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.     

Nuclear magnetic resonance: preclinical and clinical studies in tumor detection

Nuclear magnetic resonance has been applied extensively to biochemical problems over the las decade. In vitro NMR relaxation data has shown significant differences between normal and malignant tissue and in the case of breast tissue, between tumors and fibrocystic disease. In vivo, whole body NMR imaging has developed rapidly and has been used in detecting various tumors, particularly in the abdomen. To date, no harmful effects of NMR scanning have been found. NMR scanning is likely to become a major imaging technique with significant applications, particularly in the detection of malignancies.     

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.     

Fibrin sealant for left ventricular rupture after mitral valve replacement

Despite safer surgical procedures, left ventricular rupture remains a rare but potentially lethal complication of mitral valve replacement. The use of fibrin sealant has substantially improved the outcome of many difficult bleeding episodes after cardiac surgery. We describe a case of left ventricular rupture successfully treated with fibrin sealant combined with external Teflon-pledgeted sutures.     

Formulating clinical strategies for angiotensin antagonism: a review of preclinical and clinical studies

Extensive animal studies and a growing number of human clinical trials have now definitively demonstrated the central role of the renin-angiotensin-aldosterone system in the expression and modulation of cardiovascular disease. In contrast to the original hypothesis, the benefits of angiotensin antagonism do not emanate from the antihypertensive effect alone. Subsequent extensive investigations of angiotensin blockade suggest that the benefits of this approach may also result from the pharmacologic alteration of endothelial cell function and the ensuing changes in the biology of the vasculature. The more recent availability of direct antagonists of the AT(1) angiotensin receptor has introduced an element of doubt into this realm of clinical decision making. The receptor antagonists and the more widely studied converting-enzyme inhibitors share many endpoint attributes. Nevertheless, the partially overlapping mechanisms of action for the two classes of angiotensin antagonists confer distinct pharmacologic properties, including side effect profiles, mechanisms of action, and theoretic salutary effects upon the expression of cardiovascular disease. The current review will attempt to contrast the biology of angiotensin converting-enzyme inhibition with angiotensin II receptor antagonism. A discussion of the differential effects of these drug classes on endothelial cell function and on the modulation of vascular disease will be utilized to provide a theoretic framework for clinical decision making and therapeutics.     

Review of preclinical studies with ofloxacin.

Most Enterobacteriaceae, enteropathogens, and fastidious gram-negative bacteria are highly susceptible to ofloxacin, a new tricyclic fluoroquinolone. Aerobic gram-negative bacilli and gram-positive bacteria are generally not as susceptible to ofloxacin. Obligate anaerobes are generally resistant to ofloxacin, while many mycobacteria, chlamydiae, legionellae, and mycoplasmas are susceptible. Ofloxacin is generally less active than ciprofloxacin against gram-negative bacteria, is similarly active against gram-positive bacteria, mycobacteria, legionellae, and mycoplasmas, and is more active against chlamydiae. However, numerous animal studies have shown these two fluoroquinolones to be similar. Ofloxacin inhibits DNA synthesis, is rapidly bactericidal, and is 1,000-2,400 times more potent against prokaryotic gyrase than against eukaryotic gyrase. The bactericidal effect of ofloxacin is not completely neutralized by inhibitors of protein or RNA synthesis. Resistance to ofloxacin arises from mutations within chromosomal genes involved with DNA gyrase and drug permeation. Selection of resistant mutants by ofloxacin is not as frequent as that seen with nalidixic acid. However, due to the cross-resistance between ofloxacin and other fluoroquinolones, all of these drugs should be used judiciously to preserve their clinical utility.     

