A combination of biochemical and MRI markers will allow improved measurement of osteoarthritis (OA) progression. The biomarkers, described in BioMed Central's open access journal Arthritis Research and Therapy, will be useful for the design and interpretation of trials of new disease modifying drugs.
Erik Dam, from Nordic Bioscience, Denmark, worked with a team of researchers to develop and evaluate the markers. He said, "Presently, there is no disease-modifying OA drug with a consistent, documented effect despite several clinical attempts in late stage phases. We believe that effective therapies could be demonstrated, if tools were available that allow identification of rapid progressors for inclusion in trials. With this in mind, we investigated whether combinations of biochemical and MRI-based biomarkers might improve diagnosis and prognosis of knee osteoarthritis".
Dam and his colleagues included 159 subjects in their trial. After exclusions, a total of 287 knees were measured. At baseline and after 21 months, biochemical (urinary collagen type II C-telopeptide fragment, CTX-II) and MRI-based markers were quantified. MRI markers included cartilage volume, thickness, area, roughness, homogeneity, and curvature in the medial tibio-femoral compartment. Joint space width, the presently accepted marker for population selection in clinical studies, was measured from radiographs. According to Dam, "The best individual diagnostic marker was cartilage roughness and the best individual prognostic marker was homogeneity. The aggregate cartilage longevity marker (combining CTX-II, volume, area, thickness, congruity, roughness, and homogeneity) performed very well both diagnostically and prognostically - and superior to the individual biochemical and MRI markers. We attribute this to the combination of markers with complementary information about cartilage quantity (e.g. volume), quality (e.g. homogeneity), and breakdown (CTX-II) that together allow superior diagnosis/prognosis".
The proposed aggregate marker methodology may have a direct impact on the design of clinical studies. The researchers claim, "By allowing the selection of a high risk population, the study sample size can be lowered while still improving the chance of a positive study outcome. This should facilitate the development of effective drugs".
Notes:
Identification of progressors in osteoarthritis by combining biochemical and MRI-based markers
Erik B Dam, Marco Loog, Claus Christiansen, Inger Byrjalsen, Jenny Folkesson, Mads Nielsen, Arish A Qazi, Paola C Pettersen, Patrick Garnero and Morten A Karsdal
Arthritis Research & Therapy (in press) arthritis-research/
Source:
Graeme Baldwin
BioMed Central
понедельник, 6 июня 2011 г.
воскресенье, 5 июня 2011 г.
BioCryst To Present New Data For BCX4208 Monotherapy At The 74th Annual American College Of Rheumatology (ACR) Scientific Meeting
BioCryst Pharmaceuticals, Inc. (NASDAQ: BCRX) announced the presentation of new data related to the efficacy and safety of BCX4208 for the treatment of gout at the 74th ACR Scientific Meeting being held in Atlanta, Georgia.
The data will be presented during a poster session scheduled for today, November 8, 2010 from 9:00-11:00 a.m. Eastern Time. The poster to be presented during the session is entitled:
-- "Effects of a Purine Nucleoside Phosphorylase Inhibitor, BCX4208, on the Serum Uric Acid Concentrations in Patients with Gout". This poster concludes that BCX4208 doses administered at 40, 80, 120, 160 and 240 mg once-daily monotherapy rapidly and significantly reduced serum uric acid (sUA) in patients with gout. BCX4208 was generally safe and well-tolerated at the doses evaluated in this study.
About BCX4208
BCX4208 is a next generation purine nucleoside phosphorylase (PNP) inhibitor with the potential for once-a-day dosing suitable for chronic administration. With its unique mechanism of action, clinical activity and safety in clinical studies to date as well as its potential synergy with approved therapies, BCX4208 has the potential to address unmet medical needs across a broad spectrum of inflammatory and autoimmune diseases. In September 2010, BioCryst reported positive results from its Phase 2 study of BCX4208 alone and in combination with allopurinol in patients with gout, announcing that the study met its primary endpoint related to serum uric acid (sUA) reduction, demonstrated a dose-response for both BCX4208 and allopurinol, and that the combination of BCX4208 and allopurinol was shown to be superior to either drug alone in sUA reduction.
Forward-Looking Statements
This press release contains forward-looking statements, including statements regarding future results, performance or achievements. These statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performances or achievements expressed or implied by the forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Some of the factors that could affect the forward-looking statements contained herein include: that ongoing and future pre-clinical and clinical development of BCX4208 may not have positive results; that we or our licensees may not be able to enroll the required number of subjects in planned clinical trials of our product candidates and that such clinical trials may not be successfully completed; that BioCryst or its licensees may not commence as expected additional human clinical trials with our product candidates; that our product candidates may not receive required regulatory clearances from the FDA; that ongoing and future pre-clinical and clinical development may not have positive results; that we or our licensees may not be able to continue future development of our current and future development programs; that our development programs may never result in future product, license or royalty payments being received by BioCryst; that BioCryst may not be able to retain its current pharmaceutical and biotechnology partners for further development of its product candidates or it may not reach favorable agreements with potential pharmaceutical and biotechnology partners for further development of its product candidates; that our actual cash burn rate may not be consistent with our expectations; that BioCryst may not have sufficient cash to continue funding the development, manufacturing, marketing or distribution of its products and that additional funding, if necessary, may not be available at all or on terms acceptable to BioCryst. Please refer to the documents BioCryst files periodically with the Securities and Exchange Commission, specifically BioCryst's most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and current reports on Form 8-K, all of which identify important factors that could cause the actual results to differ materially from those contained in our projections and forward-looking statements.
Source: BioCryst
The data will be presented during a poster session scheduled for today, November 8, 2010 from 9:00-11:00 a.m. Eastern Time. The poster to be presented during the session is entitled:
-- "Effects of a Purine Nucleoside Phosphorylase Inhibitor, BCX4208, on the Serum Uric Acid Concentrations in Patients with Gout". This poster concludes that BCX4208 doses administered at 40, 80, 120, 160 and 240 mg once-daily monotherapy rapidly and significantly reduced serum uric acid (sUA) in patients with gout. BCX4208 was generally safe and well-tolerated at the doses evaluated in this study.
