- 3,000 estimated from the elution volume upon gel filtration
chromatography under nondenaturing conditions. These data suggested that each of the GAFs consists of a single polypeptide
chain and has no subunit structures. These three purified GAFs had almost the same growth-stimulating effect on glial cells
in vitro, and the half-maximal dose was around 10(-11) M. Concanavalin A staining and glycopeptide N-glycosidase treatment
of GAFs indicated that an asparagine-linked oligosaccharide chain(s) was attached to these three kinds of GAFs. Microsequencing
of each GAF revealed a single amino-terminal sequence with no significant homology to any known protein, and the amino-terminal
sequence of the 30-kDa GAF included that of the 29-kDa GAF. GAFs also stimulated the cell growth of oligodendrocyte type 2
astrocyte progenitor cells, BALB/c3T3 fibroblasts, and PC-12 cells but not that of human umbilical vein endothelial cells.
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