Use In Clinical Trials Research Articles

Angiogenesis in Multiple Myeloma: Implications in Myeloma Therapy

Angiogenesis, or the formation of new blood vessels from pre-existing vasculature through sprouting or invagination, is a complex process involving many factors. The role of angiogenesis in the progression of cancer has been extensively explored, and it is now well established that elevated levels of angiogenesis in many solid tumors correlates with poor prognosis. Similarly, recent evidence suggests that blood vessel formation plays a pivotal role in the progression of hematological malignancies, including the plasma cell malignancy, multiple myeloma. Several studies have shown that bone marrow angiogenesis is significantly increased in patients with active multiple myeloma and is indicative of poor prognosis. Malignant myeloma cells are known to secrete several angiogenic factors which may play a role in the increased angiogenesis in the bone marrow of myeloma patients. Anti-angiogenic therapy with thalidomide is now considered to be a standard therapy for advanced myeloma patients and a number of new anti-angiogenic therapies are currently undergoing clinical trials for use in this disease.

Pregnancy-related constipation.

Constipation is a common complaint in pregnancy. Its symptoms may include infrequent defecation, hard or scybalous stool, or excessive straining. An extensive evaluation is usually unnecessary for women who present with constipation for the first time during pregnancy. Most patients respond to dietary measures or simple laxatives. Few laxatives have been evaluated in clinical trials for use in pregnancy. Evidence supports treatment with fiber supplements and senna. The use of a pharmacologic agent for treatment of constipation during pregnancy must be weighed against possible adverse effects. Most laxatives carry a pregnancy category B or C classification. First-line therapy includes increasing fiber intake through diet or supplements. Osmotic laxatives may be beneficial for some patients. The short-term use of osmotic or stimulant laxatives is generally reserved for patients who fail to respond to dietary changes or bulking agents.

Mechanism of action of oritavancin and related glycopeptide antibiotics.

Oritavancin (LY333328) is a semisynthetic glycopeptide antibiotic having excellent bactericidal activity against glycopeptide-susceptible and -resistant Gram-positive bacteria. Oritavancin is the N-alkyl-p-chlorophenylbenzyl derivative of chloroeremomycin (LY264826) and is currently in phase III clinical trials for use in Gram-positive infections. Studies show that oritavancin and related alkyl glycopeptides inhibit bacterial cell wall formation by blocking the transglycosylation step in peptidoglycan biosynthesis in a substrate-dependent manner. As with other glycopeptide antibiotics, including vancomycin, the effects of oritavancin on cell wall synthesis are attributable to interactions with dipeptidyl residues of peptidoglycan precursors. Unlike vancomycin, however, oritavancin is strongly dimerized and can anchor to the cytoplasmic membrane, the latter facilitated by its alkyl side chain. Cooperative interactions derived from dimerization and membrane anchoring in situ can be of sufficient strength to enable binding to either dipeptidyl or didepsipeptidyl peptidoglycan residues of vancomycin-susceptible and -resistant enterococci, respectively. This review describes the antibacterial activity of oritavancin, and examines the evidence supporting the proposed mechanism of action for this agent and related analogs.

Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603

AbstractAcute graft-versus-host diseases (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). T helper 1 (Th1)-type cytokines such as interferon-γ or tumor necrosis factor-α have been implicated in the pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative, which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study was designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates lethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not only the production of Th1-type cytokines, but also the proportion of Th1 cells in CD4+ helper T cells in this GVHD mouse model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.

Murine monoclonal antibodies reactive with a human monoclonal anti-RhD antibody (BRAD-5).

BRAD-3 and BRAD-5 are human monoclonal antibodies that recognize the RhD antigen on red blood cells. Both antibodies are currently in clinical trials for use as a replacement for polyclonal anti-RhD in the prophylactic treatment of haemolytic disease of the newborn. We have produced three murine IgG1 antibodies that cause agglutination of cells sensitized with BRAD-5 and also block binding of BRAD-5 to its target antigen. Using a haemagglutination assay, these antibodies, 1D7, 2E6 and 3B1, have shown specificity for BRAD-5 as they did not bind to other monoclonal anti-RhD antibodies of differing specificity or derived from other donors. This assay has also been used to show a lack of reactivity with anti-RhD antibodies present in 198 human serum samples from 44 anti-RhD immune individuals. The three anti-BRAD-5 antibodies have been shown to recognize different epitopes on the BRAD-5 molecule using a blocking ELISA. These antibodies appear to recognize private idiotopes on BRAD-5 that were not detectable in RhD immune sera, and therefore they will be of use for monitoring BRAD-5 in clinical trials.

The heat shock protein gp96: a receptor-targeted cross-priming carrier and activator of dendritic cells.

