Fibrin sealant in preclinical and clinical studies.

Fibrin sealant, now commercially available in the United States, is a virally inactivated preparation of highly purified human fibrinogen and human thrombin that includes aprotinin to reduce fibrinolysis. Although the product is relatively expensive, cost can be justified when the sealant is used to produce localized hemostasis in surgery in which bleeding cannot be controlled by sutures. Fibrin sealant can also be justified as an alternative to factor concentrates in patients with coagulopathies who have a localized site of bleeding. Newer formulations of fibrinogen and thrombin in a freeze-dried form applied as a bandage may be useful in immediate, on-site treatment of trauma victims in either a civilian or military setting.     

Interleukin-2 in bone marrow transplantation: preclinical studies.

Interleukin-2 (IL-2) promotes the generation and proliferation of killer cells in the peripheral blood and bone marrow (BM) both in vitro and in vivo. When employed in a syngeneic bone marrow transplantation (BMT) setting and followed by IL-2 therapy, murine BM cells activated with IL-2 in vitro (ABM) demonstrate potent graft-versus-leukemia (GVL) and anticytomegalovirus effects. ABM cells retain the capacity to reconstitute the hemopoietic system both in normal and leukemic mice. This therapy does not cause graft-versus-host disease (GVHD). Human ABM cells carry out purging of leukemia without loss of progenitor cell activity in vitro. The purging ability of ABM can be augmented by interleukin-1, interferon, and tumor necrosis factor. IL-2 therapy stimulates the veto suppressor cell activity of T cell-depleted BM, and has reduced GVHD and permitted engraftment of mismatched allogeneic BM in murine models. Future studies should determine the optimum treatment schedules with IL-2 for improving the GVL effect in autologous BMT, and for abolishing GVHD in allogeneic BMT settings.     

Schistosoma mansoni: preclinical studies with 9-Acridanone-hydrazones in Cebus monkeys experimentally infected.

Derivatives of acridine (9-Acridanone-hydrazones) were tested in Cebus monkeys experimentally infected with Schistosoma mansoni, at the dosages of 50, 25, and 12.5 mg/kg (p.o., single dose). At least, four compounds seemed to be very promising, promoting alterations in the oogram and reducing the worm burden drastically, even at the lowest dose (12.5 mg/kg). No side effects could be detected after drug administration.     

Hepatic encephalopathy:Lessons from preclinical studies

Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.     

Adoptive T-cell therapy for B-cell acute lymphoblastic leukemia: preclinical studies.

We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8(+) and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti-leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.     

Eribulin -- a review of preclinical and clinical studies

Eribulin mesylate is a non-taxane, structurally simplified, completely synthetic, halichondrin B derivative with an end poisoning, microtubule inhibitory action. Preclinical studies have demonstrated activity in various cancer cell lines and synergistic action with gemcitabine, epirubicin, trastuzumab, cisplatin, docetaxel and vinorelbine. Eribulin has recently been approved by United States Food and Drug Administration as a third line therapy for metastatic breast cancer patients, who have previously been treated with an anthracycline and a taxane. It has also advanced to phase II trials in non-small cell lung cancer, pancreatic, prostate, bladder, head and neck cancers, sarcomas and ovarian and other gynecological tumors. Combination trials with carboplatin, gemcitabine, pemetrexed, cisplatin, and erlotinib are currently ongoing. Eribulin potentially has a low incidence of peripheral neuropathy. The predominant side effects are neutropenia and fatigue, which are manageable. This article reviews the available information on eribulin with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, preclinical studies and clinical trials.     

Idarubicin in the treatment of acute leukemias. An overview of preclinical and clinical studies

Idarubicin is a new derivative of Daunorubicin which was found to be more potent and more active than Daunorubicin and Doxorubicin in several experimental leukemias. Its antileukemic activity in preclinical models prompted the introduction of Idarubicin into clinical studies. As a single agent, Idarubicin produced complete remission in 20% and 30% of patients with heavily pretreated pediatric and adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) respectively. Idarubicin combined with Cytarabine and/or other antileukemic agents produced complete remissions in 46% of patients with refractory or relapsed AML and in 58% of patients with refractory or relapsed ALL (adult and pediatric). Subsequently, Idarubicin has been employed in untreated AML patients in combination with Cytarabine and/or Etoposide, producing complete remissions in more than 80% of patients. In ALL patients the drug has been used in combination with Vincristine, Cytarabine and Prednisone, producing complete remissions in 82% of patients. Recently, Idarubicin has been utilized in combination with intermediate doses of Cytarabine in refractory or relapsed ALL and AML, and 70% of patients achieved complete remission. Preliminary results of ongoing prospective randomized studies in untreated adult AML seem indicate that Idarubicin is at least equivalent, if not superior to Daunorubicin. The antileukemic activity of Idarubicin given orally as single agent, or in combination with other drugs, has been shown in AML and myelodysplastic syndromes. The toxicity of Idarubicin includes mild nausea and vomiting, alopecia and liver dysfunction. Ongoing randomized trials comparing Idarubicin to Daunorubicin should provide more information about the potential cardiotoxicity of this drug.     

