Three new oral blood-thinning drugs nearing approval by the Food and Drug Administration are more convenient than the standard drug Coumadin® because they do not require monthly visits to adjust doses.
But the promising drugs also could be subject to dangerous interactions when taken alongside widely used prescription drugs, over-the-counter medicines such as aspirin and even herbal supplements such as St. John's Wort, according to a Loyola University Health System study.
"Many unknowns remain as to how the new anticoagulants will behave in the real world patient population," researchers conclude in a review article in the June issue of the International Journal of Clinical Practice.
While the new drugs offer "significant potential advantages," their lack of extensive clinical experience "should not be underestimated," researchers wrote.
Lead author is blood clot specialist Jeanine Walenga, PhD, a professor in the Cardiovascular Institute and departments of Thoracic and Cardiovascular Surgery and Pathology at Loyola University Chicago Stritch School of Medicine. Co-author is Cafer Adiguzel, MD, who completed a fellowship at Loyola.
Coumadin reduces the risk of life-threatening blood clots in patients who have chronic conditions such as irregular heart rhythms or have undergone recent surgeries such as hip and knee replacements.
Coumadin (generic name, warfarin) must be carefully monitored. If the dose is too high, a patient could experience excessive bruising and be at higher risk for brain hemorrhages. If the dose is too low, the drug would be ineffective in preventing life-threatening blood clots. Patients typically must come in every month for a blood test to determine whether the dose needs to be adjusted.
The three new drugs do not need to be monitored every month, according to their manufacturers. They are rivaroxaban (Xarelto®), dabigatran etexilate (Pradaxa®) and apixaban. Rivaroxaban and dabigatran etexilate have been approved in Europe and apixaban is under development. Manufacturers of all three drugs have asked for or are expected to seek approval from the U.S. Food and Drug Administration.
Interactions with other drugs can make the new blood-thinning drugs either ineffective or too effective. For example, St. John's wort, typically taken for depression, can make the drugs less effective, while aspirin can make them more potent and thereby increase the risk of bleeding.
One study found that one-third of older adults use aspirin. A second study found that 29 percent of adults ages 57 to 85 take at least five prescription drugs.
"A high proportion of adults in the United States consume at least one of the drugs known to have some level of interaction with one of the new oral anticoagulants," the Loyola researchers write.
So far, most of what's known about potential drug interactions comes from animal studies or clinical trials that included relatively healthy patients who were carefully monitored. Less is known about elderly patients who have multiple health problems and might miss doses or take incorrect doses.
"The impact of any drug interaction will only become known with increasing clinical experience of these new oral anticoagulants," researchers wrote.
Source
Loyola University Health System
View drug information on Warfarin Sodium tablets.
суббота, 21 мая 2011 г.
пятница, 20 мая 2011 г.
Cord Blood Transplantation, Even Unrelated And Mismatched, Can Still Help Children With Deadly Conditions
An unrelated cord blood transplant, even from a mismatched donor, can be effective in treating children with a host of life-threatening diseases and disorders including cancer, sickle cell anemia, and other genetic diseases, according to researchers in the Duke Pediatric Blood and Marrow Transplantation Program. Unrelated cord blood may be easier to obtain than adult bone marrow, allowing for the treatment of more patients.
"We have done a terrific job in this country of increasing the number of volunteer donors listed in the National Marrow Donor Program registry over the past several years," said Vinod Prasad, M.D., a pediatric oncologist at Duke. "But the fact remains that for many patients, finding a matched donor can be difficult. Ethnic and racial minorities have the hardest time finding a fully matched donor."
The researchers presented their findings in an oral presentation at the American Society of Bone Marrow Transplantation in Tampa, Florida, on Friday, February 13, 2009. The study was partially funded by the National Institutes of Health.
"Our study found that using cord blood can be effective, without increased complications, and can provide more matches for patients, including ethnic minorities," said Prasad, who was the lead investigator. "Based on the findings of our study, we believe that unrelated cord blood transplant should be considered as an option for many of our young patients in need of a transplant."
Bone marrow transplantation has proven to be an effective treatment for thousands of children in the United States each year diagnosed with diseases such as leukemia and sickle cell disease, and inherited metabolic disorders such as Hurler's syndrome. Patients without a suitable match within their families can turn to the bone marrow registry, which currently lists more than seven million donors. Despite that number, however, many patients, particularly ethnic and racial minorities, are unable to find a completely matched donor.
The vast majority of these patients will find a partially matched donor within the public cord blood banks despite a smaller inventory of donor units, Prasad said.
"In order to match a donor to a recipient, doctors compare HLA typing, a test usually performed on a blood sample. In every individual, HLA typing includes the specific genetic make-up at three locations -- within those locations, you are looking at one set from the mother and one from the father, so it ends up to be six-point comparison," Prasad said. "In this analysis of children whose donor units were matched at four of six points, the transplant was successful in many patients, with low incidence of complications. Results were similar to those seen in patients receiving closer matched transplants. Thus the use of the 4/6 matched donors improved access to transplant for patients, especially those of ethnic and racial minorities."
The researchers studied data taken from 314 patients treated at Duke between 1993 and 2007. The patients ranged in age from six months to 21 years and suffered from both malignant and non-malignant conditions.
"We found that transplantation using 4/6 matched cord blood was effective and also carried a low probability of graft versus host disease, a complication caused by the attacking immune cells from the transplanted blood or marrow that perceive the recipient as 'foreign,' in the same way a healthy body's immune system might fight off a virus," Prasad said. "The incidence of other complications was low as well, and the data suggest that using 4/6 matched cord blood could improve access for all patients."
Duke has the largest cord blood transplantation program in the country, and the first unrelated cord blood transplant was performed by Duke physician Joanne Kurtzberg in 1993, on a patient with leukemia.
