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The benefits of treating patients with mildly elevated blood pressure who are free of cardiovascular disease are unclear, according to a Cochrane review. These findings conflict with current hypertension treatment guidelines in the U.S., Canada, and Europe.
Researchers analyzed data from nearly 9000 participants in four trials and found no obvious benefit of drug treatment in patients with mild hypertension (systolic BP, 140 to 159 mm Hg and/or diastolic BP, 90 to 99 mm Hg) in terms of total mortality or cardiovascular events at 5 years’ follow-up. They did, however, see an increased likelihood of drug withdrawal due to adverse effects (relative risk, 4.8).
The change from 2011 is that children aged 6 months through 8 years who have never received influenza vaccine or who have not received two or more doses of seasonal influenza vaccine since July 2010 should receive two doses of 2012–2013 vaccine (given at least 4 weeks apart).
Source: MMWR article
The FDA announced today that it has approved the first generic version of pioglitazone tablets, which are used in conjunction with diet and exercise to improve glycemic control in adults with type 2 diabetes.
“Controlling blood sugar levels is very important in preventing or reducing the long-term health complications of diabetes,” Gregory P. Geba, MD, MPH, director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research, said in the release. “Generic versions of this widely used product will offer affordable treatment options for patients who must manage this chronic and potentially serious condition.”
Pioglitazone (Actos, Takeda) is dispensed with a patient medication guide that provides important instructions about its use and drug safety information. The drug also has a boxed warning to emphasize that pioglitazone may cause or worsen heart failure, particularly in certain patient populations. The agency recommends careful monitoring of patients when starting the drug or increasing the. Additionally, the product label states that the use of pioglitazone for more than 1 year is associated with the risk of bladder cancer.
The most common side effects reported by patients using pioglitazone include headache, sinus infection, muscle pain and sore throat.
Source: Endocrine Today.
Melanoma is 10 times more common in Australia than in most countries,1 and kills more than 1300 Australians every year.2 The good news is that we now have effective drug treatments for metastatic melanoma. Two drugs, ipilimumab3,4 and vemurafenib,5 are now approved by the United States Food and Drug Administration and the Australian Therapeutic Goods Administration in recognition of convincing evidence for prolongation of life in treated patients, at least in the short term. Australia has played an important role in the development of drug treatment for melanoma,6,7 including the practice-changing discovery of the effectiveness of drug therapy against brain metastases.8
The bad news is that, like all new cancer drugs, these drugs are expensive, with price tags in the six-figure realm for each treated patient. Vemurafenib, which targets the mutated BRAF oncogene present in 50% of melanomas, produces dramatic tumour regressions in most cases. However, the average duration of the response is just 6 months, with a median extension in overall survival of just under 4 months. Ipilimumab, a potent but non-specific immunostimulant, rarely induces tumour regressions, but the disease stabilises for 3 or more years in a subset of around 10% of patients. This subset cannot yet be presumptively identified by biomarkers or other tests, so most treated patients do not benefit. Although these advances appear modest, they must be viewed against a background of dismal treatment outcomes for people with this disease, for whom even toxic chemotherapy combinations have had minimal benefit and failed to prolong life.1 These drugs are therefore enthusiastically welcomed by melanoma oncologists, patients and their carers as the first in a predicted series of stepwise advances that promise considerable improvements in survival time for patients with metastatic melanoma.
Not surprisingly, however, the Australian Pharmaceutical Benefits Advisory Committee (PBAC), which advises the federal government on reimbursement of drug costs, has baulked at the cost–benefit equation for ipilimumab, which is currently marketed in Australia at $120 000 for four injections. The PBAC considered the case for vemurafenib at its July meeting in 2012. Even if the PBAC recommends that vemurafenib be approved for subsidy, it must also be approved by the Health Minister, and this is never automatic.
