Wednesday, December 31, 2008
Stem cells stam cellen
Stem-Cell Biology Moves Closer to Becoming Stem-Cell Medicine
For a topic to be a Journal Watch Top Story in 2 successive years is unusual, but that is the case with stem cells.
As I summarized in 2007 (JW Dec 28 2007), the great excitement about the potential of embryonic stem cells (ESCs) to treat disease had been tempered by scientific obstacles and ethics questions. No person could be treated by his or her own genetically identical ESCs, because they are long gone. And, using ESCs from a genetically dissimilar embryo would not only impart risk for immune rejection and require immunosuppression but also would raise ethics concerns for some.
As a way around these difficulties, scientists asked an audacious question: What if one could "reprogram" the genes of a specialized adult cell so as to transform it back into a cell with all the potential of an ESC? In 2006, a Japanese team identified a handful of genes that are turned on exclusively in ESCs. In 2007, that Japanese team and several American teams used retroviruses to insert four of those genes into easily obtained skin cells, from mice and humans. Remarkably, this genetic reprogramming transformed the specialized cells into what were called induced pluripotent stem (iPS) cells, which had all the potential of ESCs: They could figuratively turn back the clock and create, for each individual, cells that were equivalent to his or her own long-lost, genetically identical ESCs.
Studies in rodents showed that these iPS cells indeed could fulfill their potential: They effectively cured sickle cell anemia (JW Dec 13 2007) and Parkinson disease in mice. Other researchers created iPS cells from patients with Parkinson disease, Huntington disease, and type 1 diabetes, bringing us one step closer to therapeutic applications for humans (JW Aug 26 2008). Two of the four genes used in creating iPS cells were oncogenes, which, along with the retroviral vector used to deliver them to the cell, imparted risk for iPS cells to become cancerous. However, late in 2008, Japanese and American teams reported that iPS cells could be produced even more simply — without oncogenes or retroviruses (JW Oct 28 2008). Even more remarkably, an American team reported being able to use reprogramming to transform one specialized cell (a pancreatic exocrine cell) into another (a pancreatic β cell) in living mice, thereby curing experimentally produced diabetes, without ever creating iPS cells ex vivo (JW Sep 23 2008).
These discoveries demonstrate that specialized adult cells are much more "plastic" than once imagined and appear to eliminate some of the thornier scientific challenges — as well as the ethics concerns — of stem-cell therapy.
Published in Journal Watch General Medicine December 29, 2008
jupiter, statins, CRP
Statins for Primary Prevention of Cardiovascular Disease — The JUPITER Study
Among patients with high CRP levels, rosuvastatin lowered risk for adverse cardiovascular events.
One of 2008’s most hotly debated studies has the potential to change prevention recommendations for millions of Americans. In the industry-sponsored JUPITER study, researchers investigated the role of statins in primary prevention when patients’ cholesterol levels were not markedly high but high-sensitivity C-reactive protein (hsCRP) was elevated (JW Nov 18 2008). Nearly 18,000 subjects (ages: men, 
50; women, 60) without known cardiovascular (CV) disease and with normal LDL-cholesterol levels (<130 src="http://general-medicine.jwatch.org/math/ge.gif" alt="≥" border="0">2 mg/L), were randomized to receive daily rosuvastatin (Crestor; 20 mg) or placebo. Extensive exclusion criteria eliminated many patients (e.g., those with diabetes, uncontrolled hypertension, or various other chronic diseases; those who used cholesterol-lowering drugs).
After a median follow-up of 1.9 years (the trial was stopped early, due to markedly positive results for rosuvastatin), rosuvastatin lowered LDL-cholesterol levels by a mean of 50% and hsCRP levels by 37%. Incidence of the primary endpoint (first major cardiovascular event, including unstable angina, myocardial infarction, stroke, arterial revascularization, or death from cardiovascular causes) was significantly lower in the rosuvastatin group than in the placebo group (hazard ratio, 0.56), as was overall mortality (HR, 0.8). For every 1000 patients who received rosuvastatin for 1 year, roughly six fewer primary-endpoint events and three fewer deaths occurred. Incidences of physician-reported diabetes and glycosylated hemoglobin levels were both significantly higher in the rosuvastatin group than in the placebo group.