Other researchers involved in this study include Premjit Gill, Suhag Parikh, Paul Szabolcs, Timothy Driscoll, Kristin Page, Susan Wood, Deborah Semmel, Paul Martin, and Kurtzberg of Duke; and Adam Mendizabal and Shelly Carter, statisticians at the EMMES Corporation.
Source: Lauren Shaftel Williams
Duke University Medical Center
"We have done a terrific job in this country of increasing the number of volunteer donors listed in the National Marrow Donor Program registry over the past several years," said Vinod Prasad, M.D., a pediatric oncologist at Duke. "But the fact remains that for many patients, finding a matched donor can be difficult. Ethnic and racial minorities have the hardest time finding a fully matched donor."
The researchers presented their findings in an oral presentation at the American Society of Bone Marrow Transplantation in Tampa, Florida, on Friday, February 13, 2009. The study was partially funded by the National Institutes of Health.
"Our study found that using cord blood can be effective, without increased complications, and can provide more matches for patients, including ethnic minorities," said Prasad, who was the lead investigator. "Based on the findings of our study, we believe that unrelated cord blood transplant should be considered as an option for many of our young patients in need of a transplant."
Bone marrow transplantation has proven to be an effective treatment for thousands of children in the United States each year diagnosed with diseases such as leukemia and sickle cell disease, and inherited metabolic disorders such as Hurler's syndrome. Patients without a suitable match within their families can turn to the bone marrow registry, which currently lists more than seven million donors. Despite that number, however, many patients, particularly ethnic and racial minorities, are unable to find a completely matched donor.
The vast majority of these patients will find a partially matched donor within the public cord blood banks despite a smaller inventory of donor units, Prasad said.
"In order to match a donor to a recipient, doctors compare HLA typing, a test usually performed on a blood sample. In every individual, HLA typing includes the specific genetic make-up at three locations -- within those locations, you are looking at one set from the mother and one from the father, so it ends up to be six-point comparison," Prasad said. "In this analysis of children whose donor units were matched at four of six points, the transplant was successful in many patients, with low incidence of complications. Results were similar to those seen in patients receiving closer matched transplants. Thus the use of the 4/6 matched donors improved access to transplant for patients, especially those of ethnic and racial minorities."
The researchers studied data taken from 314 patients treated at Duke between 1993 and 2007. The patients ranged in age from six months to 21 years and suffered from both malignant and non-malignant conditions.
"We found that transplantation using 4/6 matched cord blood was effective and also carried a low probability of graft versus host disease, a complication caused by the attacking immune cells from the transplanted blood or marrow that perceive the recipient as 'foreign,' in the same way a healthy body's immune system might fight off a virus," Prasad said. "The incidence of other complications was low as well, and the data suggest that using 4/6 matched cord blood could improve access for all patients."
Duke has the largest cord blood transplantation program in the country, and the first unrelated cord blood transplant was performed by Duke physician Joanne Kurtzberg in 1993, on a patient with leukemia.
Other researchers involved in this study include Premjit Gill, Suhag Parikh, Paul Szabolcs, Timothy Driscoll, Kristin Page, Susan Wood, Deborah Semmel, Paul Martin, and Kurtzberg of Duke; and Adam Mendizabal and Shelly Carter, statisticians at the EMMES Corporation.
Source: Lauren Shaftel Williams
Duke University Medical Center
четверг, 19 мая 2011 г.
Costs Of Home Hemodialysis Offset By Better Health, Fewer Hospitalizations
Daily hemodialysis administered
in patients' homes is associated with better health outcomes compared
with peritoneal dialysis, according to an article in the October issue
of the American Journal of Kidney Diseases, the official journal of the
National Kidney Foundation.
As a result, the extra cost of providing in-home hemodialysis is
balanced out by lower expenditures for medications and hospital
admissions, physicians at a health maintenance organization in southern
California report.
Dialysis is a way of cleaning blood when a person's kidneys can no
longer do the job. It gets rid of the body's wastes, extra salt and
water, and helps to control blood pressure. There are two kinds of
dialysis: hemodialysis and peritoneal dialysis.
In hemodialysis, blood is pumped out of the patient's body to an
artificial kidney machine where the blood is filtered through a special
membrane, called a dialyzer, and then returned to the body.
In peritoneal dialysis, the inside lining of the patient's own belly
acts as a natural filter. Wastes are taken out by means of a cleansing
fluid called dialysate, which is washed in and out of the abdomen in
cycles through a surgically placed soft plastic tube (catheter).
"You can do hemodialysis at a dialysis center where a nurse or
technician performs the tasks required during treatment," says Dr.
Kerry Willis, Senior Vice President for Scientific Activities at the
National Kidney Foundation. "You can also do hemodialysis at home
where you and a care partner are the ones doing your treatment. At
home, you may be better able to fit your treatments into your daily
schedule."
In addition to the convenience, "many reports indicate that people
using daily home hemodialysis take less medication to control blood
pressure and anemia, feel better during dialysis and less 'washed
out' afterward, and have more energy for daily tasks,," Dr.
Willis pointed out.
However, it has been suggested that better health outcomes may simply
be the result of healthier patients opting for home treatment.
In their article, Dr. Victoria A. Kumar and her associates at the
Southern California Permanente Medical Group in Los Angeles tested this
theory by comparing one group of patients treated with daily home
hemodialysis with a group of patients treated with peritoneal dialysis.
Home dialysis was performed on average 5.4 times per week.
Dr. Kumar's group treated the 22 patients in the daily hemodialysis
group and the 64 in the peritoneal dialysis group for at least 6 months
between 2003 and 2007. The groups were comparable in age, the number of
patients with diabetes, and causes of kidney failure.
