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Planegg, Germany

Eileen Bird J.,Bristol Myers Squibb | Smith P.L.,Bristol Myers Squibb | Wang X.,Agennix Inc. | Schumacher W.A.,Bristol Myers Squibb | And 3 more authors.
Thrombosis and Haemostasis | Year: 2012

Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged bleeding time. Prekallikrein antisense oligonucleo-tide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl 3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type litter-mates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl 3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average tail bleeding time increased modestly in knockout mice compared to wild-type. Average renal bleeding times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach. © Schattauer 2012. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 557.32K | Year: 2008

DESCRIPTION (provided by applicant): This project aims to develop talactoferrin (TLF, recombinant human lactoferrin) as a therapeutic agent to treat prematurely born neonates. The treatment will be given orally shortly after birth to prevent nosocomial inf ections (NIs) due to abnormal bacterial invasion of neonatal intestinal epithelia and consequently to limit systemic bacteremia and necrotizing enterocolitis (NEC). The overall incidence of prospectively studied NIs in hospitalized neonates has been report ed to be 10.8 NI/100 patients. The incidence increases with decreasing birth weight, being as high as 81.8 NI/100 patients in Very Low Birth Weight group (birth weight lt 1500 g). Recent data from the National Institute of Child Health and Human Developmen t-sponsored Neonatal Network indicated that 29% of infants born at 25 to 28 weeks' gestation and 46% of infants born at less than 25 weeks' gestation experience a serious NIs during hospitalization in the NICU. The most common NI sites were sepsis and NE C. We therefore focus development of TLF on providing a sustained way to prevent and treat consequences of NIs in infants born prematurely and weighing from 750 to 1500 g at birth. The study shall enroll a total of 396 infants in a double-blind, randomized prospective study where TLF or placebo will be administered, in addition to the standard of care, to preterm infants before 24 hours of age. The study shall consist of four study groups: 1) mother's milk + placebo, 2) mother's milk + TLF, 3) formula feedi ng + placebo, and 4) formula feeding + TLF. The Phase-I part of the study shall determine the safety of TLF (at a dose of 300 mg/kg) when administered orally for 30 days. Using the total of (4 x 30) = 120 patients, safety of TLF shall be evaluated by deter mining the incidence and severity of adverse clinical events including laboratory and radiographic abnormalities. It is anticipated that adverse events might not be related to TLF, but rather to preterm birth, and TLF may mitigate those complications of pr ematurity [e.g., bronchopulmonary dysplasia]. The subsequent, continuous Phase-II part of the study shall ascertain the efficacy of TLF to enhance post-natal growth and to attenuate the incidence of nosocomial infections (including bacteremia, pneumonia, u rinary infection, necrotizing enterocolitis [NEC] plus NEC scares , and meningitis). All 396 patients recruited into the study (Phase I and Phase II) shall be used to evaluate efficacy of TLF. The Primary Endpoint shall be the time to regain birth weight, daily weight gain, and number of days to hospital discharge, Incidence of nosocomial infections [late-onset bacteremia, pneumonia, necrotizing enterocolitis, urinary tract infection, and meningitis] and incidence of NEC Scares , neonatal sepsis syndrome or systemic inflammatory response syndrome without proven evidence of infection. Additionally, Secondary Efficacy Parameters shall evaluate the number of days on mechanical ventilation and/or nasal positive airway pressure, number of days on supplement al oxygen, and overall morbidity and mortality (%). A consortium of clinical centers has been formed to ensure adequate number of patients and the rate of recruitment to complete the project within 2 years from its initiation. The consortium includes the S outhern Illinois University School of Medicine (St. John's Children's Hospital), The University of Louisville (Kosair Children's Hospital and the University of Louisville Hospital) and University of Southern California (Children's Hospital of Los Angeles a nd Hollywood Presbyterian Medical Center). Effectiveness of TLF in controlling NIs in neonates would likely find a logical extension to other populations of patients. More than 2,000,000 NIs occur each year in the USA (in infants and adults). This represen ts a major unmet medical need as well as a significant market. Marketing approval for TLF to treat NIs would be of great benefit to the patients and the comm