So, where do we go from here? Statins lowered the rate of adverse CV events in this large study of apparently healthy subjects who were at CV risk because of high hsCRP levels; however, in an accompanying editorial, the author notes that the absolute effect size was relatively modest and that the higher incidence of diabetes and lack of long-term data on hazards of therapy are worrisome. Nonetheless, these data almost certainly will prompt review of current guidelines on use of statins in primary prevention, as well as generate a flurry of calls to physicians about hsCRP testing. Some media reports on JUPITER have couched the study results as supporting widespread use of hsCRP testing, but the editorialist reminds us that this is a randomized trial of statin therapy, not of hsCRP testing, and he advocates selective rather than routine CRP testing (JW Nov 18 2008).
— Kirsten E. Fleischmann, MD, MPH
Published in Journal Watch General Medicine December 29,Tuesday, December 23, 2008
From Heartwire — a professional news service of WebMD
December 3, 2008 — Generic cardiovascular drugs are just as good as brand-name drugs, a new analysis suggests [1]. Authors of the study say they hope their findings will help convince physicians and patients that generics are no different than brand-name agents, even if anecdotes in the media or drug manufacturers have suggested otherwise.
"There have been generic drugs on the market for decades and decades, and the fact that we haven't seen any systematic problems with generic drugs in cardiovascular disease — or in any field, for that matter — should give patients and physicians more confidence using them," lead author on the study, Dr Aaron S Kesselheim (Brigham and Women's Hospital, Boston, MA), told heartwire. "There's a perception, fueled in part, I think, by the brand-name industry and by physicians and patients who don't understand the US Food and Drug Administration (FDA) approval process, that brand-name drugs are superior. People tend to equate generic drugs with generic products that they might buy at a supermarket, that they feel are of lower quality than brand-name products. But in the field of drugs, generic products are just as safe and effective as brand-name drugs."
Kesselheim and colleagues reviewed peer-reviewed publications and International Pharmaceutical Abstracts from 1984 to 2008, identifying 38 randomized controlled trials (RCTs) comparing nine subclasses of generic and brand-name cardiovascular drugs. They found that clinical equivalence was demonstrated in the vast majority of trials for all the major cardiovascular disease drug classes, including the so-called "narrow-therapeutic-index drugs," such as antiarrhythmics and warfarin.
Number of trials showing clinical equivalence
| Class | Trials showing clinical equivalence |
| Beta-blockers | 7/7 |
| Diuretics | 10/11 |
| Calcium-channel blockers | 5/7 |
| Antiplatelet agents | 3/3 |
| Statins | 2/2 |
| ACE inhibitors | 1/1 |
| Alpha blockers | 1/1 |
| Class 1 antiarrhythmic agents | 1/1 |
| Warfarin | 5/5 |
Strikingly, however, more than half of all editorials, perspectives, commentaries, and letters to the editor published during the study period discussing brand-name vs generic drugs expressed a "negative view" of substituting a generic for a brand-name drug. Why editorials would take this view remains a mystery, the authors write, although one possibility is that editorials and commentaries rely less on data and more on anecdotal stories or nonclinical trial settings. Another possibility is that editorialists had undisclosed financial relationships with brand-name pharmaceutical companies — just half of the trials studied disclosed sources of funding, whereas "nearly all" of the editorials and commentaries made no mention of financial conflicts of interest, the authors note.
Distrust of generics
Speaking with heartwire, Kesselheim explained that distrust of generics also stems from misconceptions that generic drugs are not as rigorously vetted by the FDA. "The FDA, when it approves generic drugs, approves them on the basis of biochemical bioequivalence. Unfortunately, there is this perception out there that bioequivalence might not necessarily translate into clinical equivalence. And there isn't a lot of incentive out there for either brand-name or generic companies to conduct the kind of head-to-head tests to look at that question more substantively."
Kesselheim believes their analysis proves that bioequivalence, at least for the agents studied, means clinical equivalence. "The message to the cardiovascular community is that the data that are out there do not point to any clinical superiority of brand-name drugs when a generic equivalent is available."