Heat shock proteins like gp96 (grp94) are able to induce specific cytotoxic T-cell (CTL) responses against cells from which they originate and are currently studied in clinical trials for use in immunotherapy of tumors. We have recently demonstrated that gp96 binds to at least one yet unidentified receptor restricted to antigen-presenting cells (APCs) like dendritic cells (DCs) but not to T cells. Moreover we have shown, that for CTL activation by gp96-chaperoned peptides receptor-mediated uptake of gp96 by APCs is required. Lately, we have discovered a second function of gp96 when interacting with professional APCs. Gp96 is able to mediate maturation of DCs as determined by upregulation of MHC class II, CD86 and CD83 molecules, secretion of pro-inflammatory cytokines IL-12 and TNF-alpha and enhanced T-cell simulatory capacity. Furthermore, the gp96 receptor(s) are down-regulated on mature DCs, suggesting that the gp96 receptor(s) behave similar to other endocytic receptors like CD36, mannose receptor etc. Our findings now provide additional evidence for the remarkable immunogenicity of gp96: first, the existence of specific gp96 receptors on APCs and second, the capacity to activate dendritic cells which is strictly required to enable these highly sophisticated APCs to prime CTL responses.

Human erythrocyte acetylcholinesterase inhibition by cis-diamminediaquaplatinum (II): a novel kinetic approach

The present work addresses the analyses of some novel kinetic parameters ( k t, K v, t 50, K ir, t c, m c, IC 50, IC 99 and K i) of human erythrocyte membrane-bound acetylcholinesterase (AChE, EC 3.1.1.7) inhibition by cis-diamminediaquaplatinum II (PDC). PDC is under a clinical trial for use as an antineoplastic drug. The authors recently reported that PDC and cisplatin have the ability to inhibit AChE activity in vitro. Therefore this study was designed to determine the estimation of time constant ( k t), velocity constant ( K v), 50% inhibition time ( t 50), inhibition rate constant ( K ir), transition concentration ( t c), meeting concentration ( m c), 50% inhibition (IC 50), 99% inhibition (IC 99) and inhibition constant ( K i) by novel methods. The details are described in the text.

PRECLINICAL TRIAL OF A BlOARTlFlClAL LIVER SUPPORT SYSTEM IN A PORCINE FULMINANT HEPATIC FAILURE MODEL

This study describes the pre-clinical trials of an extracorporeal bioartificial liver support system (BALSS). It includes the biochemical changes which occur in the plasma and blood of pigs with devascularized livers when the plasma is treated in a BALSS, and the testing of the system for presence or absence of infective agents, pyrogens and for toxicity. Hepatic cells were prepared from littermate juvenile white landrace pigs with a double-step collagenase digest technique. The cell preparations were incubated with collagen-coated dextran microspheres (CDM) for 3 h and the medium was tested to determine cellular metabolic activity. Incubation continued for a further 20 h during which the hepatic cells attach to the CDM. The CDM-attached cells were inoculated into a hollow fibre bioreactor which was part of an extracorporeal liver support system. Hepatic cell content of the bioreactor was 6 x 10(9) +/- 3 x 10(8) cells, equivalent to those present in half a pig's liver. The system was tested in a controlled trial with the plasma of pigs with fulminant hepatic failure (FHF) due to devascularized livers. When plasma from FHF pigs was circulated through the device there was significantly less of an increase in the accumulation of ammonia, lactate and most amino acids when hepatic cells were included in the circuit compared with those in control experiments when they were excluded. Similar changes occurred in procine blood. There were few infections diagnosed and an absence of pyrogens, endotoxins and toxicity in the bioreactor contents or in the terminating reservoir or animal blood samples. We believe that the results, demonstrating function of the porcine hepatic cells in the circuit, together with low risks, justify a clinical trial of use of the BALSS in Australia.

The effect of the desglycinyl metabolite of remacemide on cortical wedges prepared from DBA/2 mice

Remacemide hydrochloride is currently undergoing clinical trials for use as an anticonvulsant agent in the treatment of epilepsy. It is considered that the desglycinyl metabolite (FPL 12495AA) of the parent compound accounts for the majority of the anticonvulsant activity. In this study we have investigated the effects of FPL 12495AA on electrical activity in the cortical wedges prepared from audiogenic seizure-prone DBA/2 mice. FPL 12495AA at varying concentrations (50–200 μM) significantly reduced both the spontaneous depolarizations (IC 50 102 μM) and the associated afterpotentials (IC 50 50 μM) which are characteristic in this preparation under magnesium-free conditions. The compound also concentration-dependently reduced N-methyl- d-aspartate (NMDA)-induced depolarizations of the tissue (IC 50 43 μM) and the antagonism by FPL 12494AA was not overcome by increasing NMDA concentrations. FPL 12495AA had no effect on ( S)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-induced depolarizations. The results suggest that FPL 12495AA has a specific antagonistic effect on the NMDA receptor complex possibly through non-competitive inhibition at the phencyclidine site in the ion channel. Such an action could contribute to its anticonvulsant properties.

Rapamycin (sirolimus, rapamune).

Rapamycin is a novel immunosuppressive agent that is undergoing clinical trials for use in allograft rejection therapy. This paper reviews its in-vitro biological properties, the current state of knowledge concerning its mechanism of action, and its therapeutic applications.

Meta-analysis. A review of its place in therapeutic decision making.