Healing of ischemic colonic anastomosis: Fibrin sealant does not improve wound healing

Fibrin adhesives have been advocated as a protective sealant in high-risk colonic anastomoses to prevent leakage. To assess the effect of fibrin glue sealing on the healing ischemic anastomosis, we compared the healing of sutured colonic anastomoses in the rat, with and without fibrin adhesive (Groups IA and IB), and ischemic anastomoses with and without fibrin adhesive (Groups IIA and IIB). On days two, four, and seven, 10 animals in each group were sacrificed. Adhesion formation was scored, and the in situ bursting pressure was measured. The collagen concentration and degradation were estimated by measuring hydroxyproline. Adhesion formation was more prominent in Groups IB, IIA, and IIB on day four only; abscesses were noted in the ischemic group in four rats. Anastomotic bursting pressure was significantly lower in sealed (IB) and ischemic anastomoses (IIA) than in normal anastomoses (IA) on day four. Sealing of ischemic anastomoses did not change bursting pressures on days two, four, and seven. The relative decrease of collagen in the sealed anastomoses is significantly higher on day four only. It is concluded that sealing of normal colonic anastomoses in the rat has a negative effect on wound healing. Ischemia at the anastomotic site results in weaker anastomotic strength on day four postoperatively. Also in ischemic anastomoses, fibrin sealant does not improve wound healing during the first seven days. Adhesion formation on ischemic intestinal anastomoses was not prevented by fibrin sealing.     

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.     

Correlating preclinical animal studies and human clinical trials of a multifunctional,polymeric nanoparticle

Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.     

Cytokines in coagulation and thrombosis: a preclinical and clinical review.

The cytokine network is a complex and dynamic system, involved in numerous biological responses in the human body. This review of the current literature describes the role of cytokines and their interaction with the coagulation system, specifically in the maintenance of the thrombo-hemorrhagic balance in vivo in human subjects and in animals. In general, cytokines are thrombogenic, but they are amenable to therapeutic manipulations and hence are a potentially attractive tool in the clinician's armamentarium. Studies of the effects of cytokines in vivo are difficult because cytokines act in a very finite microenvironment and, although their actions are significant, they are transient. Most of the available clinical data related to interactions between cytokines and the coagulation system focuses on the role of tumor necrosis factor-alpha and interleukin-1 in septicemia and septic shock. However, several other cytokines and related proteins, such as platelet activating factor and plasminogen activator inhibitor, are also known to influence coagulation and thrombosis. These factors interact closely with cytokines, and have been included in this review for a better understanding of their interactions with traditional cytokines. Studies that utilize cell culture systems do not accurately model the in vivo status of this complex system and, hence, this review has excluded such studies. The role of the cytokine network in coronary artery disease, angiogenesis, or neoplasia has been addressed elsewhere by other workers and is not discussed here. By emphasizing important in vivo interactions, the intention of this review is to serve as an impetus to further translational research, both clinical and in the laboratory.     

Fibrin glue and clinical impact on haemophilia care

Fibrin glues, a kind of biological sealant, have been used for enhancement of local haemostasis, tissue sealing and wound healing for haemophilia and similar disorders. Commercial viral-inactivated fibrin glue products are available in Europe and have recently been approved in the USA. Using fibrin glue, hospitalization, medical cost, viral transmission risk and factor supplementation will be reduced. In the near future, the role of fibrin glues will be increased in the haemophilia field.     

Developing idiotype vaccines for lymphoma: from preclinical studies to phase III clinical trials

Therapeutic vaccines for B-cell non-Hodgkin lymphoma (NHL) using the clonal tumour immunoglobulin idiotype (Id) have been under development for more than three decades. A major obstacle for rapid progress in the field has been that the Id vaccine is patient-specific and required the generation of a custom-made product. The manufacturing issues were recently overcome by advances in hybridoma and recombinant DNA technology which facilitated the completion of several phase I and II clinical trials. The strong immunogenicity and apparent clinical benefit observed on the early phase studies led to the initiation of three randomized phase III clinical trials that are also nearing completion. This review will focus on the development of Id vaccines before and after the introduction of rituximab for the treatment of B-cell NHL and also discuss potential strategies to enhance the efficacy of active immunotherapy in the future.     

Modulating T‐cell homeostasis with IL‐7: preclinical and clinical studies

Interleukin‐7 (IL‐7) is required for the development and survival of T cells and plays a critical role in modulating T‐cell homeostasis. This review will address current understanding of IL‐7 biology, review recent clinical experiences and discuss potential future clinical applications of IL‐7, or IL‐7 blockade, in the setting of disease.