Physicians need to understand that using generics can have a real impact on patient's survival and quality of life. "Lower-cost generic drugs, which are available for nearly every therapeutic drug class, can be a part of a medication regimen that leads to better patient adherence to important cardiovascular drugs. If patients aren't taking their drugs because they are expensive, and the economy is in difficult times, and they don't have full drug insurance, and they're doing that because they think they need a brand-name drug, that is a suboptimal outcome," Kesselheim stressed to heartwire. "To improve the clinical care of patients, we think that generic drugs should be a part of a physician's prescribing patterns. This study should give some reassurance to physicians that in the cardiovascular arena. There's no evidence that brand-name drugs are superior."
The study was supported in part by a grant from the Attorney General Prescriber and Consumer Education Grant Program. Dr. Kesselheim was supported by an Agency for Healthcare Research and Quality Postdoctoral Fellowship in Health Services Research at the Harvard School of Public Health. Coauthor M. Alan Brookhart, PhD, is supported by a career development award from the National Institute on Aging. Coauthor William H. Shrank, MD, MSHS, is supported by a career development award from the National Heart, Lung, and BloThursday, December 18, 2008
Postmenopausal Women Taking Bisphosphonates
Posted 12/09/2008
Question
How long should postmenopausal women continue to take bisphosphonate therapy for osteoporosis?
Commentary from Paul D. Miller, MD
Bisphosphonates are biological analogues of naturally occurring pyrophosphates, by-products of adenosine metabolism, and were developed after the discovery that these nonmetabolized compounds have a high affinity for the calcium-phosphorus surface and can prevent both bone resorption or mineralization, depending on the type and dose of bisphosphonate.[1] The second-generation aminobisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) have a ratio of inhibiting bone resorption to bone formation of greater than 1,000:1 and therefore do not inhibit mineralization or induce osteomalacia.
Bisphosphonates have a long retention time in bone and, while their affinity and detachment to the denuded resorptive cavity differ among bisphosphonates in vitro and in vivo in animal models, it is unknown if there are differences in the so-called bone half-life in human beings.[2] Nevertheless, the bisphosponates do get buried in bone and can remain there for years.
There have been several clinical and biochemical developments that have led clinicians to rethink how to use bisphosphonates in their postmenopausal population. These include:
|
The advancements made in understanding bisphosphonate biology in the past decade have been enormous.[3-4] The knowledge that bisphosphonates are recycled back into the circulation by two separate mechanisms (transcytosis, emanating through the osteoclast cell membrane; and detachment from bone during remodeling, retaining their molecular structure and biological activity) has given bisphosphonates as a class pharmacokinetic properties that are nonexistent for any other drugs used in any disease management.[5] After a bone "loading" period, it appears that the amount of bisphosphonate released back into the circulation can maintain BMD and BTM for a period of time, possibly years.[6-7] There may be differences among bisphosphonates in the duration of this effect, and a finite period of administration may be needed (possibly 5 y) before this sustained benefit after discontinuation can be observed.[8] Nevertheless, based on these data, there is a wider discussion evolving in medical practice concerning a "drug holiday" in postmenopausal women after 5 to 7 years of bisphosphonate administration, monitoring BMD and BTM on an annual basis to assess if the biological activity of sustaining the lower bone turnover is maintained. There are numerous opinions on which populations should be offered a drug holiday, and there is no standard of care for these approaches.[9-10]
The use of bisphosphonates in younger postmenopausal women increased following the publication of the Women's Health Initiative (WHI), after which many women discontinued estrogen yet were concerned about their skeletal health. Women who were osteopenic were often prescribed bisphosphonates, at which time the metabolic bone community began to ask the question: "Is this use for life?" This question was not often asked when bisphosphonates were initiated in older patients. As data defined the sustained biological effect and persistence of effect of bisphosphonates after long term use, and the absolute fracture risk data from the World Health Organization (WHO) 10-year fracture risk assessment model (FRAX) clarified that these younger, untreated postmenopausal women were actually at fairly low 10-year fracture risk,[11] clinicians began to ask questions about duration of therapy. Whatever low risk these patients had before treatment was now even lower with treatment, and discussions surrounding drug holiday became more common. While there is no consensus on these approaches and management must be individualized, higher-risk patients (who had a previous low-trauma fracture, or were more elderly [≥65 y] with BMD criteria for osteoporosis) are often not offered a drug holiday since their baseline risk is high.