The potential value of meta-analysis has captured the imagination of many investigators. Epidemiologists have, appropriately, greeted its broad application with considerable caution, yet practical matters, such as the need to consolidate and extract information from available data, have forced a more accepting approach. Meta-analysis has been employed in many clinical settings to evaluate efficacy and safety of a variety of therapeutic interventions. It is likely that it will continue to have a role in extrapolating data from clinical trials for use in the clinic.

Whole-blood cyclosporin G in renal transplant recipients determined by two immunoassays and liquid chromatography

Cyclosporin G (CsG) is less nephrotoxic than cyclosporin A (CsA) and is undergoing clinical trials for use as an immunosuppressive agent after renal transplantation. Three assays for whole-blood CsA-HPLC, RIA (INCSTAR, Cyclo-Trac SP), and FPIA (Abbott TDx)--were adapted for use with CsG and were assessed for analytical suitability and to determine which assay was capable of deriving CsG values rapidly after transplantation. The assays were acceptable in terms of sensitivity, linearity, analytical recovery, and precision. When considering blood samples (n = 107) from renal transplant recipients receiving a low dose of CsG (5 mg/kg per day) and a high dose (10 mg/kg per day), we obtained the following correlation data: RIA = 0.974HPLC + 27.89 (r = 0.9798, Sy/x = 39.24); FPIA = 0.964HPLC + 33.59 (r = 0.9819, Sy/x = 36.66); and FPIA = 0.977RIA + 9.50 (r = 0.9894, Sy/x = 28.12). The FPIA of CsG is recommended as the most rapid method, although it is the most expensive. HPLC, RIA, and FPIA were capable of accurately deriving projected CsG concentrations at various stages of the clinical trial when the low- and high-dose regimes were tapered over a period of 16 weeks.

Acid-base management: A statement for the advanced life support working party of the European Resuscitation Council

The management of acid-base balance in circulatory arrest and CPR is still subject of much research and discussion. In fact, all elements in the debate on diagnosis, treatment and prognosis are questioned because of lack of, or conflicting research data. It is unclear to what extend acidosis does occur, given ‘adequate’ CPR with good chest compression and ventilation. Clinical trials of use of buffer agents in human pre-hospital and in-hospital CPR are scant or completely lacking. Animal models of circulatory arrest give much pathophysiological insight, but fail to convince clinicians who are confronted with prolonged CPR procedures with multifactorial disturbances. What emerges from these bits of information is the questionable value of large doses of bicarbonate used indiscreminately in the resuscitation procedure. However, how much to give of what and when is still unclear. In the following paragraphs we attempted to summarize these bits of information.

Unenhanced and gadolinium-DTPA-enhanced MR imaging in postoperative evaluation in pediatric brain tumors.

Gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) is a chelated paramagnetic contrast agent under clinical trial for use in magnetic resonance (MR) imaging. The increased signal intensity following the intravenous infusion of contrast medium may improve the ability of MR imaging to delineate tumors. The use of this method in 15 pediatric patients with suspected brain-tumor recurrence was analyzed. All 15 patients underwent postoperative Gd-DTPA-enhanced MR imaging, and residual tumor was demonstrated in nine of them. Based on the findings of the enhanced MR studies, four patients had additional surgery, two underwent radiation therapy, and one was given immunotherapy. Continued surveillance was recommended for the remaining eight patients. In all cases the enhanced MR imaging studies were superior to the unenhanced studies in regard to the qualitative and quantitative assessment of the residual tumor. Gadolinium-DTPA-enhanced MR imaging appears to be a safe and effective means of providing an accurate postoperative assessment of residual disease in pediatric brain-tumor patients. It is as effective as contrast-enhanced computerized tomography and has the sensitivity and anatomic resolution provided by MR imaging. The most useful role of this agent was in the postoperative period, in assessing the adequacy of surgical resection. This technique is recommended as the procedure of choice in the postoperative assessment and long-term surveillance of patients with brain tumors.

Suloctidil-induced hepatotoxicity

Suloctidil is a new drug that is currently being evaluated in many clinical trials for use in dementia and thrombotic disorders. Hepatotoxicity has to date been reported exclusively in the European literature, and the few available histologic descriptions have been reported in the French language. We report a case of suloctidil-induced hepatotoxicity documented by serum liver biochemical tests and liver biopsy. Histologic features included focal necrosis of hepatocytes, mild hyperplasia of Kupffer cells, and other features suggestive of mild acute hepatitis.

Convulsive syndrome induced by the intracerebroventricular injection of alpha-difluoromethylornithine in rats.

In adult rats, the intracerebroventricular injection of alpha-difluoromethylornithine (DFMO), a polyamine antimetabolite which specifically inhibits ornithine-decarboxylase, induces a typical convulsive syndrome (ED50 = 100 micrograms/rat) and death (LD50 = 300 micrograms/rat). Histological lesions are seen only with the highest doses and are essentially restricted to the Ammon's horn neurones. Since DFMO is currently undergoing clinical trials for use in cancer chemotherapy, including brain tumours, its CNS toxicity should be carefully considered.