About BCX4208
BCX4208 is a next generation purine nucleoside phosphorylase (PNP) inhibitor with the potential for once-a-day dosing suitable for chronic administration. With its unique mechanism of action, clinical activity and safety in clinical studies to date as well as its potential synergy with approved therapies, BCX4208 has the potential to address unmet medical needs across a broad spectrum of inflammatory and autoimmune diseases. In September 2010, BioCryst reported positive results from its Phase 2 study of BCX4208 alone and in combination with allopurinol in patients with gout, announcing that the study met its primary endpoint related to serum uric acid (sUA) reduction, demonstrated a dose-response for both BCX4208 and allopurinol, and that the combination of BCX4208 and allopurinol was shown to be superior to either drug alone in sUA reduction.
Forward-Looking Statements
This press release contains forward-looking statements, including statements regarding future results, performance or achievements. These statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performances or achievements expressed or implied by the forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Some of the factors that could affect the forward-looking statements contained herein include: that ongoing and future pre-clinical and clinical development of BCX4208 may not have positive results; that we or our licensees may not be able to enroll the required number of subjects in planned clinical trials of our product candidates and that such clinical trials may not be successfully completed; that BioCryst or its licensees may not commence as expected additional human clinical trials with our product candidates; that our product candidates may not receive required regulatory clearances from the FDA; that ongoing and future pre-clinical and clinical development may not have positive results; that we or our licensees may not be able to continue future development of our current and future development programs; that our development programs may never result in future product, license or royalty payments being received by BioCryst; that BioCryst may not be able to retain its current pharmaceutical and biotechnology partners for further development of its product candidates or it may not reach favorable agreements with potential pharmaceutical and biotechnology partners for further development of its product candidates; that our actual cash burn rate may not be consistent with our expectations; that BioCryst may not have sufficient cash to continue funding the development, manufacturing, marketing or distribution of its products and that additional funding, if necessary, may not be available at all or on terms acceptable to BioCryst. Please refer to the documents BioCryst files periodically with the Securities and Exchange Commission, specifically BioCryst's most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and current reports on Form 8-K, all of which identify important factors that could cause the actual results to differ materially from those contained in our projections and forward-looking statements.
Source: BioCryst
суббота, 4 июня 2011 г.
Repurposing Of Enbrel For Alzheimer's Disease
At Cambridge Healthtech Institute's Third Annual Drug Repositioning Summit on Monday, October 6 in Boston, the audience is scheduled to hear, as a Keynote Presentation, the story of how an individual physician has charted an entirely new course for a therapeutic which is already one of the most successful of all time.
Enbrel® (etanercept) has proven effective for treating a host of medical conditions, from rheumatoid arthritis to psoriasis, generating more than $4 billion dollars per year in revenue for its owner, Amgen. Yet despite this success Amgen has failed to initiate study of etanercept's emerging off-label uses in the field of neurology, which could potentially address enormous unmet medical needs and help people throughout the world. Etanercept is one of a new class of medications, produced through biotechnology, which specifically neutralize an immune signaling molecule called TNF. Excess TNF is centrally involved in scores of diseases, including rheumatoid arthritis, Alzheimer's, sciatica pain, and psoriasis. In Alzheimer's disease excess TNF has been documented in the cerebrospinal fluid, and the rationale for anti-TNF treatment is supported by genetic, epidemiologic, basic science, and clinical data (1-11).
The Keynote Presentation, entitled "Repurposing of Enbrel for Alzheimer's Disease" will be made by Edward Tobinick MD, Director of the Institute for Neurological Research, a private medical group, inc. in Los Angeles. Dr. Tobinick is the inventor and patent holder of the etanercept off-label indication for Alzheimer's Disease, as well as more than 200 different inventions involving new off-label uses of TNF blockers, such as etanercept, in neurology, opthalmology, and for a variety of additional innovative clinical indications(12-17). Many of the novel uses of etanercept which Dr. Tobinick invented, beginning nearly a decade ago, such as for sciatica, Alzheimer's, and myasthenia gravis, have subsequently been supported by peer-reviewed, published studies performed by independent researchers from academic centers across the globe(18-26).
As an example, a recently completed, double-blind, placebo-controlled study conducted by independent researchers at Johns Hopkins/Walter Reed Army Medical Center has confirmed the efficacy of etanercept for sciatica, using a patented, perispinal method of administration of etanercept which Dr. Tobinick invented(27).
Dr. Tobinick has been invited to and has presented his clinical and research findings at multiple prestigious medical research meetings, including this year's International Congress on Alzheimer's Disease (ICAD 2008), the 7th International Alzheimer's Drug Discovery Conference; at the Karolinska Institutet in Stockholm, Sweden, the home of the Nobel Prize in medicine; and in multiple, peer-reviewed, published medical articles(1-5, 27-31).
His published, peer-reviewed scientific articles have been cited by more than 150 scientific publications from around the world(1-6, 18, 20, 23-25, 32, 33). In addition, his groundbreaking work has been recognized by the Dana Alliance for Brain Initiatives, the world's leading organization of neuroscientists, which counts among its members ten Nobel Laureates(34); by leading journals, including Nature Clinical Practice Neurology(35); by the Faculty of 1000 Biology, the expert guide to the most important advances in biology(36); and featured in news articles from around the world(37-39). Despite the immense potential to help countless people, the great unmet medical need, and their enormous continuing revenue from etanercept sales, Amgen has yet to confirm its intention to begin even preliminary clinical study in this direction.
A failure to investigate is perhaps even more puzzling in view of the increasing scientific support from cutting edge research, which is in addition to the genetic studies which have identified excess TNF as a therapeutic target in Alzheimer's(9, 10, 33, 40-43). For example, scientists from the Trinity College Institute of Neuroscience in Ireland have demonstrated that defects in hippocampal learning and memory mechanisms created by forms of amyloid are mediated by TNF(41-43). Perhaps even more significant is the recent identification of TNF as a gliotransmitter which regulates synaptic transmission in the brain(39, 44, 45).