Even though the Fracture Intervention Trial Long-term Extension (FLEX) data did not show an increase in hip, nonvertebral, or morphometric vertebral fractures in those subsets of patients randomized from the original Fracture Intervention Trials (FIT) taking alendronate for 5 years following 5 years without treatment, there was a statistically significant increase in clinical vertebral fractures in those patients off of alendronate for 5 years.[6] Hence, despite the limitations of the FLEX data (selection bias and cofounders due to selection of some but not all of the original FIT population), it still remains unclear if bone strength is maintained at all skeletal sites during a drug holiday. There are observational data that a lower hip fracture risk off of alendronate may not be certain if the initial duration of use of alendronate is under 2 years.[8] Hence, if a drug holiday is considered in lower-risk, younger women, a minimum duration of 5 years of alendronate use seems reasonable. As mentioned, there may be differences among the bisphosphonates in duration of effect, though there are not head-to-head data defining these durations or offset period. There are preliminary data that the reduction in bone turnover after a single injection of zoledronic acid (4-5 mg) may be sustained beyond a year[12] even though the standard of care is to follow the registered labeling from the Food and Drug Administration (FDA) for zoledronic acid (5 mg/y × 3 y) following the reduction in all fractures in the pivotal zoledronic acid clinical trial.[13] Monitoring BMD and BTM is, at the present time, the only means to judge sustained biological efficacy.[14-15]
Another less scientifically sound reason for considering a drug holiday is the anecdotal observational data on the risk of either ONJ or diaphyseal (femur) fractures in very small numbers of patients on bisphosphonates. In contrast to the greater risk (1%-10%) for ONJ seen in the oncology population who have received high doses of intravenous pamidronate or zoledronic acid in combination with chemotherapy for metastatic (to bone) carcinomas or multiple myeloma, there have been fewer than 100 adjudicated cases of ONJ validated in the osteoporosis population who receive the far lower doses of bisphosphonates.[16] Yet, the perception in the general dental and lay public is that ONJ is common, which has often led to unnecessary discontinuation of bisphosphonates. Such a decision in high-risk patients could possibly render them at far greater risk for fracture than the calculated attributable risk of ONJ in the postmenopausal population (<0.7>
Finally, there have been several anecdotal reports of the development of spontaneous, often bilateral diaphyseal femoral shaft fractures with long-term (≥5 y) use of alendronate.[17] The mechanism associated with these fractures is unknown. It is also unknown if these types of fractures are seen in people not exposed to bisphosphonates because the reporting of such cases has not been systematic. Once large Medicare databases are carefully studied, we may know if these unusual fractures are confined to the bisphosphonate-exposed population. To date, all of these cases have been associated with long-term alendronate use. It is unknown if this is a class effect or not, since alendronate was the first FDA-approved bisphosphonate for osteoporosis management and has the largest exposed population. Therefore, only time and careful reporting will tell if these fractures are specific to alendronate, or if they might also be seen with other bisphosphonates or in nonbisphosphonate-treated populations. Nevertheless, due to the intense media exposure and the unique litigation climate that pervades US medicine, patients and our colleagues are starting to question drug holidays for this potential fracture risk concern as well. There is no science to guide us here, and patient management must be individualized. Like the broader issue of a drug holiday in any patient, the potential risks and benefits of discontinuation need to be discussed.
Bisphosphonates will continue to be used to benefit patients with a variety of diseases including postmenopausal osteoporosis. The vast majority of treated patients have reduced fracture burden and costs, along with an exceptional safety record. It is the responsibility of practitioners to examine the issue of drug holidays, given the strong science that has evolved in bisphosphonate pharmacokinetics, and be open-minded about potential safety issues that demand good science to clarify. In the meantime, consideration of bisphosphonate drug holidays continues to be based on opinion, without a standard of care, and individualized for each patient.
