Month: September 2010

Mitoxantrone: Update on Cardiac Risk

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In a retrospective chart review, posttreatment cardiotoxicity occurred more frequently than was observed in clinical trials.

In 2000, mitoxantrone was approved by the FDA for secondary progressive, worsening relapsing-remitting, and progressive-relapsing forms of multiple sclerosis (MS). The drug’s use has been limited by concerns about potential cardiotoxicity and acute leukemia. To provide more data on its cardiotoxicity, researchers conducted this retrospective chart review of 163 patients followed at their clinic for nearly 10 years.

Median follow-up duration was slightly more than 1 year, and mean cumulative dose (59.7 mg/m2) was well below the suggested lifetime ceiling of 140 mg/m2. Nonetheless, 14% of mitoxantrone-treated patients with normal baseline left ventricular ejection fractions experienced decreased ejection fractions on follow-up multiple-gated acquisition (MUGA) scans. This effect persisted in half of these patients and reversed in three patients (17%); the other six patients did not receive a follow-up MUGA study. One patient developed congestive heart failure. Sex, age, disease duration, and cumulative dose were not predictors of cardiac risk. The authors also identified other adverse effects of mitoxantrone (neutropenia, liver toxicity, and anemia).

Comment: Recently, the FDA imposed stringent guidelines for mitoxantrone use, requiring that treated patients undergo annual echocardiograms indefinitely to detect late-developing cardiac damage. Although this study showed no relation between total dose and cardiac effect, other studies involving higher mean dosages have done so. The lack of association in this study likely reflects the restricted dosing range. The cardiotoxicity reported here is greater than was seen in the phase II and III trials and in some but not all postmarketing studies. This difference is especially noteworthy considering the low cumulative doses and short follow-up. Taken together with other postmarketing work, including some studies suggesting a risk for leukemia as high as 3% with mitoxantrone (Neurology 2010; 74:1463), these finding clearly indicate that clinicians must carefully consider safety risks before prescribing mitoxantrone.

— James Stankiewicz, MD

Published in Journal Watch Neurology September 28, 2010

Physical activity, sedentary behaviours, and the prevention of endometrial cancer

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Physical activity has been hypothesised to reduce endometrial cancer risk, but this relationship has been difficult to confirm because of a limited number of prospective studies. However, recent publications from five cohort studies, which together comprise 2663 out of 3463 cases in the published literature for analyses of recreational physical activity, may help resolve this question. To synthesise these new data, we conducted a meta-analysis of prospective studies published through to December 2009. We found that physical activity was clearly associated with reduced risk of endometrial cancer, with active women having an approximately 30% lower risk than inactive women. Owing to recent interest in sedentary behaviour, we further investigated sitting time in relation to endometrial cancer risk using data from the NIH-AARP Diet and Health Study. We found that, independent of the level of moderate–vigorous physical activity, greater sitting time was associated with increased endometrial cancer risk. Thus, limiting time in sedentary behaviours may complement increasing level of moderate–vigorous physical activity as a means of reducing endometrial cancer risk. Taken together with the established biological plausibility of this relation, the totality of evidence now convincingly indicates that physical activity prevents or reduces risk of endometrial cancer.

source: BJC

Management of Menstrual Migraine: A Review of Current Abortive and Prophylactic Therapies

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Sullivan E et al. – After menarche, women have an increased prevalence of migraine compared to men. There is significant variability in the frequency and severity of migraine throughout the menstrual cycle. Women report migraines occur more frequently during menses, and that those are more severe than other migraines. This creates a unique challenge of effectively treating menstrually related and pure menstrual migraines. As with treatment of other migraines, both abortive and prophylactic treatment regimens are used. Triptans demonstrate efficacy in the abortive management of menstrually related and pure menstrual migraines. For migraines that occur primarily during menses or that are particularly resistant to other therapies, intermittent prophylactic therapies can be used. Naproxen and estrogens have been studied for this use. More recently, triptans have been examined and have shown efficacy for intermittent prophylaxis of menstrual migraine.

Urinary Antigen Testing for Community-Acquired Pneumonia

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Urinary pneumococcal antigen testing should be incorporated into the standard approaches for guiding treatment in community-acquired pneumonia, an Archives of Internal Medicine study concludes.

Researchers studied some 500 cases of CAP, establishing definite or probable S. pneumoniae infection by culture or Gram stain in about one third. The urinary antigen test was found to have a sensitivity of about 70% in detecting S. pneumoniae, a specificity of about 95%, and a positive predictive value of about 90%.

The authors conclude that the test “should be incorporated into clinical guidelines at the same level as classic microbiological studies because it can supplement, but not replace, their results.”

source:Archives of Internal Medicine article

Gorillas spread malaria to humans, say scientists

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gorilla_Flickr_nouQraz.jpgMalaria culprit? Gorillas — rather than bonobos or chimpanzees — may have spread the disease to humans

Flickr/nouQraz

Gorillas are likely to have been the original source of malaria in humans, and the parasite probably jumped across the species about 5,000 years ago, say scientists, who will begin screening humans living near gorillas to see if the parasite is still moving between the populations today.

An international team of scientists working in Cameroon, Central African Republic and the Democratic Republic of Congo (DRC), has shown that the parasite Plasmodium falciparum, which causes the most dangerous form of malaria, probably made a single jump from gorillas — not bonobos or chimpanzees as previously thought.

The discovery could influence the understanding of malaria in the same way that comparisons of the biology of HIV with its equivalents in apes have given scientists greater insight into the mechanisms behind the disease.

The team, whose work is published in Nature today (23 September), collected thousands of samples of ape faeces to screen for malaria parasites.