The synaptic effects of TNF which regulate learning, memory, and neurotransmission provide a most exciting area for scientific research. These synaptic effects, which may occur with extreme rapidity, provide a rational and scientifically plausible explanation for the rapid clinical effects of etanercept which have been documented in multiple, peer-reviewed scientific studies and in multiple patients(1-5, 18, 28, 30). To ignore this new direction in scientific thinking, which recognizes the role of TNF not just in inflammation but also as an immune regulator of synaptic communication and other aspects of brain function, would be to impede scientific progress.
Fortunately, with the expiration of Amgen's patents on etanercept approaching in 2012, other pharmaceutical companies will soon have the ability to explore these extraordinary discoveries which have the potential to help millions of patients around the world.
The Keynote Presentation will cover over ten years of research, highlighting the difficult hurdles which new breakthroughs in science and medicine must surmount before they are even considered by the scientific and medical communities.
For further information on this Keynote Presentation, please visit AlzheimerVideoNews , or the INR® website.
Institute for Neurological Research
View drug information on Enbrel.
Enbrel® (etanercept) has proven effective for treating a host of medical conditions, from rheumatoid arthritis to psoriasis, generating more than $4 billion dollars per year in revenue for its owner, Amgen. Yet despite this success Amgen has failed to initiate study of etanercept's emerging off-label uses in the field of neurology, which could potentially address enormous unmet medical needs and help people throughout the world. Etanercept is one of a new class of medications, produced through biotechnology, which specifically neutralize an immune signaling molecule called TNF. Excess TNF is centrally involved in scores of diseases, including rheumatoid arthritis, Alzheimer's, sciatica pain, and psoriasis. In Alzheimer's disease excess TNF has been documented in the cerebrospinal fluid, and the rationale for anti-TNF treatment is supported by genetic, epidemiologic, basic science, and clinical data (1-11).
The Keynote Presentation, entitled "Repurposing of Enbrel for Alzheimer's Disease" will be made by Edward Tobinick MD, Director of the Institute for Neurological Research, a private medical group, inc. in Los Angeles. Dr. Tobinick is the inventor and patent holder of the etanercept off-label indication for Alzheimer's Disease, as well as more than 200 different inventions involving new off-label uses of TNF blockers, such as etanercept, in neurology, opthalmology, and for a variety of additional innovative clinical indications(12-17). Many of the novel uses of etanercept which Dr. Tobinick invented, beginning nearly a decade ago, such as for sciatica, Alzheimer's, and myasthenia gravis, have subsequently been supported by peer-reviewed, published studies performed by independent researchers from academic centers across the globe(18-26).
As an example, a recently completed, double-blind, placebo-controlled study conducted by independent researchers at Johns Hopkins/Walter Reed Army Medical Center has confirmed the efficacy of etanercept for sciatica, using a patented, perispinal method of administration of etanercept which Dr. Tobinick invented(27).
Dr. Tobinick has been invited to and has presented his clinical and research findings at multiple prestigious medical research meetings, including this year's International Congress on Alzheimer's Disease (ICAD 2008), the 7th International Alzheimer's Drug Discovery Conference; at the Karolinska Institutet in Stockholm, Sweden, the home of the Nobel Prize in medicine; and in multiple, peer-reviewed, published medical articles(1-5, 27-31).
His published, peer-reviewed scientific articles have been cited by more than 150 scientific publications from around the world(1-6, 18, 20, 23-25, 32, 33). In addition, his groundbreaking work has been recognized by the Dana Alliance for Brain Initiatives, the world's leading organization of neuroscientists, which counts among its members ten Nobel Laureates(34); by leading journals, including Nature Clinical Practice Neurology(35); by the Faculty of 1000 Biology, the expert guide to the most important advances in biology(36); and featured in news articles from around the world(37-39). Despite the immense potential to help countless people, the great unmet medical need, and their enormous continuing revenue from etanercept sales, Amgen has yet to confirm its intention to begin even preliminary clinical study in this direction.
A failure to investigate is perhaps even more puzzling in view of the increasing scientific support from cutting edge research, which is in addition to the genetic studies which have identified excess TNF as a therapeutic target in Alzheimer's(9, 10, 33, 40-43). For example, scientists from the Trinity College Institute of Neuroscience in Ireland have demonstrated that defects in hippocampal learning and memory mechanisms created by forms of amyloid are mediated by TNF(41-43). Perhaps even more significant is the recent identification of TNF as a gliotransmitter which regulates synaptic transmission in the brain(39, 44, 45).
The synaptic effects of TNF which regulate learning, memory, and neurotransmission provide a most exciting area for scientific research. These synaptic effects, which may occur with extreme rapidity, provide a rational and scientifically plausible explanation for the rapid clinical effects of etanercept which have been documented in multiple, peer-reviewed scientific studies and in multiple patients(1-5, 18, 28, 30). To ignore this new direction in scientific thinking, which recognizes the role of TNF not just in inflammation but also as an immune regulator of synaptic communication and other aspects of brain function, would be to impede scientific progress.
Fortunately, with the expiration of Amgen's patents on etanercept approaching in 2012, other pharmaceutical companies will soon have the ability to explore these extraordinary discoveries which have the potential to help millions of patients around the world.
The Keynote Presentation will cover over ten years of research, highlighting the difficult hurdles which new breakthroughs in science and medicine must surmount before they are even considered by the scientific and medical communities.
For further information on this Keynote Presentation, please visit AlzheimerVideoNews , or the INR® website.
Institute for Neurological Research
View drug information on Enbrel.
пятница, 3 июня 2011 г.
Hand Osteoarthritis' Aggressive Nature
In just two years, patients with hand osteoarthritis (OA) experienced a significant increase in pain and functional limitations, according to new data presented at EULAR 2007, the Annual European Congress of Rheumatology in Barcelona, Spain. Statistically significant radiological progression was also detected in 20% of subjects.