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 571.73K | Year: 2009

DESCRIPTION (provided by applicant): This project aims to develop talactoferrin (TLF, recombinant human lactoferrin) as a therapeutic agent to treat prematurely born neonates. The treatment will be given orally shortly after birth to prevent nosocomial infections (NIs) due to abnormal bacterial invasion of neonatal intestinal epithelia and consequently to limit systemic bacteremia and necrotizing enterocolitis (NEC). The overall incidence of prospectively studied NIs in hospitalized neonates has been reported to be 10.8 NI/100 patients. The incidence increases with decreasing birth weight, being as high as 81.8 NI/100 patients in Very Low Birth Weight group (birth weight lt 1500 g). Recent data from the National Institute of Child Health and Human Development-sponsored Neonatal Network indicated that 29% of infants born at 25 to 28 weeks' gestation and 46% of infants born at less than 25 weeks' gestation experience a serious NIs during hospitalization in the NICU. The most common NI sites were sepsis and NEC. We therefore focus development of TLF on providing a sustained way to prevent and treat consequences of NIs in infants born prematurely and weighing from 750 to 1500 g at birth. The study shall enroll a total of 396 infants in a double-blind, randomized prospective study where TLF or placebo will be administered, in addition to the standard of care, to preterm infants before 24 hours of age. The study shall consist of four study groups: 1) mother's milk + placebo, 2) mother's milk + TLF, 3) formula feeding + placebo, and 4) formula feeding + TLF. The Phase-I part of the study shall determine the safety of TLF (at a dose of 300 mg/kg) when administered orally for 30 days. Using the total of (4 x 30) = 120 patients, safety of TLF shall be evaluated by determining the incidence and severity of adverse clinical events including laboratory and radiographic abnormalities. It is anticipated that adverse events might not be related to TLF, but rather to preterm birth, and TLF may mitigate those complications of prematurity [e.g., bronchopulmonary dysplasia]. The subsequent, continuous Phase-II part of the study shall ascertain the efficacy of TLF to enhance post-natal growth and to attenuate the incidence of nosocomial infections (including bacteremia, pneumonia, urinary infection, necrotizing enterocolitis [NEC] plus NEC scares , and meningitis). All 396 patients recruited into the study (Phase I and Phase II) shall be used to evaluate efficacy of TLF. The Primary Endpoint shall be the time to regain birth weight, daily weight gain, and number of days to hospital discharge, Incidence of nosocomial infections [late-onset bacteremia, pneumonia, necrotizing enterocolitis, urinary tract infection, and meningitis] and incidence of NEC Scares , neonatal sepsis syndrome or systemic inflammatory response syndrome without proven evidence of infection. Additionally, Secondary Efficacy Parameters shall evaluate the number of days on mechanical ventilation and/or nasal positive airway pressure, number of days on supplemental oxygen, and overall morbidity and mortality (%). A consortium of clinical centers has been formed to ensure adequate number of patients and the rate of recruitment to complete the project within 2 years from its initiation. The consortium includes the Southern Illinois University School of Medicine (St. John's Children's Hospital), The University of Louisville (Kosair Children's Hospital and the University of Louisville Hospital) and University of Southern California (Children's Hospital of Los Angeles and Hollywood Presbyterian Medical Center). Effectiveness of TLF in controlling NIs in neonates would likely find a logical extension to other populations of patients. More than 2,000,000 NIs occur each year in the USA (in infants and adults). This represents a major unmet medical need as well as a significant market. Marketing approval for TLF to treat NIs would be of great benefit to the patients and the community, and would also be of a substantial commercial value.


Patent
Agennix Inc. | Date: 2012-10-09

The present invention provides a novel pyrazolo[3,4-d]pyrimidin-4-one, specifically a derivative of 1-(pyridine-4-yl)-pyrazolo[3,4-d]pyrimidin-4-one. This compound is a kinase inhibitor that shows unexpected anti-proliferative activity against cells, including against tumor cells, and anti-tumor activity in xenograft tumor models. The compound or a suitable salt or prodrug thereof is useful for the treatment of individuals suffering from a cancer or another proliferative disorder or disease.


The present invention relates to methods of treating a hyperproliferative disease by administering a composition of lactoferrin alone or in combination with standard anti-cancer therapies.

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