Despite these similarities, patients treated by peritoneal dialysis
spent nearly twice as many days each year in the hospital compared with
patients treated with home hemodialysis (average 5.6 days/patient-year
versus 3.3 days/patient-year).
Those treated by daily home hemodialysis were also able to reduce the
number of medications required to keep their blood pressure under
control, and had better nutritional status than they did prior to
starting treatment, as shown by higher serum albumin levels.
Dr. Kumar and her associates point out that their organization could
support the program of home hemodialysis because the cost of equipment,
supplies, and patient training was offset by lower expenditures for
hospital care and medications.
Unfortunately, many patients do not have the option of home dialysis
because Medicare does not fully reimburse health care providers for the
costs associated with such a program and not all dialysis centers offer
education and training for home hemodialysis. Another challenge relating
to home hemodialysis is the need for a care partner.
"If the costs of providing more frequent hemodialysis treatments do
not pose a financial burden on the Medicare system," Dr. Kumar and her
associates state, "the modality should be freely available to
motivated patients with end-stage renal disease."
The National Kidney Foundation, Inc. (NKF) is the major voluntary
health organization dedicated to preventing kidney disease, improving
the health and well-being of individuals and families affected by kidney
disease, and increasing the availability of all organs for
transplantation.
To learn more about chronic kidney disease, risk factors or
hemodialysis, contact the National Kidney Foundation at kidney.
National Kidney Foundation
in patients' homes is associated with better health outcomes compared
with peritoneal dialysis, according to an article in the October issue
of the American Journal of Kidney Diseases, the official journal of the
National Kidney Foundation.
As a result, the extra cost of providing in-home hemodialysis is
balanced out by lower expenditures for medications and hospital
admissions, physicians at a health maintenance organization in southern
California report.
Dialysis is a way of cleaning blood when a person's kidneys can no
longer do the job. It gets rid of the body's wastes, extra salt and
water, and helps to control blood pressure. There are two kinds of
dialysis: hemodialysis and peritoneal dialysis.
In hemodialysis, blood is pumped out of the patient's body to an
artificial kidney machine where the blood is filtered through a special
membrane, called a dialyzer, and then returned to the body.
In peritoneal dialysis, the inside lining of the patient's own belly
acts as a natural filter. Wastes are taken out by means of a cleansing
fluid called dialysate, which is washed in and out of the abdomen in
cycles through a surgically placed soft plastic tube (catheter).
"You can do hemodialysis at a dialysis center where a nurse or
technician performs the tasks required during treatment," says Dr.
Kerry Willis, Senior Vice President for Scientific Activities at the
National Kidney Foundation. "You can also do hemodialysis at home
where you and a care partner are the ones doing your treatment. At
home, you may be better able to fit your treatments into your daily
schedule."
In addition to the convenience, "many reports indicate that people
using daily home hemodialysis take less medication to control blood
pressure and anemia, feel better during dialysis and less 'washed
out' afterward, and have more energy for daily tasks,," Dr.
Willis pointed out.
However, it has been suggested that better health outcomes may simply
be the result of healthier patients opting for home treatment.
In their article, Dr. Victoria A. Kumar and her associates at the
Southern California Permanente Medical Group in Los Angeles tested this
theory by comparing one group of patients treated with daily home
hemodialysis with a group of patients treated with peritoneal dialysis.
Home dialysis was performed on average 5.4 times per week.
Dr. Kumar's group treated the 22 patients in the daily hemodialysis
group and the 64 in the peritoneal dialysis group for at least 6 months
between 2003 and 2007. The groups were comparable in age, the number of
patients with diabetes, and causes of kidney failure.
Despite these similarities, patients treated by peritoneal dialysis
spent nearly twice as many days each year in the hospital compared with
patients treated with home hemodialysis (average 5.6 days/patient-year
versus 3.3 days/patient-year).
Those treated by daily home hemodialysis were also able to reduce the
number of medications required to keep their blood pressure under
control, and had better nutritional status than they did prior to
starting treatment, as shown by higher serum albumin levels.
Dr. Kumar and her associates point out that their organization could
support the program of home hemodialysis because the cost of equipment,
supplies, and patient training was offset by lower expenditures for
hospital care and medications.
Unfortunately, many patients do not have the option of home dialysis
because Medicare does not fully reimburse health care providers for the
costs associated with such a program and not all dialysis centers offer
education and training for home hemodialysis. Another challenge relating
to home hemodialysis is the need for a care partner.
"If the costs of providing more frequent hemodialysis treatments do
not pose a financial burden on the Medicare system," Dr. Kumar and her
associates state, "the modality should be freely available to
motivated patients with end-stage renal disease."
The National Kidney Foundation, Inc. (NKF) is the major voluntary
health organization dedicated to preventing kidney disease, improving
the health and well-being of individuals and families affected by kidney
disease, and increasing the availability of all organs for
transplantation.
To learn more about chronic kidney disease, risk factors or
hemodialysis, contact the National Kidney Foundation at kidney.
National Kidney Foundation
среда, 18 мая 2011 г.
Improving Understanding Of Hematopoiesis Through Systems Biology
Our body reacts to blood loss by stimulating the production of red blood cells (erythrocytes). The cells of the hematopoietic (blood-forming) system in the bone marrow do so upon receipt of a signal by a hormone called erythropoietin, or Epo for short. This hormone is produced mainly by the kidney that increases the Epo level by up to a thousand-fold as a response to falling oxygen saturation of the blood.
The hematopoietic cells receive the Epo signal through Epo receptors on their surface. How do the blood progenitor cells that carry only few receptor molecules manage to react adequately to a high rise in the Epo level and to always provide the required amount of red blood cells? "If too much of the hormone floods too few receptor molecules, we would expect the saturation point to be reached soon. This would mean that the hematopoietic cell can no longer respond to a further increase in the hormone level," says Dr. Ursula KlingmГјller of DKFZ.