OA is the most common form of arthritis. It generally affects older people, especially women and can occur in multiple areas of the hand and wrist, causing pain and stiffness and affecting everyday activities requiring fine motor control and hand grip e.g. writing. Over time, if left untreated, the bones that make up the joint can lose their normal shape, causing further pain and limited motion. However, knowledge about the progression of hand OA and effective therapies to prevent its progression has been lacking.
Led by Dr Stella Botha-Scheepers of Leiden University, The Netherlands, this study followed 172 patients (mean age 60.5 years, 78.5% women) with hand OA (defined by the American College of Rheumatology criteria) for two years, assessing: pain intensity upon lateral pressure in the DIP, IP, PIP and CMC 1 joints on a four-point scale; self-reported hand pain and functional limitations with subscales of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN LK 3.0); and osteophytes and joint space narrowing in the right and left DIP joints, IP joints of the thumbs, PIP joints and CMC 1 joints through standardized radiographs.
Despite a relatively short follow-up period of two years, statistically significant increases in pain intensity on lateral pressure standard response mean (SRM) 0.67), AUSCAN pain scores (SRM 0.25) and AUSCAN function scores (SRM 0.23) occurred. Statistically significant radiological progression was also seen in 20% of patients, in terms of joint space narrowing (SRM 0.34) and osteophytes (SRM 0.35), with progression of osteophytes occurring more often in women and middle-aged patients, and especially in women in an early post-menopausal stage.
Dr Botha-Scheepers commented: "The findings of this study underline the critical need for early, effective intervention in hand OA to prevent irreversible progression, given the dramatic deterioration of clinical and radiological disease status seen in just two years."
Hand OA tends to appear in a predictable pattern, most commonly affecting the small joints of the fingers and the joint at the base of the thumb. It can be diagnosed by medical examination and X-rays of the hand. Treatment options for arthritis of the hand and wrist include oral medication, injections, splinting and surgery.
Abstract number: OPO029
About EULAR
* The European League Against Rheumatism (EULAR) is the organization which represents the patient, health professional and scientific societies of rheumatology of all the European nations.
* The aims of EULAR are to reduce the burden of rheumatic diseases on the individual and society and to improve the treatment, prevention and rehabilitation of musculoskeletal diseases. To this end, EULAR fosters excellence in education and research in the field of rheumatology. It promotes the translation of research advances into daily care and fights for the recognition of the needs of people with musculoskeletal diseases by the governing bodies in Europe.
* Diseases of bones and joints, such as rheumatoid arthritis and osteoarthritis cause disability in 4 - 5 % of the adult population and are predicted to rise as people live longer.
* As new treatments emerge and cellular mechanisms are discovered, the 8th Annual European Congress of Rheumatology in Barcelona (EULAR 2007) brings together more than 10,000 experts - scientists, clinicians, healthcare workers, pharmaceutical companies and patients - to share their knowledge in a global endeavour to challenge the pain and disability caused by musculo-skeletal disorders.
* To find out more information about the activities of EULAR, visit: eular/
Contact: Rory Berrie
European League Against Rheumatism
OA is the most common form of arthritis. It generally affects older people, especially women and can occur in multiple areas of the hand and wrist, causing pain and stiffness and affecting everyday activities requiring fine motor control and hand grip e.g. writing. Over time, if left untreated, the bones that make up the joint can lose their normal shape, causing further pain and limited motion. However, knowledge about the progression of hand OA and effective therapies to prevent its progression has been lacking.
Led by Dr Stella Botha-Scheepers of Leiden University, The Netherlands, this study followed 172 patients (mean age 60.5 years, 78.5% women) with hand OA (defined by the American College of Rheumatology criteria) for two years, assessing: pain intensity upon lateral pressure in the DIP, IP, PIP and CMC 1 joints on a four-point scale; self-reported hand pain and functional limitations with subscales of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN LK 3.0); and osteophytes and joint space narrowing in the right and left DIP joints, IP joints of the thumbs, PIP joints and CMC 1 joints through standardized radiographs.
Despite a relatively short follow-up period of two years, statistically significant increases in pain intensity on lateral pressure standard response mean (SRM) 0.67), AUSCAN pain scores (SRM 0.25) and AUSCAN function scores (SRM 0.23) occurred. Statistically significant radiological progression was also seen in 20% of patients, in terms of joint space narrowing (SRM 0.34) and osteophytes (SRM 0.35), with progression of osteophytes occurring more often in women and middle-aged patients, and especially in women in an early post-menopausal stage.
Dr Botha-Scheepers commented: "The findings of this study underline the critical need for early, effective intervention in hand OA to prevent irreversible progression, given the dramatic deterioration of clinical and radiological disease status seen in just two years."
Hand OA tends to appear in a predictable pattern, most commonly affecting the small joints of the fingers and the joint at the base of the thumb. It can be diagnosed by medical examination and X-rays of the hand. Treatment options for arthritis of the hand and wrist include oral medication, injections, splinting and surgery.
Abstract number: OPO029
About EULAR
* The European League Against Rheumatism (EULAR) is the organization which represents the patient, health professional and scientific societies of rheumatology of all the European nations.
* The aims of EULAR are to reduce the burden of rheumatic diseases on the individual and society and to improve the treatment, prevention and rehabilitation of musculoskeletal diseases. To this end, EULAR fosters excellence in education and research in the field of rheumatology. It promotes the translation of research advances into daily care and fights for the recognition of the needs of people with musculoskeletal diseases by the governing bodies in Europe.
* Diseases of bones and joints, such as rheumatoid arthritis and osteoarthritis cause disability in 4 - 5 % of the adult population and are predicted to rise as people live longer.
* As new treatments emerge and cellular mechanisms are discovered, the 8th Annual European Congress of Rheumatology in Barcelona (EULAR 2007) brings together more than 10,000 experts - scientists, clinicians, healthcare workers, pharmaceutical companies and patients - to share their knowledge in a global endeavour to challenge the pain and disability caused by musculo-skeletal disorders.
* To find out more information about the activities of EULAR, visit: eular/
Contact: Rory Berrie
European League Against Rheumatism
четверг, 2 июня 2011 г.