From the NAMS Menopause e-Consult-newsletter released October 2008
For more, please visit http://www.menopause.org/Members/eConsulteNewsletter.aspx
NAMS. 2008; ©2008 The North American Menopause Society
Menopause e-Consult® is a registered trademark of The North American Menopause Society
biphosphanates
From The North American Menopause Society (NAMS)
NAMS Menopause e-Consult
Postmenopausal Women Taking Bisphosphonates
Posted 12/09/2008
Question
How long should postmenopausal women continue to take bisphosphonate therapy for osteoporosis?
Commentary from Paul D. Miller, MD
Bisphosphonates are biological analogues of naturally occurring pyrophosphates, by-products of adenosine metabolism, and were developed after the discovery that these nonmetabolized compounds have a high affinity for the calcium-phosphorus surface and can prevent both bone resorption or mineralization, depending on the type and dose of bisphosphonate.[1] The second-generation aminobisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) have a ratio of inhibiting bone resorption to bone formation of greater than 1,000:1 and therefore do not inhibit mineralization or induce osteomalacia.
Bisphosphonates have a long retention time in bone and, while their affinity and detachment to the denuded resorptive cavity differ among bisphosphonates in vitro and in vivo in animal models, it is unknown if there are differences in the so-called bone half-life in human beings.[2] Nevertheless, the bisphosponates do get buried in bone and can remain there for years.
There have been several clinical and biochemical developments that have led clinicians to rethink how to use bisphosphonates in their postmenopausal population. These include:
|
The advancements made in understanding bisphosphonate biology in the past decade have been enormous.[3-4] The knowledge that bisphosphonates are recycled back into the circulation by two separate mechanisms (transcytosis, emanating through the osteoclast cell membrane; and detachment from bone during remodeling, retaining their molecular structure and biological activity) has given bisphosphonates as a class pharmacokinetic properties that are nonexistent for any other drugs used in any disease management.[5] After a bone "loading" period, it appears that the amount of bisphosphonate released back into the circulation can maintain BMD and BTM for a period of time, possibly years.[6-7] There may be differences among bisphosphonates in the duration of this effect, and a finite period of administration may be needed (possibly 5 y) before this sustained benefit after discontinuation can be observed.[8] Nevertheless, based on these data, there is a wider discussion evolving in medical practice concerning a "drug holiday" in postmenopausal women after 5 to 7 years of bisphosphonate administration, monitoring BMD and BTM on an annual basis to assess if the biological activity of sustaining the lower bone turnover is maintained. There are numerous opinions on which populations should be offered a drug holiday, and there is no standard of care for these approaches.[9-10]
The use of bisphosphonates in younger postmenopausal women increased following the publication of the Women's Health Initiative (WHI), after which many women discontinued estrogen yet were concerned about their skeletal health. Women who were osteopenic were often prescribed bisphosphonates, at which time the metabolic bone community began to ask the question: "Is this use for life?" This question was not often asked when bisphosphonates were initiated in older patients. As data defined the sustained biological effect and persistence of effect of bisphosphonates after long term use, and the absolute fracture risk data from the World Health Organization (WHO) 10-year fracture risk assessment model (FRAX) clarified that these younger, untreated postmenopausal women were actually at fairly low 10-year fracture risk,[11] clinicians began to ask questions about duration of therapy. Whatever low risk these patients had before treatment was now even lower with treatment, and discussions surrounding drug holiday became more common. While there is no consensus on these approaches and management must be individualized, higher-risk patients (who had a previous low-trauma fracture, or were more elderly [≥65 y] with BMD criteria for osteoporosis) are often not offered a drug holiday since their baseline risk is high.