Researchers in her department, who participate in the Helmholtz Alliance for Systems Biology and the MedSys Network LungSys funded by the Federal Ministry of Education and Research (BMBF), collaborated with colleagues of a working group headed by Professor Jens Timmer at Freiburg University to find out how hematopoietic cells can react in a linear way if Epo levels increase by several orders of magnitude. To do so, the researchers combined experimental data with mathematical models in a systems biology approach.
The research team was able to show that after binding of Epo to its receptor both molecules are rapidly taken up into the interior of the hematopoietic cells where they are broken down. During the process, the cell surface is continuously equipped with newly synthesized receptor molecules that are supplied from intracellular storage places. "This turnover of receptor molecules is a very rapid process," Jens Timmer explains who is a member of the Freiburg Institute for Advances Studies (FRIAS) as well as the excellence cluster BIOSS. "Thus, the cell keeps being able to recognize further hormone molecules in its environment and to react accordingly."
Genetically engineered Epo is an important medication for treating anemia, for example in dialysis patients who often suffer from low counts of red blood cells because these are destroyed during dialysis and, in addition, the failure of renal function leads to a lack of natural Epo. The results of the Heidelberg and Freiburg scientists may contribute to developing Epo variants with enhanced binding properties and thus increase the effectiveness of anemia treatment.
Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer, Ursula KlingmГјller: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor. Science 2010, DOI: 10.1126/science.1184913
Source:
Dr. Sibylle Kohlstaedt
Helmholtz Association of German Research Centres
The hematopoietic cells receive the Epo signal through Epo receptors on their surface. How do the blood progenitor cells that carry only few receptor molecules manage to react adequately to a high rise in the Epo level and to always provide the required amount of red blood cells? "If too much of the hormone floods too few receptor molecules, we would expect the saturation point to be reached soon. This would mean that the hematopoietic cell can no longer respond to a further increase in the hormone level," says Dr. Ursula KlingmГјller of DKFZ.
Researchers in her department, who participate in the Helmholtz Alliance for Systems Biology and the MedSys Network LungSys funded by the Federal Ministry of Education and Research (BMBF), collaborated with colleagues of a working group headed by Professor Jens Timmer at Freiburg University to find out how hematopoietic cells can react in a linear way if Epo levels increase by several orders of magnitude. To do so, the researchers combined experimental data with mathematical models in a systems biology approach.
The research team was able to show that after binding of Epo to its receptor both molecules are rapidly taken up into the interior of the hematopoietic cells where they are broken down. During the process, the cell surface is continuously equipped with newly synthesized receptor molecules that are supplied from intracellular storage places. "This turnover of receptor molecules is a very rapid process," Jens Timmer explains who is a member of the Freiburg Institute for Advances Studies (FRIAS) as well as the excellence cluster BIOSS. "Thus, the cell keeps being able to recognize further hormone molecules in its environment and to react accordingly."
Genetically engineered Epo is an important medication for treating anemia, for example in dialysis patients who often suffer from low counts of red blood cells because these are destroyed during dialysis and, in addition, the failure of renal function leads to a lack of natural Epo. The results of the Heidelberg and Freiburg scientists may contribute to developing Epo variants with enhanced binding properties and thus increase the effectiveness of anemia treatment.
Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer, Ursula KlingmГјller: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor. Science 2010, DOI: 10.1126/science.1184913
Source:
Dr. Sibylle Kohlstaedt
Helmholtz Association of German Research Centres
вторник, 17 мая 2011 г.
Surface Logix Starts Phase 2a Clinical Trial Of SLx-4090 In Dyslipidemia
Surface Logix Inc. today announced the
initiation of a Phase 2a clinical trial of SLx-4090 in patients with
dyslipidemia (abnormal levels of lipids in the bloodstream). The trial will
investigate the drug's effect on reducing plasma lipid levels by preventing
the intestinal absorption of cholesterol and triglycerides. SLx-4090 is an
enterocyte-specific microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia.
"This study builds on the positive data from Phase 1 trials completed
last year, in which SLx-4090 was shown to have a clear impact on reducing
the peaks of triglyceride seen after meals and reducing overall levels of
LDL," said Jim Mahoney, President and Chief Executive Officer of Surface
Logix. "The impressive tolerability and safety profile seen to-date
reflects the fact that SLx-4090 works selectively in the gastrointestinal
tract but is not absorbed into the blood stream."
"Based on the preclinical data and the effects seen in the Phase 1
trials, SLx-4090 is predicted in longer-term patient studies to reduce LDL
cholesterol, impact favorably HDL/LDL ratios, and reduce fasting
triglyceride levels," Mahoney continued. "If the data continues as we have
seen to date, we believe SLx-4090 will have utility as an additional
treatment option for patients who do not reach lipid and triglyceride
target levels on current therapies."
The Phase 2a trial is a single center, randomized, double-blind,
placebo- controlled study that will enroll 24 patients with dyslipidemia
(high cholesterol and triglyceride levels). The primary study objective is
to investigate the effect on post prandial plasma triglycerides of repeat
oral doses of SLx-4090 for 14 days. Secondary trial objectives are to
evaluate the effect of SLx-4090 on additional pharmacodynamic parameters
such as HDL, LDL, total cholesterol, and apoB values; and to determine the
candidate's safety, tolerability, and pharmacokinetics.