Enzyme's newly discovered role may make it target for arthritis treatment
Scientists have found a new role for a previously identified enzyme that may make it a target for anti-inflammatory
treatments.
The finding by researchers at Washington University School of Medicine in St. Louis shows that an enzyme known as cathepsin G
regulates the ability of immune cells known as neutrophils to secrete chemicals that attract other immune cells and start the
local inflammatory process. Over time, the excessive accumulation of immune cells can lead to tissue and cartilage damage in
joints, causing pain and limiting mobility.
"Cathepsin G affects a very early step in this kind of immune response, so inhibiting it has attractive potential for
developers of therapeutics," says senior author Christine T.N. Pham, M.D., assistant professor of medicine and a
rheumatologist at Barnes-Jewish Hospital.
The study appears in the June 2005 issue of Immunity.
Cathepsin G, which is made by the neutrophils it regulates, is also an attractive target because it belongs to a class of
enzymes known as proteases. One principal type of treatment for HIV, the virus that causes AIDS, inhibits proteases, so
scientists who try to block cathepsin G's role in inflammation will already have an extensive body of research results to
refer to.
Pham's lab uses mouse models of arthritis to study the contributions of proteases and other factors to inflammation and
arthritis. One such model involves injecting mice with collagen from calf joints.
"The mice make antibodies to that protein because it's somewhat foreign, but the antibodies have enough cross-reactivity that
they will bind to the mouse's own cartilage and collagen and initiate an inflammation," Pham explains. "This leads to a
condition similar to rheumatoid arthritis in the mice."
Three years ago, Pham's lab published results showing that mice deficient in cathepsin G and other closely related proteases
failed to develop arthritis after the injections. This led them to look for the mechanisms by which these proteases regulate
inflammation.
Observations made by Pham's lab and other groups had linked the earliest stages of inflammation in the animal models to
neutrophils, which are a kind of immune system firestarter. They arrive first at sites of injury, infection or irritation and
secrete chemicals that bring in secondary waves of other immune attack cells.
"The contributions of the neutrophil weren't always appreciated by scientists," Pham notes. "When patients come to their
doctors with arthritis symptoms, the inflammation typically is so well-established that neutrophils are no longer the
predominant cell type."
Animal models of inflammation let scientists watch all stages of the inflammatory process and allowed them to see how
important neutrophils are to the early stages of that process.
In the new study, Pham and her colleagues showed that cathepsin G is secreted by neutrophils, binds to the cells' surface
membranes, and affects the rearrangement of integrins, an important group of adhesion compounds on the surface of
neutrophils.
"The way these integrins rearrange and cluster on the cell surface can send a signal back into the cell that modifies the
cell's behavior, allowing it to do things like secrete inflammatory factors," Pham explains. "The proteases' ability to
affect integrin rearrangement is dependent on their catalytic activity, and that's an ability that can be taken away from
them."
Pham suspects this class of proteases may also be making significant contributions to other autoimmune and inflammatory
conditions besides arthritis. She plans further studies to investigate this possibility. Her lab is also working to determine
what molecules cathepsin G is sticking to and interacting with on the surfaces of neutrophils and other cells.
Raptis SZ, Shapiro SD, Simmons PM, Cheng AM, Pham CTN. Serine protease Cathepsin G regulates adhesion-dependent neutrophil
effector functions by modulation integrin clustering. Immunity, June 7, 2005, 679-691.
Funding from the Arthritis Foundation and the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its
affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Contact: Michael C. Purdy
purdymwustl
314-286-0122
Washington University School of Medicine
medinfo.wustl
treatments.
The finding by researchers at Washington University School of Medicine in St. Louis shows that an enzyme known as cathepsin G
regulates the ability of immune cells known as neutrophils to secrete chemicals that attract other immune cells and start the
local inflammatory process. Over time, the excessive accumulation of immune cells can lead to tissue and cartilage damage in
joints, causing pain and limiting mobility.
"Cathepsin G affects a very early step in this kind of immune response, so inhibiting it has attractive potential for
developers of therapeutics," says senior author Christine T.N. Pham, M.D., assistant professor of medicine and a
rheumatologist at Barnes-Jewish Hospital.
The study appears in the June 2005 issue of Immunity.
Cathepsin G, which is made by the neutrophils it regulates, is also an attractive target because it belongs to a class of
enzymes known as proteases. One principal type of treatment for HIV, the virus that causes AIDS, inhibits proteases, so
scientists who try to block cathepsin G's role in inflammation will already have an extensive body of research results to
refer to.
Pham's lab uses mouse models of arthritis to study the contributions of proteases and other factors to inflammation and
arthritis. One such model involves injecting mice with collagen from calf joints.
"The mice make antibodies to that protein because it's somewhat foreign, but the antibodies have enough cross-reactivity that
they will bind to the mouse's own cartilage and collagen and initiate an inflammation," Pham explains. "This leads to a
condition similar to rheumatoid arthritis in the mice."
Three years ago, Pham's lab published results showing that mice deficient in cathepsin G and other closely related proteases
failed to develop arthritis after the injections. This led them to look for the mechanisms by which these proteases regulate
inflammation.
Observations made by Pham's lab and other groups had linked the earliest stages of inflammation in the animal models to
neutrophils, which are a kind of immune system firestarter. They arrive first at sites of injury, infection or irritation and
secrete chemicals that bring in secondary waves of other immune attack cells.
"The contributions of the neutrophil weren't always appreciated by scientists," Pham notes. "When patients come to their
doctors with arthritis symptoms, the inflammation typically is so well-established that neutrophils are no longer the
predominant cell type."
Animal models of inflammation let scientists watch all stages of the inflammatory process and allowed them to see how
important neutrophils are to the early stages of that process.
In the new study, Pham and her colleagues showed that cathepsin G is secreted by neutrophils, binds to the cells' surface
membranes, and affects the rearrangement of integrins, an important group of adhesion compounds on the surface of
neutrophils.