Even though the Fracture Intervention Trial Long-term Extension (FLEX) data did not show an increase in hip, nonvertebral, or morphometric vertebral fractures in those subsets of patients randomized from the original Fracture Intervention Trials (FIT) taking alendronate for 5 years following 5 years without treatment, there was a statistically significant increase in clinical vertebral fractures in those patients off of alendronate for 5 years.[6] Hence, despite the limitations of the FLEX data (selection bias and cofounders due to selection of some but not all of the original FIT population), it still remains unclear if bone strength is maintained at all skeletal sites during a drug holiday. There are observational data that a lower hip fracture risk off of alendronate may not be certain if the initial duration of use of alendronate is under 2 years.[8] Hence, if a drug holiday is considered in lower-risk, younger women, a minimum duration of 5 years of alendronate use seems reasonable. As mentioned, there may be differences among the bisphosphonates in duration of effect, though there are not head-to-head data defining these durations or offset period. There are preliminary data that the reduction in bone turnover after a single injection of zoledronic acid (4-5 mg) may be sustained beyond a year[12] even though the standard of care is to follow the registered labeling from the Food and Drug Administration (FDA) for zoledronic acid (5 mg/y × 3 y) following the reduction in all fractures in the pivotal zoledronic acid clinical trial.[13] Monitoring BMD and BTM is, at the present time, the only means to judge sustained biological efficacy.[14-15]
Another less scientifically sound reason for considering a drug holiday is the anecdotal observational data on the risk of either ONJ or diaphyseal (femur) fractures in very small numbers of patients on bisphosphonates. In contrast to the greater risk (1%-10%) for ONJ seen in the oncology population who have received high doses of intravenous pamidronate or zoledronic acid in combination with chemotherapy for metastatic (to bone) carcinomas or multiple myeloma, there have been fewer than 100 adjudicated cases of ONJ validated in the osteoporosis population who receive the far lower doses of bisphosphonates.[16] Yet, the perception in the general dental and lay public is that ONJ is common, which has often led to unnecessary discontinuation of bisphosphonates. Such a decision in high-risk patients could possibly render them at far greater risk for fracture than the calculated attributable risk of ONJ in the postmenopausal population (<0.7>
Finally, there have been several anecdotal reports of the development of spontaneous, often bilateral diaphyseal femoral shaft fractures with long-term (≥5 y) use of alendronate.[17] The mechanism associated with these fractures is unknown. It is also unknown if these types of fractures are seen in people not exposed to bisphosphonates because the reporting of such cases has not been systematic. Once large Medicare databases are carefully studied, we may know if these unusual fractures are confined to the bisphosphonate-exposed population. To date, all of these cases have been associated with long-term alendronate use. It is unknown if this is a class effect or not, since alendronate was the first FDA-approved bisphosphonate for osteoporosis management and has the largest exposed population. Therefore, only time and careful reporting will tell if these fractures are specific to alendronate, or if they might also be seen with other bisphosphonates or in nonbisphosphonate-treated populations. Nevertheless, due to the intense media exposure and the unique litigation climate that pervades US medicine, patients and our colleagues are starting to question drug holidays for this potential fracture risk concern as well. There is no science to guide us here, and patient management must be individualized. Like the broader issue of a drug holiday in any patient, the potential risks and benefits of discontinuation need to be discussed.
Bisphosphonates will continue to be used to benefit patients with a variety of diseases including postmenopausal osteoporosis. The vast majority of treated patients have reduced fracture burden and costs, along with an exceptional safety record. It is the responsibility of practitioners to examine the issue of drug holidays, given the strong science that has evolved in bisphosphonate pharmacokinetics, and be open-minded about potential safety issues that demand good science to clarify. In the meantime, consideration of bisphosphonate drug holidays continues to be based on opinion, without a standard of care, and individualized for each patient.
From the NAMS Menopause e-Consult-newsletter released October 2008
For more, please visit http://www.menopause.org/Members/eConsulteNewsletter.aspx
NAMS. 2008; ©2008 The North American Menopause Society
Menopause e-Consult® is a registered trademark of The North American Menopause Society
Wednesday, December 17, 2008
hypertension
| |
| |
-blockers, clonidine, spironolactone, and loop diuretics were permitted.Friday, December 05, 2008
colon cancer
Top 10 artikels 2008
Medscape top 10 2-12-2008
The advantages of the stool tests are that they are noninvasive, they do not require a bowel preparation, they can be done in the privacy of the patient's home, and they are more readily available to patients without adequate insurance coverage or local resources.
However, these noninvasive tests are less likely to prevent cancer vs the invasive tests; they must be repeated at regular intervals to be effective; and, if the test is abnormal, an invasive test, namely colonoscopy, will be required. For patients who are unwilling to have repeated testing or to undergo colonoscopy if the test results are abnormal, stool testing is ineffective and should not be recommended.