The Australian reaction is not unique. Reimbursement for ipilimumab was rejected in the United Kingdom. Only patients in certain European countries, or who are insured in the US, or wealthy, have ready access to the drug (although means-tested access programs also exist in the US). It appears to be the size of the cohort of patients with projected ability to pay that largely determines business modelling for the initial drug price in the international marketplace.
This problem is about to become much worse, and not just for melanoma. The molecular biology revolution is now delivering a rapidly expanding cascade of rational designer anticancer drugs that target cancer-specific molecular changes, or cleverly reverse immunological tolerance to the disease. The strategy of combining these approaches is in its infancy, but promises advances that are complementary and synergistic across multiple tumour types, with toxicity profiles far lower than those of traditional chemotherapy. Oncologists will rapidly adopt double and triple drug treatments in multipronged therapy for metastatic cancer. This strategy holds the real promise of being able to convert metastatic melanoma from a rapidly fatal illness to a chronic disease within the next decade. A doublet of two highly effective targeted drugs, dabrafenib and trametinib,9 will, like vemurafenib, shortly be tested as adjuvant therapy for high-risk melanoma after surgical excision, and the results of a similar trial of ipilimumab are anticipated in mid 2013. If these therapeutic strategies work as well as we anticipate, years may be added to the lives of patients who have undergone resection of lymph node metastases. A large proportion of these patients are young adults.
However, the price of this success will be an exponential escalation of drug costs. Even if the extension of life is measured in years with these strategies, and some cures are seen, it seems that not even the top end of the US market can sustain this development.
Drug development is already a high-risk investment, with a 1% chance of any candidate molecule surviving the rigours of preclinical and clinical testing and making it into the marketplace. The cost of this pathway for a single successful cancer drug is often over $1 billion, and many fail at the final challenge of large-scale Phase 3 testing. The precedent of the failure to sell ipilimumab in countries like Australia and the continuing pressure for inevitable price cutting and lower returns may influence the board rooms of pharmaceutical companies to move away from cancer drugs and towards potentially easier, faster and safer investments.
The stakes for human health seem too high to trust the solution entirely to the marketplace. Certainly, growing competition between new drugs may drive down prices. Smarter, smaller, more selective cancer-drug trials may reduce drug development costs by improving the accuracy with which patients who are likely to benefit are identified. There will be increased incentive to cut layers of unnecessary legalistic and bureaucratic flab from the gigantically inefficient clinical trials and drug-approval machinery.
But there are only so many things the market can do, and wider policy decisions are urgently needed. How do therapies for advanced cancer stack up as a priority against some of the other big-ticket items for the Australian Pharmaceutical Benefits Scheme (PBS), like statins and protein-pump inhibitors? How much of the health dollar should be justifiably expended on cancer drugs? Is a smarter, less toxic, incrementally beneficial, but expensive, drug, such as PBS-approved paclitaxel protein-bound for metastatic breast cancer, a justifiable priority over older, cheaper, off-patent drugs?
If public funding cannot withstand the impost of effective high-cost drugs, should there be inducements for specific private health insurance that does? (This, of course, would not resolve the issue for the uninsured.) Can governments work internationally with the pharmaceutical industry to sustain strategic invention, subsidise the costs of drug development and minimise its risks and costs?
Patients, carers, the medical profession, governments, the pharmaceutical industry, private health insurers and taxpayers need to contribute to solving this dilemma. One in every three Australians will need cancer treatment at some time. Many of them will need drug treatment. There is now an urgent need for an informed public debate about how to pay for it.
Researchers in the United Kingdom have found a link between impaired glucose tolerance and microvascular and macrovascular function, as well as a direct association between retinal microcirculatory changes and established plasma markers for cardiovascular disease.
Sunni R. Patel, PhD, a postdoctoral fellow at University Health Network in Toronto and former researcher for the Vascular Research Laboratory and Ophthalmic Research Group at the School of Life and Health Sciences at Aston University in Birmingham, United Kingdom, and colleagues conducted a study involving 60 age- and sex-matched white European adults, 30 with IGT and 30 with normal glucose tolerance.