"The way these integrins rearrange and cluster on the cell surface can send a signal back into the cell that modifies the
cell's behavior, allowing it to do things like secrete inflammatory factors," Pham explains. "The proteases' ability to
affect integrin rearrangement is dependent on their catalytic activity, and that's an ability that can be taken away from
them."
Pham suspects this class of proteases may also be making significant contributions to other autoimmune and inflammatory
conditions besides arthritis. She plans further studies to investigate this possibility. Her lab is also working to determine
what molecules cathepsin G is sticking to and interacting with on the surfaces of neutrophils and other cells.
Raptis SZ, Shapiro SD, Simmons PM, Cheng AM, Pham CTN. Serine protease Cathepsin G regulates adhesion-dependent neutrophil
effector functions by modulation integrin clustering. Immunity, June 7, 2005, 679-691.
Funding from the Arthritis Foundation and the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its
affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Contact: Michael C. Purdy
purdymwustl
314-286-0122
Washington University School of Medicine
medinfo.wustl
среда, 1 июня 2011 г.
Congressional Hearing Focuses on Merck's Marketing for COX-2 Drug Vioxx
Merck sales associates were given detailed instructions not to mention certain potential cardiovascular risks when promoting the company's COX-2 inhibitor Vioxx to doctors, according to an analysis of 20,000 pages of internal documents by congressional investigators for the... House Committee on Government Reform delivered at a hearing Thursday, the Washington Post reports (Kaufman, Washington Post, 5/6). Merck in September 2004 voluntarily withdrew Vioxx from the market, citing cardiovascular safety risks.
Vioxx Marketing History
In March 2000, a Merck-funded study called VIGOR showed increased heart attack risks associated with Vioxx (Cohen, Newark Star-Ledger, 5/6). The study showed a fivefold increase in heart attacks among those who took Vioxx compared with those who took the painkiller naproxen. Merck said that the findings possibly were a result of a protective effect on the heart that naproxen provided, not an increased risk associated with Vioxx (Appleby, USA Today, 5/6). According to company documents included in the congressional investigation, Merck in April 2000 developed a "Cardiovascular Card" for use in sales representatives' presentations to physicians. According to the committee, Merck's 3,000 sales representatives were instructed to refer doctors who raised questions about cardiovascular risks to the card, which indicated that Vioxx was eight to 11 times safer than other similar painkillers. Information on the card was taken from several studies submitted to FDA and omitted any reference to the VIGOR study. An FDA advisory committee in 2001 voted that physicians should be informed of the VIGOR study findings. According to the committee, Merck subsequently sent a memo to sales representative that stated, "Do not initiate discussions of the FDA arthritis committee ... or the results of the ... VIGOR study." Further, representatives were specifically directed to respond to doctors' questions about the study by saying, "I cannot discuss the study with you" (Newark Star-Ledger, 5/6). Additional cardiovascular risks of Vioxx were cited in an August 2001 study in the Journal of the American Medical Association (USA Today, 5/6).
Label Change, Sales Instructions
After "extensive negotiations" with FDA, Merck in April 2002 agreed to a label change for Vioxx that included risks found in the VIGOR study. The label also included a statement that the significance of the findings was "unknown." According to the committee, Merck told sales representatives "to emphasize the uncertainty of the VIGOR study to counter physicians' concerns," the Star-Ledger reports (Newark Star-Ledger, 5/6). Sales representatives were told to encourage doctors to submit any questions in writing to Merck's medical services department. The company received 123,000 inquiries from physicians, according to Dennis Erb, Merck's vice president for regulatory issues (Alonso-Zaldivar, Los Angeles Times, 5/6).
Sales Techniques
According to the Post, Merck documents unearthed in the investigation indicate that sales representatives were given detailed instructions about how to approach physicians when selling Vioxx. "They were trained how to smile, speak and position themselves most effectively when talking with doctors," the Post reports (Washington Post, 5/6). Representatives also were instructed how to use "verbal and nonverbal" cues to gain a physician's trust. Training materials indicated that representatives should shake a doctor's hand for no longer than three seconds. Merck officials also informed representatives about "different personality types of doctors and recommended [sales] techniques for each type," the Star-Ledger reports (Newark Star-Ledger, 5/6). The training included motivational courses in which representatives were "taught not to take no for an answer." The courses compared milestones in sales of Merck drugs to points in the lives of Martin Luther King and Helen Keller. Campaigns were titled "Project Offense" and "Project XXcelleration." In documents, doctors' concerns about risks were termed "obstacles." The company also used "sophisticated databases" to track the prescribing patterns of individual doctors and set targets for sales, according to the Los Angeles Times (Los Angeles Times, 5/6). Representatives were given $2,000 bonuses for meeting sales goals (AP/New York Times, 5/6). According to the Los Angeles Times, Merck's marketing campaign was "astoundingly successful," with the "overwhelming majority" of prescriptions dispensed after concerns about heart risks had surfaced. Vioxx achieved sales of $2 billion annually "faster than any previous Merck drug," the Los Angeles Times reports (Los Angeles Times, 5/6).
Committee Report
The committee report states, "When concerns about Vioxx's safety arose, Merck appeared to use this highly trained force to present a misleading picture to physicians about the drug's cardiovascular risks." The report also said that Merck instructed its sales force to "emphasize outdated and misleading data that indicated Vioxx was safer than alternatives" (Newark Star-Ledger, 5/6). Committee ranking member Henry Waxman (D-Calif.) at the hearing said, "This sales force is given extraordinary training so that it can capitalize on virtually every interaction with doctors. Yet when it comes to the one thing doctors most need to know about Vioxx -- its health risks -- Merck's answer seems to be disinformation and censorship" (Washington Post, 5/6). He asked, "Why did doctors write so many Vioxx prescriptions even as evidence of harm mounted?" He added that the company's "goal was sales, not education" (AP/New York Times, 5/6). Rep. Gil Gutknecht (R-Minn.) called Merck's omission of potential risks in its presentations "confusing and, in some respects, embarrassing." He added that no one "wants to take responsibility for putting out information that an outside observer might call ... disingenuous."