About SLx-4090 in Dyslipidemia
SLx-4090 is a novel microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia (abnormal
levels of lipids in the bloodstream). Surface Logix designed SLx-4090 using
its proprietary small molecule Pharmacomer(TM) Technology to act
specifically in the gastrointestinal (GI) tract to prevent the transport of
fats through the intestinal wall. This unique feature of intestinal
selectivity allows activity against fat uptake while avoiding toxicity at
other sites of MTP expression including the liver, heart, testis, ovary,
and eye. Surface Logix is also exploring the use of SLx-4090 in other
metabolic disorders, including obesity and diabetes.
Dyslipidemia currently affects approximately 10% of the global
population, with 25% of these patients having elevated triglyceride levels.
In addition, there is an increasing prevalence and medical need for
lipid-modifying drugs in obese patients and patients with type 2 diabetes,
as a high proportion of type 2 diabetic patients have abnormal
concentrations of lipoproteins. In the U.S., Japan and Europe, it is
estimated that there are more than 240 million people with abnormal
lipoprotein levels. Of these, more than 55 million are estimated to have
low high density lipoprotein (HDL) and/or high triglyceride levels.
About Surface Logix Inc.
Surface Logix Inc. uses its expertise in biophysical chemistry to
create and develop novel small molecule drugs (NCE's) with superior
intrinsic drug- like properties that are clearly differentiated from
competitive products. The company is advancing multiple internal programs
focused primarily on cardiovascular, metabolic, inflammatory and fibrotic
diseases. For more information, please visit surfacelogix.
Surface Logix Inc.
surfacelogix
initiation of a Phase 2a clinical trial of SLx-4090 in patients with
dyslipidemia (abnormal levels of lipids in the bloodstream). The trial will
investigate the drug's effect on reducing plasma lipid levels by preventing
the intestinal absorption of cholesterol and triglycerides. SLx-4090 is an
enterocyte-specific microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia.
"This study builds on the positive data from Phase 1 trials completed
last year, in which SLx-4090 was shown to have a clear impact on reducing
the peaks of triglyceride seen after meals and reducing overall levels of
LDL," said Jim Mahoney, President and Chief Executive Officer of Surface
Logix. "The impressive tolerability and safety profile seen to-date
reflects the fact that SLx-4090 works selectively in the gastrointestinal
tract but is not absorbed into the blood stream."
"Based on the preclinical data and the effects seen in the Phase 1
trials, SLx-4090 is predicted in longer-term patient studies to reduce LDL
cholesterol, impact favorably HDL/LDL ratios, and reduce fasting
triglyceride levels," Mahoney continued. "If the data continues as we have
seen to date, we believe SLx-4090 will have utility as an additional
treatment option for patients who do not reach lipid and triglyceride
target levels on current therapies."
The Phase 2a trial is a single center, randomized, double-blind,
placebo- controlled study that will enroll 24 patients with dyslipidemia
(high cholesterol and triglyceride levels). The primary study objective is
to investigate the effect on post prandial plasma triglycerides of repeat
oral doses of SLx-4090 for 14 days. Secondary trial objectives are to
evaluate the effect of SLx-4090 on additional pharmacodynamic parameters
such as HDL, LDL, total cholesterol, and apoB values; and to determine the
candidate's safety, tolerability, and pharmacokinetics.
About SLx-4090 in Dyslipidemia
SLx-4090 is a novel microsomal triglyceride transfer protein (MTP)
inhibitor being developed for the treatment of dyslipidemia (abnormal
levels of lipids in the bloodstream). Surface Logix designed SLx-4090 using
its proprietary small molecule Pharmacomer(TM) Technology to act
specifically in the gastrointestinal (GI) tract to prevent the transport of
fats through the intestinal wall. This unique feature of intestinal
selectivity allows activity against fat uptake while avoiding toxicity at
other sites of MTP expression including the liver, heart, testis, ovary,
and eye. Surface Logix is also exploring the use of SLx-4090 in other
metabolic disorders, including obesity and diabetes.
Dyslipidemia currently affects approximately 10% of the global
population, with 25% of these patients having elevated triglyceride levels.
In addition, there is an increasing prevalence and medical need for
lipid-modifying drugs in obese patients and patients with type 2 diabetes,
as a high proportion of type 2 diabetic patients have abnormal
concentrations of lipoproteins. In the U.S., Japan and Europe, it is
estimated that there are more than 240 million people with abnormal
lipoprotein levels. Of these, more than 55 million are estimated to have
low high density lipoprotein (HDL) and/or high triglyceride levels.
About Surface Logix Inc.
Surface Logix Inc. uses its expertise in biophysical chemistry to
create and develop novel small molecule drugs (NCE's) with superior
intrinsic drug- like properties that are clearly differentiated from
competitive products. The company is advancing multiple internal programs
focused primarily on cardiovascular, metabolic, inflammatory and fibrotic
diseases. For more information, please visit surfacelogix.
Surface Logix Inc.
surfacelogix
понедельник, 16 мая 2011 г.
The 454 Genome Sequencing System Detects A Novel Virus Responsible For South African Hemorrhagic Fever Outbreak
A study published online in PLoS Pathogens reports that researchers at Columbia University, the South African National Health Laboratory Services, the US Centers for Disease Control, and 454 Life Sciences have discovered a new virus that is responsible for a highly fatal hemorrhagic fever outbreak in Zambia and South Africa late 2008(1). The previously unknown arenavirus, which is distantly related to the Lassa virus and Lymphocytic choriomeningitis virus, was characterized using the rapid and sensitive sequencing technology of 454 Life Sciences. The new species, named "Lujo virus" for the geographic origin of the outbreak (Lusaka, Zambia and Johannesburg, South Africa), is the first hemorrhagic fever-associated arenavirus from Africa identified in the past three decades. Characterization of the novel virus confirms the utility of unbiased high-throughput sequencing for pathogen discovery and provides an opportunity for public health efforts to quickly curb emerging viral pandemics in the future.