Patients with IGT had higher blood pressure values (P<.001), fasting triglyceride levels and triglyceride-to-HDL ratios (P<.001) vs. patients with normal glucose tolerance. According to data, blood glutathione levels were lower (reduced glutathione, P<.001; glutathione disulfide, P=.039; and total glutathione, P<.001), whereas plasma von Willebrand factor was increased in patients with IGT when compared with the control group (P=.014).
Moreover, patients with IGT displayed higher intima-media thickness in the right (P=.017) and left carotid arteries (P=.005) and larger brachial artery diameter (P=.015). Patients with IGT also had lower flow-mediated dilation percentage (P=.026) and glyceryl trinitrate-induced dilation (P=.012) than healthy control patients.
“The results of our pilot study suggest that IGT individuals demonstrate signs of early vascular dysfunction as measured by functional (at macro- and microcirculatory levels) and circulatory markers. Moreover, in addition to a relationship between functional macro- and microvascular parameters, there appears to be a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD risk,” the researchers wrote.
Due to these observations, researchers wrote that there should be a possible emphasis on early CV screenings and interventions for those with a prediabetes diagnosis, including those with IGT.
“Retinal vascular imaging could emerge as a possible future option for individual risk stratification in diseased patients but also in individuals at risk for metabolic and CV pathologies,” the researchers wrote.
Source: Endocrine Today.
In a 2-year randomized, controlled trial of 127 men aged 55 years to 80 years, researchers concluded that olive oil increases the body’s concentration of the serum osteocalcin, which protects the bone. Participants had no prior history of cardiovascular disease, but had either type 2 diabetes or at least three risk factors for developing the disease, including family history, hypertension and dyslipidemia.
“The intake of olive oil has been related to the prevention of osteoporosis in experimental and in vitro models,” José Manuel Fernández-Real, MD, PhD, lead author from the Hospital Dr. Josep Trueta in Girona, Spain, stated in a press release. “This is the first randomized study which demonstrates that olive oil preserves bone, at least as inferred by circulating bone markers, in humans.”
This study was published ahead of print in the Journal of Clinical Endocrinology and Metabolism.
Fernández-Real and colleagues also measured HDL-cholesterol, total cholesterol, glucose and triglycerides at baseline in addition to osteocalcin, but only olive oil as well as a Mediterranean diet proved to increase levels of osteocalcin and other bone formation markers in the body.
In the release, Fernández-Real noted that osteocalcin in the body has other effects, such as increasing insulin secretion, in addition to protecting bone.
“It is important to note that circulating osteocalcin was associated with preserved insulin secretion in subjects taking olive oil,” Fernández-Real stated. “Osteocalcin has also been described to increase insulin secretion in experimental models.”
Fernández-Real JM, Bulló M, Moreno-Navarrete JM, et al. A Mediterranean diet enriched with olive oil is associated with higher serum total osteocalcin levels in elderly men at high cardiovascular risk. J Clin Endocrinol Metab. 2012 Aug 1. Epub ahead of print.
Source: Endocrine Today.
The Endocrine Society has revised its 2007 Clinical Practice Guideline on the management of thyroid disease in pregnant and postpartum women. Updates include recommendations regarding diagnosis and treatment before, during and after pregnancy.
“Pregnancy may affect the course of thyroid diseases, and conversely, thyroid diseases may affect the course of pregnancy,” Leslie De Groot, MD, a researcher from the University of Rhode Island, said in a press release. “Pregnant women may be under the care of multiple health care professionals, including obstetricians, nurse midwives, family practitioners and endocrinologists, making the development of guidelines all the more critical.”