5-Aza-2'-deoxycytidine: preclinical studies in mice

5-Aza-2'-deoxycytidine administered to normal mice repeatedly on daily schedule affects mainly the number of blood leukocytes and bone marrow myeloid cells. Using the cell-free extract from mouse spleen phosphorylated intermediates of 5-aza-2'-deoxycytidine-3H have been isolated and kinetics of their formation both in vitro and in vivo in mouse spleen cells have been studied. The administration of the drug affects the synthesis of DNA in mouse spleen resulting in its initial depression followed later by the enhancement of thymidine uptake.     

Intrapulmonary pharmacokinetics of ofloxacin in drug-resistant tuberculosis.

OBJECTIVE: To determine the lung epithelial lining fluid (ELF) and serum levels of ofloxacin in drug-resistant tuberculosis patients during treatment. DESIGN: Ten drug-resistant tuberculosis patients treated with ofloxacin containing regimens for at least 2 weeks were enrolled in the study. Subjects ingested ofloxacin 10 mg/kg and other anti-tuberculosis agents after overnight fasting. RESULTS: Serum and bronchoalveolar lavage fluid were collected at 4 hours after treatment and assayed by high performance liquid chromatography. The mean concentrations of ofloxacin in serum and ELF were 5.889 +/- 1.096 and 16.583 +/- 8.697 mg/L, respectively. The mean ratio of ELF-to-serum ofloxacin concentration was 2.825 +/- 1.275. CONCLUSION: Ofloxacin can penetrate well into the intra-alveolar fluid of patients treated for drug-resistant tuberculosis. The lung ELF concentrations were consistently higher than the minimal inhibitory concentrations of Mycobacterium tuberculosis as determined in vitro.     

Novel therapies in MM: from the aspect of preclinical studies

During the last decade, thalidomide, lenalidomide, and bortezomib have been approved by the US Food and Drug Administration for the treatment of MM; however, MM remains incurable. The development and progression of multiple myeloma (MM) is a complex multi-step process involving genetic abnormalities in tumor cells at both early and late stages. Moreover, soluble factors and cell–cell contact within the tumor bone marrow (BM) microenvironment promotes MM cell growth, survival, and drug resistance. A number of novel agents targeting both tumor cells and growth factors in the BM milieu have been developed. Currently they are under evaluation in preclinical studies, as single agents and/or in combination, to improve outcome of MM patients.     

Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies

OBJECTIVE: Humans have a non-sense codon inserted into the 5 prime end of the open reading frame of urate oxidase, and thus express an enzymatically inactive fragment of this enzyme; and consequently are unable to metabolize uric acid into allantoin and are prone to develop hyperuricemia and gout. Various urate oxidases (uricase) from mammals and microorganisms have been administered to humans with hyperuricemia and gout. Although successful in lowering plasma uric acid, these therapies have had limited application due to undesirable biochemical properties of the enzymes used, the short circulating half-life, and inherent antigenicity of these preparations. METHODS: We compared urate oxidase from a variety of sources for specific enzyme activity, pH optimum, affinity, and retention of enzyme activity under physiological conditions. A variety of polyethylene glycols (PEG) were tested to formulate uricase. RESULTS: Urate oxidase from Candida utilis had more favorable enzymatic properties and PEG of 20,000 MW (termed uricase-PEG 20) had greatly reduced antigenicity and increased circulating half-life as compared to those previously described. CONCLUSION: It is anticipated that uricase-PEG 20 may have utility as a treatment for hyperuricemia and gout.     

Update of preclinical and human studies of calcium and colon cancer prevention

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The predictive value of hemodynamic studies in preclinical ischemic necrosis of bone

This study evaluated the predictive value of bone marrow pressures and intraosseous venography in joints at risk for developing ischemic necrosis of bone. Forty-two patients with ischemic necrosis of bone had hemodynamic studies performed on their contralateral, asymptomatic joint. A followup evaluation of symptoms and radiographs was obtained to establish the prevalence of clinical ischemic necrosis in the index joints. Thirty-six of 48 joints had increased bone marrow pressure and of these, 15 (42%) developed histologically or radiographically confirmed ischemic necrosis of bone. In none of the 12 bones with normal bone marrow pressure did ischemic necrosis of bone occur (p = 0.005). Venography was also significantly predictive for ischemic necrosis of bone, both alone and in conjunction with bone marrow pressure. Our study reaffirms the risk of developing bilateral ischemic necrosis of bone (31% at a mean followup of 47 months) once the diagnosis has been made on one side. Bone pressure measurements are of predictive value in establishing those joints which require close clinical followup so that detection of disease may be in the precollapse stage of ischemic necrosis of bone.