In September and October, 2008 five cases of undiagnosed hemorrhagic fever were recognized in South Africa after air transfer of a critically ill individual from Zambia. The disease was fatal in four of the five cases, including the originally infected individual, the paramedic who attended the patient during air transfer, the nurse who attended the patient in the intensive care unit in South Africa, and a member of the hospital staff who cleaned the room after the death of the patient. Unbiased, high-throughput sequencing with the 454 Sequencing system revealed the presence of a previously undiscovered Old World arenavirus. While the distantly related Lymphocytic choriomeningitis virus is generally harmless in healthy humans, the Lujo virus demonstrates an unprecedented high case fatality rate of 80% and unusual degree of pathogenicity.
"Within 72 hours of the sample arriving at JFK Airport, we identified the novel virus using high throughput sequencing," said Thomas Briese, Associate Director of the Center for Infection and Immunity at the Mailman School of Public Health of Columbia University.
"It is reassuring that we now have the tools needed to rapidly detect and respond to the challenges of previously unknown killer viruses. A key challenge that remains is deployment of these technologies to the 'hot spots' where new viruses frequently emerge," explained Ian Lipkin, MD, John Snow Professor of Epidemiology and Professor of Neurology and Pathology at Columbia University and the director of the Center. "We remain committed to this important public health effort as it represents a unique opportunity to prevent the next pandemic, be it a threat like HIV or SARS."
The unbiased, high-throughput 454 Sequencing System has been shown to be a powerful pathogen discovery tool in a series of recent studies. In early 2008, a study published in the New England Journal of Medicine reported the identification of a new virus responsible for the death of three transplant recipients using the technology of 454 Sequencing (2). Another study published last year employed the sequencing system to uncover a novel ebola virus responsible for a 2007 hemorrhagic fever outbreak in Uganda (3).
"454 Sequencing enables researchers to quickly identify the organisms present in a complex sample," explained Michael Egholm, study co-author and Chief Technology Officer and Vice President of Research and Development at 454 Life Sciences. "Our work with Lipkin and colleagues, in developing a comprehensive approach to pathogen detection, has borne fruit in resolving a number of recent disease outbreaks and confirms that it has the potential to be a critical tool for public health. We were honored in this most recent example to work with outstanding investigators at the Centers for Disease Control, World Health Organization, and the National Institute for Communicable Diseases in South Africa. "
454 Life Sciences, a center of excellence of Roche Applied Science, develops and commercializes the innovative 454 Sequencing System for ultra-high-throughput DNA sequencing. Specific applications include de novo sequencing and re-sequencing of genomes, metagenomics, RNA analysis, and targeted sequencing of DNA regions of interest. The hallmarks of the 454 Sequencing System are its simple, unbiased sample preparation and long, highly accurate sequence reads, including paired-end reads. The technology of the 454 Sequencing System has enabled hundreds of peer-reviewed studies in diverse research fields, such as cancer and infectious disease research, drug discovery, marine biology, anthropology, paleontology and many more.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.
In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: roche.
The 454 GS FLX is sold for life science research use only.
454, 454 SEQUENCING, 454 LIFE SCIENCES and GS FLX TITANIUM are trademarks of Roche.
(1) Briese et al. Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa. (2009) PloS Pathogens. ePub April xx.
(2) Palacios et al. A new arenavirus in a cluster of fatal transplant-associated diseases. (2008) New England Journal of Medicine 358: 991-998.
(3) Towner et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. (2008) PLoS Pathogens 4(11): e1000212.
Source
Roche
In September and October, 2008 five cases of undiagnosed hemorrhagic fever were recognized in South Africa after air transfer of a critically ill individual from Zambia. The disease was fatal in four of the five cases, including the originally infected individual, the paramedic who attended the patient during air transfer, the nurse who attended the patient in the intensive care unit in South Africa, and a member of the hospital staff who cleaned the room after the death of the patient. Unbiased, high-throughput sequencing with the 454 Sequencing system revealed the presence of a previously undiscovered Old World arenavirus. While the distantly related Lymphocytic choriomeningitis virus is generally harmless in healthy humans, the Lujo virus demonstrates an unprecedented high case fatality rate of 80% and unusual degree of pathogenicity.
"Within 72 hours of the sample arriving at JFK Airport, we identified the novel virus using high throughput sequencing," said Thomas Briese, Associate Director of the Center for Infection and Immunity at the Mailman School of Public Health of Columbia University.
"It is reassuring that we now have the tools needed to rapidly detect and respond to the challenges of previously unknown killer viruses. A key challenge that remains is deployment of these technologies to the 'hot spots' where new viruses frequently emerge," explained Ian Lipkin, MD, John Snow Professor of Epidemiology and Professor of Neurology and Pathology at Columbia University and the director of the Center. "We remain committed to this important public health effort as it represents a unique opportunity to prevent the next pandemic, be it a threat like HIV or SARS."
The unbiased, high-throughput 454 Sequencing System has been shown to be a powerful pathogen discovery tool in a series of recent studies. In early 2008, a study published in the New England Journal of Medicine reported the identification of a new virus responsible for the death of three transplant recipients using the technology of 454 Sequencing (2). Another study published last year employed the sequencing system to uncover a novel ebola virus responsible for a 2007 hemorrhagic fever outbreak in Uganda (3).