FDA Testimony
FDA officials at the hearing testified that they were unaware of the details of Merck's marketing campaign, the Los Angeles Times reports (Los Angeles Times, 5/6). Steven Galson, director of FDA's Center for Drug Evaluation and Research, said that Merck is legally obligated only to provide information that was approved in drug labeling (Newark Star-Ledger, 5/6). Galson said that that the promotional materials used by Merck sales representatives were "accurate based on the label, which was the standard we use" (Rovner, Congress Daily, 5/5). However, Galson added that is "important that the company convey truthful information that is up to date." He also said that Merck appears not to have given doctors "the entire picture" (Newark Star-Ledger, 5/6). Galson acknowledged that the agency may have taken too long to remove Vioxx from the market (CQ HealthBeat, 5/6). However, he said FDA is taking steps to improve awareness of drug risks (New York Times, 5/6). "The most important lesson ... is that the American public, practitioners and patients want to get clear and accurate information ... in their own health care decisions," Galson said. Addressing Galson, Gutknecht said, "It seems to me there's a disconnect here. You're saying your policies are legal, but are they ethical? Isn't this the scandal?" (Washington Post, 5/6). Gutknecht also said, "Both the FDA and the pharmaceutical company sort of missed the mark" (Tansey, San Francisco Chronicle, 5/6).
Merck Response
Erb said at the hearing, "We believe Merck acted appropriately and responsibly to extensively study Vioxx after it was approved for marketing to gain more clinical information about the medicine." He added that the company "promptly disclosed the results of those studies to the FDA, physicians, the scientific community and the media" (Los Angeles Times, 5/6). When asked by Committee Chair Tom Davis (R-Va.) whether a "wide awake" physician would have been aware of the drug's risks, Erb said, "That is correct" (AP/New York Times, 5/6). Erb added, "We believed wholeheartedly in the safety of Vioxx and that Vioxx was an important treatment option. My own father was a regular user of Vioxx" (Freking, AP/Las Vegas Sun, 5/6).
Implications
According to the San Francisco Chronicle, the committee's findings "could bolster moves by Congress to beef up the FDA's powers" (San Francisco Chronicle, 5/6). Davis said, "As the committee conducted its investigation, it became apparent that the relationship between the Office of New Drugs and the Office of Drug Safety has its challenges." He said that the challenges include "a lack of communication between the offices, as well as communication up the chain of command" (CongressDaily, 5/5). The committee report could also "prove a bonanza to plaintiffs in civil suits" against Merck alleging that Vioxx caused severe side effects or death, the Chronicle reports (San Francisco Chronicle, 5/6).
Vioxx Return?
Erb said that Merck is in "preliminary discussions," with FDA to determine whether to apply for approval to resume marketing Vioxx in the United States. An FDA advisory committee in February "narrowly" voted to recommend that Vioxx could be allowed back into the U.S. market under certain conditions, the AP/Times reports (AP/New York Times, 5/6).
Gilmartin Resigns
In related news, Merck board members on Thursday named Richard Clark as new CEO after former company CEO and Chair Raymond Gilmartin resigned 10 months before his scheduled retirement, the Wall Street Journal reports. However, in an "unusual agreement," the chair position will remain open for one to two years and a three-member executive committee will advise Clark, according to the Journal (Martinez/Lublin, Wall Street Journal, 5/6). Clark, who joined Merck in 1972 as a quality control inspector, has held positions in production, new product planning and strategic planning (Johnson/Agovino, AP/Atlanta Journal Constitution, 5/6). In 1997, Clark became chief operating officer of the pharmacy benefit manager Medco Health Solutions, which Merck spun off in 2003. Clark became CEO and chair of Medco in 2002 and returned to Merck in 2003 after the spin off. Lawrence Bossidy, a former CEO of Honeywell International, will lead the executive committee and likely will become a "key player in deciding strategy" for Merck. The other executive committee members will include former Princeton University President William Bowen, who will advise Clark on litigation and corporate governance, and Harvard University professor of medicine Samuel Thier, who will advise Clark on health care policy (Wall Street Journal, 5/6). Bossidy also will serve as acting Merck chair at board meetings. Gilmartin, who will remain with Merck as a special adviser to the executive committee until 2006, said that he decided to resign voluntarily (Berenson, New York Times, 5/6). Bossidy said that the executive committee will "work closely" with Clark for as long as two years and "provide support and continuity" (Bloomberg/Los Angeles Times, 5/6). Clark said, "I can guarantee you that I would not take this job if I didn't have full responsibility as the CEO of the company" (McCoy/Appleby, USA Today, 5/6). According to the Journal, Merck board members had some concerns about whether to name an internal candidate as the new CEO but concluded that external candidates were not "head and shoulders above someone who demonstrated repeatedly that he can get results" (Wall Street Journal, 5/6).
"Reprinted with permission from kaisernetwork kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
View drug information on Vioxx.
вторник, 31 мая 2011 г.
Red meat consumption rheumatoid arthritis link
Study indicates high levels of red meat consumption as an independent risk factor in the development of inflammatory
arthritis,
A chronic inflammatory disease of the immune system, rheumatoid arthritis (RA) has been linked to a combination of genetic
and environmental factors. Aspects of lifestyle may explain as much as 40 percent of the risk.
Cigarette smoking has
consistently been found to play a role in RA's development. The role of nutritional factors is less certain. Studies have
suggested the protective benefits of eating fish, the dangers of drinking coffee, and a reduction in disease risk for women
who enjoy alcohol in moderation. Such associations, however, are still wide open to debate and further research.
Recently, a team of British researchers found that a diet lacking in fruit, especially varieties high in vitamin C, increases
the risk of inflammatory arthritis, a common early sign of RA, as much as three-fold. Building on this compelling finding,
they set out to investigate the association of other dietary habits with the onset of RA. Their results, published in the
December 2004 issue of Arthritis & Rheumatism (interscience.wiley/journal/arthritis), indicate a high level of red meat consumption as an
independent risk factor for inflammatory arthritis.