According to the release, revisions include:
Up for debate
The committee charged with updating the guidelines, however, did not reach a consensus on screening recommendations for all newly pregnant women. For instance, some members recommended screening all pregnant women for serum TSH abnormalities by the ninth week or at the time of their visit, whereas others supported aggressive case finding to identify and test high-risk women.
A full summary of the changes between the 2007 and the 2012 recommendations can be found in the August issue of the Journal of Clinical Endocrinology and Metabolism.
Source: Endocrine Today.
Evidence-based guidelines recommend intracranial pressure (ICP) monitoring for patients with severe traumatic brain injury (TBI), but there is limited evidence that monitoring and treating intracranial hypertension reduces mortality. This study uses a large, prospectively collected database to examine the effect on 2-week mortality of ICP reduction therapies administered to patients with severe TBI treated either with or without an ICP monitor.
From a population of 2134 patients with severe TBI (Glasgow Coma Scale [GCS] Score <9), 1446 patients were treated with ICP-lowering therapies. Of those, 1202 had an ICP monitor inserted and 244 were treated without monitoring. Patients were admitted to one of 20 Level I and two Level II trauma centers, part of a New York State quality improvement program administered by the Brain Trauma Foundation between 2000 and 2009. This database also contains information on known independent early prognostic indicators of mortality, including age, admission GCS score, pupillary status, CT scanning findings, and hypotension.
Age, initial GCS score, hypotension, and CT scan findings were associated with 2-week mortality. In addition, patients of all ages treated with an ICP monitor in place had lower mortality at 2 weeks (p = 0.02) than those treated without an ICP monitor, after adjusting for parameters that independently affect mortality.
In patients with severe TBI treated for intracranial hypertension, the use of an ICP monitor is associated with significantly lower mortality when compared with patients treated without an ICP monitor. Based on these findings, the authors conclude that ICP-directed therapy in patients with severe TBI should be guided by ICP monitoring.
Source: Journal of Neurosurgery.
Angiogenesis and the platelet-derived growth factor (PDGF) pathway are active in the pathogenesis of vestibular schwannomas (VSs). The purpose of this study was to test whether imatinib mesylate (Gleevec), a PDGF receptor (PDGFR) blocker, reduces angiogenic capacity in sporadic VS and in VS associated with neurofibromatosis Type 2 (NF2) using a corneal angiogenesis assay.
From 121 VS tissue samples stored in the tumor bank at the Marmara University Institute of Neurological Sciences, 10 samples (6 from sporadic cases, 4 from NF2-associated cases) were selected at random for use in this study. Expression of PDGF-A and PDGF-B and their receptors was evaluated in sporadic and NF2-associated VS as well as in glioblastoma (GBM) and normal brain tissue by means of immunohistochemistry and Western blot analysis. Corneal angiogenesis assay was then used to evaluate the angiogenic capacity of tissue specimens from sporadic and NF2-associated VS with and without imatinib treatment as well as positive and negative controls (GBM and normal brain tissue).
The angiogenic potential of the sporadic and NF2-associated VS tumor tissue differed significantly from that of the positive and negative control tissues (p <0.05). Furthermore, NF2-associated VS showed significantly lower angiogenic potential than sporadic VS (p <0.05). Imatinib treatment significantly reduced the angiogenic potential in both the sporadic VS and the NF2-associated VS groups. The level of PDGF-A and PDGFR-α as well as PDGF-B and PDGFR-β expression in sporadic VS and NF2-associated VS also differed significantly (p <0.05) from the levels in controls. Additionally the level of PDGFR-β was significantly higher in sporadic VS than in NF2-associated VS (p <0.05).
The findings of this study indicate that NF2-associated VS has significantly more angiogenic potential than sporadic VS and normal brain tissue. Additionally, imatinib reduces the angiogenic activity of both sporadic and NF2-associated VS. The authors conclude that imatinib may be a potential treatment for VS, especially for NF2-associated lesions that cannot be cured with resection or radiosurgery.
Source: Journal of Neurosurgery.