TP-10 (AVANT Immunotherapeutics)

AVANT Immunotherapeutics is developing TP-10, a recombinant soluble complement receptor type 1 (sCR1), for the potential treatment of reperfusion injury (following surgery, ischemic disease and organ transplantation), organ rejection, acute inflammatory injury to the lungs and autoimmune diseases [348669]. TP-10 has been awarded Orphan Drug status from the FDA for the prevention and reduction of adult respiratory distress syndrome (ARDS) and as a treatment for infants undergoing cardiac surgery [180849], [359588]. A placebo-controlled phase II trial, conducted at approximately 30 sites in the US and involving approximately 600 adult patients undergoing cardiac surgery utilizing cardiopulmonary bypass, was initiated in November 2000. This safety and efficacy study was designed to assess the ability of TP-10 to mitigate the injury to the heart, brain and other organs that occurs when patients are placed on cardiopulmonary bypass circuits, thus potentially improving postoperative outcomes [391437]. In September 2000, the company was planning a double-blind, placebo controlled phase IIb trial in infants undergoing cardiac surgery; AVANT expected to initiated in 30 infants in January 2001 [395086]. The data from this trial will enable the company to further define its clinical endpoints before inititating a pivotal phase III trial in 2001 [382529]. A phase I/II trial of TP-10 involving 15 infants, under 12 months of age, undergoing cardiac surgery for congenital heart defects was initiated by the company in September 1999. The trial will evaluate the ability of TP-10 to mitigate the injury to the heart and other organs when patients are placed on cardiopulmonary bypass circuits [340602]. Enrollment was complete by January 2000 [352458]. Phase I safety trials of TP-10, including studies in adult patients at risk for adult respiratory distress syndrome (ARDS), adult patients with first-time myocardial infarction (heart attack), and pediatric patients undergoing cardiac surgery demonstrated that TP-10 is well tolerated. However, after completion, in December 1997, of a phase IIa trial in nine patients with ARDS, AVANT decided to cease development for this indication. TP-10 was licensed to Novartis AG for use in xeno- and allotransplantation in July 1999. Extensive animal studies have shown TP-10 to have potential in a wide variety of complement-mediated conditions, including organ transplantation, multiple sclerosis, rheumatoid arthritis and lupus [238093]. Early work demonstrated favorable results in animal models of reperfusion injury [180849] and hyperacute xenograft rejection in guinea pig to rat and pig to primate organ transplants [191552]. AVANT has received Notices of Allowance (July 1998) from the USPTO for three separate patent applications covering pharmaceutical compositions of TP-10, methods of purification and methods of certain TP-10 glycoforms for treating diseases or disorders resulting from inappropriate complement activation [291776]. In January 1999, the company was awarded US-05856297 which covers pharmaceutical compositions of TP-10. US-05856300 was also awarded covering compositions and methods of producing the drug [312267].     

Challenges, status, and opportunities for studying developmental neuropathology in adult schizophrenia

Neurodevelopmental theories of the pathoetiology of schizophrenia have been at the forefront of schizophrenia research in recent years. Support for these theories is substantial and growing. Epidemiological, phenomenological, and clinical neurobiological research have provided compelling though still circumstantial evidence. Neuropathological investigations also have provided some evidence; however, these have yet to actualize their potential for revealing the cellular and molecular nature of developmental aberrancies in this disease. This article summarizes the clinical evidence suggesting abnormal neurodevelopment in schizophrenia, outlines some of the important anatomic, cellular, and molecular mechanisms of normal central nervous system development, reviews current neuropathological findings relevant to neurodevelopment in schizophrenia, and suggests some new directions and opportunities for discovering the molecular neurodevelopmental basis of the disorder.     