"454 Sequencing enables researchers to quickly identify the organisms present in a complex sample," explained Michael Egholm, study co-author and Chief Technology Officer and Vice President of Research and Development at 454 Life Sciences. "Our work with Lipkin and colleagues, in developing a comprehensive approach to pathogen detection, has borne fruit in resolving a number of recent disease outbreaks and confirms that it has the potential to be a critical tool for public health. We were honored in this most recent example to work with outstanding investigators at the Centers for Disease Control, World Health Organization, and the National Institute for Communicable Diseases in South Africa. "
454 Life Sciences, a center of excellence of Roche Applied Science, develops and commercializes the innovative 454 Sequencing System for ultra-high-throughput DNA sequencing. Specific applications include de novo sequencing and re-sequencing of genomes, metagenomics, RNA analysis, and targeted sequencing of DNA regions of interest. The hallmarks of the 454 Sequencing System are its simple, unbiased sample preparation and long, highly accurate sequence reads, including paired-end reads. The technology of the 454 Sequencing System has enabled hundreds of peer-reviewed studies in diverse research fields, such as cancer and infectious disease research, drug discovery, marine biology, anthropology, paleontology and many more.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.
In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: roche.
The 454 GS FLX is sold for life science research use only.
454, 454 SEQUENCING, 454 LIFE SCIENCES and GS FLX TITANIUM are trademarks of Roche.
(1) Briese et al. Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa. (2009) PloS Pathogens. ePub April xx.
(2) Palacios et al. A new arenavirus in a cluster of fatal transplant-associated diseases. (2008) New England Journal of Medicine 358: 991-998.
(3) Towner et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. (2008) PLoS Pathogens 4(11): e1000212.
Source
Roche
воскресенье, 15 мая 2011 г.
First Structure Of A Class Of Proteins That Help Guide Blood Cell Movement Revealed: Findings May Lead To New Drugs For Cancer, Immune Disorders Aids
Researchers have determined the structure of a protein that helps guide blood-forming stem cells, or hematopoetic stem cells. The protein is also one of the main receptors used by the human immunodeficiency virus (HIV) to get inside blood cells.
The findings are described in the journal Science.
The structure offers a detailed view of how the cell surface receptor, called CXCR4, interacts with molecules outside the cell. The results have implications for developing new drugs for hematopoetic stem cell transplantation, a therapeutic path to treat cancer and immune disorders, as well as for treating HIV infection.
"The structures open up entire new areas for understanding fundamental principles in chemokine GPCR signaling," said Scripps Research Professor Raymond C. Stevens, who is senior author of the collaborative study.
Sniffing Out Signals
CXCR4 belongs to a large family of more than 700 proteins known as G protein-coupled receptors (GPCRs). These proteins sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger the appropriate response inside the cell.
"My lab is really interested in how this one protein family recognizes millions of different types of ligands with incredible specificity," said Stevens, "and how when one ligand binds a receptor it may have one intracellular effect such as activation and a closely related ligand can have an opposite effect such as antagonism."
To understand how these receptors function, the Stevens group has already determined the structures of two other GPCRs: the adrenergic receptor, involved in the fight-or-flight response, and the A2A adenosine receptor, sometimes also referred to as the "caffeine" receptor. The newly solved protein CXCR4 belongs to a different group of GPCRs, one that binds to protein molecules called chemokines, which primarily function to steer the movement of blood and immune cells to their appropriate locations in the body.
Comparing Wine Glasses
To get the first-ever glimpse of a chemokine receptor bound to a ligand, Stevens and colleagues turned to GPCR biochemistry, receptor stabilization and X-ray crystallography.
"One challenging aspect of this research is the biochemistry - learning what the receptor likes and dislikes," said Stevens. "Each receptor and receptor-ligand complex has a distinctly different biophysical personality."
The crystal structure of CXCR4, just like that of other known GPCRs, resembles a wine glass stuck inside the cell membrane, with the glass opening (where the ligands bind) facing the outside of the cell and the stem portion the inside. But there are important differences.
"The adrenergic receptor looks like a pinot noir glass that curves inward towards the top to hold in the wine vapors; the A2A receptor looks like a champagne flute," explained Stevens. "The CXCR4 structure looks like chardonnay glass with a wider opening and shorter depth."
The wider mouth allows CXCR4 to bind to its chemokine ligand, CXCL-12, which is a protein and thus a larger molecule than the ligands that bind the adrenergic and A2Areceptors. CXCL-12 is the signal in the blood that guides hematopoetic stem cells to the bone marrow, a process known as homing.
Finding Therapies
One of the biggest surprises of the CXCR4 structure was that this receptor, unlike the adrenergic and A2A receptors, likes to form pairs or dimers.
"The dimerization observation was very intriguing," said Stevens. "We solved five different crystal structures in multiple crystal forms, and each one had the same dimer interface. It has long been debated how GPCRs might dimerize, if they did at all. This is the first solid observation about a consistent structural GPCR dimer."
Preventing dimerization might provide a new way to block CXCR4 function. Drugs that block CXCR4 appear to be capable of releasing hematopoietic stem cells from the bone marrow into the bloodstream - a step that is critical for stem cell transplantation. Only one such drug, called Mozobil, is currently on the market. In addition, drugs that block CXCR4 are useful in treating HIV infection.
Having determined the structure of CXCR4, Stevens and colleagues were able to determine which portions of the protein are critical to chemokine recognition. This knowledge can now be used to understand basic principles of chemokine recognition and signaling, as well as to design new therapeutic candidates or improve the affinity and efficacy of existing drugs.
Like all membrane proteins, GPCRs are notoriously difficult to crystallize, but CXCR4 was a particularly difficult structure to crack, according to Stevens.
"Each GPCR structure is a tour de force and this one took a team of several people three years to complete," he said. " I wish I could identify one step that was the most challenging, but I would say every step was hard."
Stevens credits the perseverance and creativity of Research Associate Beili Wu, (who was first author of the paper), Scientific Associate Ellen Chien, and Assistant Professor Vadim Cherezov for noteworthy breakthroughs. Stevens also notes that working in close collaboration with colleagues Alexei Brooun, Chris Bi, and Peter Wells at Pfizer La Jolla and Professors Tracy Handel and Ruben Abagyan at the University of California, San Diego (UCSD) led to much of the success where chemistry, biological insight, and structural biology were brought together in a synergistic and productive manner.