Led by Professors Alan Silman and Deborah Symmons at the University of Manchester, the team drew its subjects from a large,
established research sample--over 25,000 men and women between the ages of 45 and 75 enrolled in the European Prospective
Investigation of Cancer in Norfolk, England. Within this population, 88 new patients with inflammatory arthritis, affecting
at least two major joints, were identified.
Nearly 40 percent of these patients satisfied the American College of Rheumatology criteria for RA at baseline. The patients
were then matched, for age, sex, and body mass index, with 176 controls. At the study's onset, each participant completed a
detailed 7-day food diary, with advance instruction on measuring food portions to help them be as specific as possible in
recording their intake. Each participant also supplied information on his or her past and present status as a smoker.
Patients were more likely to have been former smokers; only 35 percent of the patients had never smoked compared with 85
percent of the controls. In terms of dietary factors, patients and controls were similar in most areas, including intake of
total calories, fat grams, and vitamin D, as well as coffee, tea, and alcohol consumption. Patients had a lower intake of
vitamin C, although the association of this factor with disease risk was not as strong as it was in the team's previous
study. The most striking difference between the two groups was directly related to red meat consumption. After adjusting for
smoking and other possible dietary confounders, patients with the highest level of red meat consumption had a two-fold risk
for the development of RA. Patients who consumed high levels of red meat combined with other meat products showed similar
high risk levels. Interestingly, a higher level of protein intake from all dietary sources was also associated with an
increased disease risk, while higher levels of dietary fats, including saturated fat, did not have an impact.
Routinely eating burgers and steak, however, may only influence people with a predisposition for RA. "It may be that the high
collagen content of meat leads to collagen sensitization and consequent production of anticollagen antibodies, most likely in
a subgroup of susceptible individuals," the authors note. "Meat consumption may be linked to either additives or even
infectious agents, but, again, there is no evidence as to what might be important in relation to RA."
"A high level of red meat consumption may represent a novel risk factor for inflammatory arthritis or may act as a marker for
a group of persons with an increased risk from other lifestyle causes," Dr. Pattison and colleagues conclude. "It is unclear
whether the association is a causative one."
Article: "Dietary Risk Factors for the Development of Inflammatory Polyarthritis: Evidence for a Role of High Level of Red
Meat Consumption," Dorothy J. Pattison, Deborah P.M. Symmons, Mark Lunt, Ailsa Welch, Robert Luben, Sheila A. Bingham,
Kay-Tee Khaw, Nicholas E. Day, and Alan J. Silman, Arthritis & Rheumatism, December 2004; 50:12; pp. 3804-3812.
John Wiley & Sons, Inc
arthritis,
A chronic inflammatory disease of the immune system, rheumatoid arthritis (RA) has been linked to a combination of genetic
and environmental factors. Aspects of lifestyle may explain as much as 40 percent of the risk.
Cigarette smoking has
consistently been found to play a role in RA's development. The role of nutritional factors is less certain. Studies have
suggested the protective benefits of eating fish, the dangers of drinking coffee, and a reduction in disease risk for women
who enjoy alcohol in moderation. Such associations, however, are still wide open to debate and further research.
Recently, a team of British researchers found that a diet lacking in fruit, especially varieties high in vitamin C, increases
the risk of inflammatory arthritis, a common early sign of RA, as much as three-fold. Building on this compelling finding,
they set out to investigate the association of other dietary habits with the onset of RA. Their results, published in the
December 2004 issue of Arthritis & Rheumatism (interscience.wiley/journal/arthritis), indicate a high level of red meat consumption as an
independent risk factor for inflammatory arthritis.
Led by Professors Alan Silman and Deborah Symmons at the University of Manchester, the team drew its subjects from a large,
established research sample--over 25,000 men and women between the ages of 45 and 75 enrolled in the European Prospective
Investigation of Cancer in Norfolk, England. Within this population, 88 new patients with inflammatory arthritis, affecting
at least two major joints, were identified.
Nearly 40 percent of these patients satisfied the American College of Rheumatology criteria for RA at baseline. The patients
were then matched, for age, sex, and body mass index, with 176 controls. At the study's onset, each participant completed a
detailed 7-day food diary, with advance instruction on measuring food portions to help them be as specific as possible in
recording their intake. Each participant also supplied information on his or her past and present status as a smoker.
Patients were more likely to have been former smokers; only 35 percent of the patients had never smoked compared with 85
percent of the controls. In terms of dietary factors, patients and controls were similar in most areas, including intake of
total calories, fat grams, and vitamin D, as well as coffee, tea, and alcohol consumption. Patients had a lower intake of
vitamin C, although the association of this factor with disease risk was not as strong as it was in the team's previous
study. The most striking difference between the two groups was directly related to red meat consumption. After adjusting for
smoking and other possible dietary confounders, patients with the highest level of red meat consumption had a two-fold risk
for the development of RA. Patients who consumed high levels of red meat combined with other meat products showed similar
high risk levels. Interestingly, a higher level of protein intake from all dietary sources was also associated with an
increased disease risk, while higher levels of dietary fats, including saturated fat, did not have an impact.
Routinely eating burgers and steak, however, may only influence people with a predisposition for RA. "It may be that the high
collagen content of meat leads to collagen sensitization and consequent production of anticollagen antibodies, most likely in
a subgroup of susceptible individuals," the authors note. "Meat consumption may be linked to either additives or even
infectious agents, but, again, there is no evidence as to what might be important in relation to RA."
"A high level of red meat consumption may represent a novel risk factor for inflammatory arthritis or may act as a marker for
a group of persons with an increased risk from other lifestyle causes," Dr. Pattison and colleagues conclude. "It is unclear
whether the association is a causative one."
Article: "Dietary Risk Factors for the Development of Inflammatory Polyarthritis: Evidence for a Role of High Level of Red
Meat Consumption," Dorothy J. Pattison, Deborah P.M. Symmons, Mark Lunt, Ailsa Welch, Robert Luben, Sheila A. Bingham,
Kay-Tee Khaw, Nicholas E. Day, and Alan J. Silman, Arthritis & Rheumatism, December 2004; 50:12; pp. 3804-3812.
John Wiley & Sons, Inc
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