Implication of ATP and sodium in arachidonic acid incorporation by placental syncytiotrophoblast brush border and basal plasma membranes in the human

The human placental syncytiotrophoblast is the main site of exchange of nutrients and minerals between the mother and her fetus. In order to characterize the placental transport of some fatty acids, we studied the incorporation of arachidonic acid, a fetal primordial fatty acid, in purified bipolar syncytiotrophoblast brush border (BBM) and basal plasma membranes (BPM) from human placenta. The basal arachidonic acid incorporation in BBM and BPM was time dependent and reached maximal values of 0.75+/-0.10 and 0.48+/-0.18 pmol/mg protein, respectively, after 2.5 min. The presence of adenosine triphosphate (ATP) (3 m m) increases significantly the maximal incorporation of arachidonic acid by sixfold (4.75+/-0.35 pmol/mg) and ninefold (4.40+/-0.84 pmol/mg) in BBM and BPM, respectively. Moreover, an increase in the arachidonic acid incorporation was also obtained in the presence of sodium where the values achieved 7.68+/-0.98 (10x) and 6.53 pmol/mg (13.6x) for BBM and BPM, respectively. We also showed that the combination of both Na(+)and ATP increases significantly the maximal incorporation of arachidonic acid in BPM to 7.89+/-0.15 pmol/mg protein, while in BBM it did not modify its incorporation (8.18+/-0.25 pmol/mg protein), as compared to the presence of sodium alone. Our results demonstrate that arachidonic acid is incorporated by both placental syncytiotrophoblast membranes, and is ATP and sodium-linked. However, different mechanisms seem to be involved in this fatty acid incorporation through BBM and BPM, since the presence of Na(+)or ATP increased it, while the association of these two elements increased it only in BPM. We also demonstrated by osmolarity experiments that both membranes bind arachidonic acid, potentially involving one or more fatty acids binding proteins.     

Molecular systematics of the phlebotomine sandflies of the subgenus Paraphlebotomus (diptera, psychodidae, phlebotomus) based on ITS2 rDNA sequences. Hypotheses Of dispersion and speciation

Phylogenetic Paraphlebotomus relationships are inferred by a study based on the sequences of ITS2, which has been sequenced in nine Paraphlebotomus species: P. alexandri, P. andrejevi, P. jacusieli, P. kazeruni, P. mireillae, P. mongolensis, P. saevus, P. sergenti and P. similis and in two out-groups species of the subgenus Phlebotomus: P. papatasi and P. duboscqi. Paraphlebotomus alexandri appears as the sister group of all other Paraphlebotomus sandflies. Among the other species, three groupings are clearly highlighted: andrejevi and mongolensis; mireillae and saevus; jacusieli, kazeruni, sergenti and similis. These groupings are related to speculations about the migration of Paraphlebotomus from a centre of dispersion located in the Middle East sometime from the early Eocene to the late Miocene.     

CAMPATH-1H (Cambridge University)

CAMPATH-1H, a T-cell-depleting, humanized monoclonal antibody, is under development by LeukoSite and ILEX for the potential treatment of chronic lymphocytic leukemia (CLL). In August 1998, ILEX completed enrollment of a pivotal clinical trial of CAMPATH-1H in the treatment of CLL. The study has enrolled 94 patients at 20 centers in the US and Europe. It is anticipated that achievement of the target response would result in a biologics license application being filed with the FDA in mid-1999. Preliminary unaudited results reported by one of the clinical sites were positive. Additional potential therapeutic areas include vasculitis and multiple sclerosis. Preliminary studies have also shown the antibody may reverse acute renal transplant rejection episodes and be useful in ex vivo purging of bone marrow to remove potentially malignant cells. The US FDA has granted Fast Track designation to CAMPATH. The product has orphan drug status.     

1,25-dihydroxycholecalciferol in renal osteodystrophy. Epiphysiolysis--anticonvulsant therapy

Three children with azotaemic renal osteodystrophy were treated with 1,25-dihydroxycholecalciferol (1,25(OH)2D3). All showed clinical, biochemical, and radiological improvement within 6 months of starting treatment. There were no complications. The dose of 1,25(OH)2D3 required was 0-5 microgram per day for 2 children aged 22 and 30 months, and 2 microgram per day for a 15-year-old boy. 2 of the patients were receiving phenobarbitone and phenytoin and in one of them prior treatment with dihydrotachysterol 0-5 mg daily and 6 microgram 1alpha-hydroxycholecalciferol (1alphaOHD3) daily had failed to induce improvement. In one patient, in whom serial iliac bone samples were available, 2 microgram 1,25(OH)2D3 resulted in histological improvement in previously severe osteomalacia. 1,25(OH)2D3 appears to be an effective and safe drug in the treatment of uraemic osteodystrophy.     

Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.