In addition to Stevens, Wu, Chien, Cherezov, Brooun, Bi, Wells, Handel, and Abagayan, the paper, "Structure of the CXCR4 chemokine receptor with small molecule and cyclic peptide antagonists," was authored by Clifford D. Mol, Gustavo Fenalti, Wei Liu, and Peter Kuhn of Scripps Research, and Vsevolod Katrich and Damon J. Hamel of UCSD.
This work was supported by the National Institutes of Health Protein Structure Initiative, NIH Common Fund, and Pfizer.
Source:
Mika Ono
Scripps Research Institute
View drug information on Mozobil.
The findings are described in the journal Science.
The structure offers a detailed view of how the cell surface receptor, called CXCR4, interacts with molecules outside the cell. The results have implications for developing new drugs for hematopoetic stem cell transplantation, a therapeutic path to treat cancer and immune disorders, as well as for treating HIV infection.
"The structures open up entire new areas for understanding fundamental principles in chemokine GPCR signaling," said Scripps Research Professor Raymond C. Stevens, who is senior author of the collaborative study.
Sniffing Out Signals
CXCR4 belongs to a large family of more than 700 proteins known as G protein-coupled receptors (GPCRs). These proteins sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger the appropriate response inside the cell.
"My lab is really interested in how this one protein family recognizes millions of different types of ligands with incredible specificity," said Stevens, "and how when one ligand binds a receptor it may have one intracellular effect such as activation and a closely related ligand can have an opposite effect such as antagonism."
To understand how these receptors function, the Stevens group has already determined the structures of two other GPCRs: the adrenergic receptor, involved in the fight-or-flight response, and the A2A adenosine receptor, sometimes also referred to as the "caffeine" receptor. The newly solved protein CXCR4 belongs to a different group of GPCRs, one that binds to protein molecules called chemokines, which primarily function to steer the movement of blood and immune cells to their appropriate locations in the body.
Comparing Wine Glasses
To get the first-ever glimpse of a chemokine receptor bound to a ligand, Stevens and colleagues turned to GPCR biochemistry, receptor stabilization and X-ray crystallography.
"One challenging aspect of this research is the biochemistry - learning what the receptor likes and dislikes," said Stevens. "Each receptor and receptor-ligand complex has a distinctly different biophysical personality."
The crystal structure of CXCR4, just like that of other known GPCRs, resembles a wine glass stuck inside the cell membrane, with the glass opening (where the ligands bind) facing the outside of the cell and the stem portion the inside. But there are important differences.
"The adrenergic receptor looks like a pinot noir glass that curves inward towards the top to hold in the wine vapors; the A2A receptor looks like a champagne flute," explained Stevens. "The CXCR4 structure looks like chardonnay glass with a wider opening and shorter depth."
The wider mouth allows CXCR4 to bind to its chemokine ligand, CXCL-12, which is a protein and thus a larger molecule than the ligands that bind the adrenergic and A2Areceptors. CXCL-12 is the signal in the blood that guides hematopoetic stem cells to the bone marrow, a process known as homing.
Finding Therapies
One of the biggest surprises of the CXCR4 structure was that this receptor, unlike the adrenergic and A2A receptors, likes to form pairs or dimers.
"The dimerization observation was very intriguing," said Stevens. "We solved five different crystal structures in multiple crystal forms, and each one had the same dimer interface. It has long been debated how GPCRs might dimerize, if they did at all. This is the first solid observation about a consistent structural GPCR dimer."
Preventing dimerization might provide a new way to block CXCR4 function. Drugs that block CXCR4 appear to be capable of releasing hematopoietic stem cells from the bone marrow into the bloodstream - a step that is critical for stem cell transplantation. Only one such drug, called Mozobil, is currently on the market. In addition, drugs that block CXCR4 are useful in treating HIV infection.
Having determined the structure of CXCR4, Stevens and colleagues were able to determine which portions of the protein are critical to chemokine recognition. This knowledge can now be used to understand basic principles of chemokine recognition and signaling, as well as to design new therapeutic candidates or improve the affinity and efficacy of existing drugs.
Like all membrane proteins, GPCRs are notoriously difficult to crystallize, but CXCR4 was a particularly difficult structure to crack, according to Stevens.
"Each GPCR structure is a tour de force and this one took a team of several people three years to complete," he said. " I wish I could identify one step that was the most challenging, but I would say every step was hard."
Stevens credits the perseverance and creativity of Research Associate Beili Wu, (who was first author of the paper), Scientific Associate Ellen Chien, and Assistant Professor Vadim Cherezov for noteworthy breakthroughs. Stevens also notes that working in close collaboration with colleagues Alexei Brooun, Chris Bi, and Peter Wells at Pfizer La Jolla and Professors Tracy Handel and Ruben Abagyan at the University of California, San Diego (UCSD) led to much of the success where chemistry, biological insight, and structural biology were brought together in a synergistic and productive manner.
In addition to Stevens, Wu, Chien, Cherezov, Brooun, Bi, Wells, Handel, and Abagayan, the paper, "Structure of the CXCR4 chemokine receptor with small molecule and cyclic peptide antagonists," was authored by Clifford D. Mol, Gustavo Fenalti, Wei Liu, and Peter Kuhn of Scripps Research, and Vsevolod Katrich and Damon J. Hamel of UCSD.
This work was supported by the National Institutes of Health Protein Structure Initiative, NIH Common Fund, and Pfizer.
Source:
Mika Ono
Scripps Research Institute
View drug information on Mozobil.
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