“By studying the closest relative to human P. falciparum in gorillas, I cannot imagine that this would not give important clues as to why the human parasite is so pathogenic [disease-causing],” lead researcher Beatrice Hahn, a professor at the University of Alabama at Birmingham (UAB), United States, told SciDev.Net.

Jean-Bosco N. Ngona, co-author of the study and a scientist at the University of Kisangani, DRC, said that more work is needed to understand whether there are malaria interactions between gorillas and humans today.

“It would give you a heads-up of what there might be to come,” said Hahn. “As future eradication efforts bear fruit, you could generate a niche for a new parasite to move in.”

Nathan Wolfe, director of the Global Viral Forecasting Initiative (GVFI), said the work was a “great finding … we need to think about the possibility that some of these parasites might be entering the human population”.

Such movements could go undetected in the developing world, he said, where diagnosing the presence of the malaria parasite is done by looking at its structure and shape rather than its genes.

“It’s very likely if any of these other parasites was found in a human it would be misdiagnosed as P. falciparum,” he said.

source:Nature

TB vaccine likely to be five years late, says review

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Nigerians_with_microscopes_140.jpg

[TALLIINN, ESTONIA] A vaccine for tuberculosis (TB) is unlikely to be ready until 2020, say scientists, who will revise the original target from 2015 in a report to be published next month.

A mid-term review of the ‘Global Plan to Stop TB 2006–2015’, which will be released after a meeting in Johannesburg, South Africa, next month (14-15 October) says that the 2015 goal was “optimistic”, and predicts a bottleneck when it comes to carrying out later stage clinical trials.

The global plan was drawn up by the Stop TB Partnership and various stakeholders in 2006, and outlines a ‘big picture’ approach to tackling TB worldwide.

“It was unreasonable to claim to have the TB vaccine by 2015,” said Michel Greco, chair of the Stop TB Partnership Working Group on New TB Vaccines. “If we have a valid vaccine produced by 2020 that will be a feat.”

“2015 was too optimistic,” Hassan Mahomed, clinical director of the South African TB Vaccine Initiative, told SciDev.Net, adding that “somewhere between 2016 and 2020 is a bit more realistic”.

The scientists were speaking on the sidelines of the Second Global Forum on TB Vaccines, in Tallinn, Estonia this week (21-24 September), where they are putting together a detailed blueprint for the development of vaccines against the disease.

TB research has yielded 13 new vaccines, the most advanced of which will be ready for phase III trials in 2013. But scientists fear it will be difficult to find sites for these trials where the incidence of TB is high enough for the trials to be executed quickly.

Although TB is one of the most serious diseases in the world, with over nine million new cases each year and 1.8 million deaths, it is widely spread. This makes it hard to find a site where there are sufficient infections occurring for the protective effects of a vaccine to be easily detected.

Helen McShane, vaccinologist at Oxford University, United Kingdom, whose team is working on the most advanced vaccine candidate so far, told SciDev.Net that the highest incidence they have found at potential trial sites has been three per cent over a period of two years — the equivalent of only three people infected per 100 tested during a whole two-year trial.

Such an incidence would require a trial of about 40,000 people in order to adequately compare vaccinated and placebo groups.

McShane added that Phase III trials on TB vaccines, in their current form, may never be possible, and new approaches may be needed, such as modelling a trial instead.

A second impediment will be the lack of skilled capacity for conducting large-scale trials, and the lack of basic infrastructure, said Greco.

Keeping that capacity going between trials will be an even bigger challenge, he added.

FDA OKs Combination Contraceptive with Folate

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The FDA has approved Beyaz, a combination oral contraceptive containing a folate to prevent neural tube defects.

Beyaz will contain the same doses of progestin and estrogen as the oral contraceptive Yaz. Both are made by Bayer.

Like Yaz, Beyaz is approved to prevent pregnancy, treat symptoms of premenstrual dysphoric disorder, and treat moderate acne. In addition, it is indicated to raise folate levels in women taking oral contraceptives. A clinical trial found that women’s folate levels stayed elevated several weeks after they stopped taking the drug. The efficacy and side effects were essentially unchanged compared with Yaz.

FDA Approves Oral Contraceptive Containing Folate

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The US Food and Drug Administration (FDA) today approved an oral contraceptive — the first of its kind — that is intended both to prevent pregnancy and reduce the risk for neural tube defects in their offspring if and when they give birth.

The new contraceptive, Beyaz (Bayer HealthCare Pharmaceuticals), contains levomefolate calcium, a metabolite of folic acid that helps produce and maintain new cells in the body. Low folate levels in women have been linked with neural tube defects in their children such as spina bifida, resulting in recommendations that women of childbearing age supplement their diet with folate.

“Combining an oral contraceptive with folate is important, because women may become pregnant during [oral contraceptive] use or shortly after discontinuation, possibly before seeking preconception counseling from their healthcare provider,” said Dr. Anita Nelson, professor of obstetrics and gynecology at the Harbor–University of California at Los Angeles Medical Center, Torrance, California, in a company press release. “For women who want to use an oral contraceptive, Beyaz offers a new option for women to receive daily folate supplementation.”

The approval is based on the already-approved oral contraceptive drospirenone/ethinyl estradiol (Yaz, Bayer HealthCare Pharmaceuticals), which contains the same doses of estrogen and progestin.

Like Yaz, Beyaz is approved for:

  • Preventing pregnancy
  • Treating symptoms of premenstrual dysphoric disorder (PMDD) in women who choose to prevent pregnancy with an oral contraceptive
  • Treating moderate acne vulgaris in women at least 14 years old who desire an oral contraceptive for birth control

For women who choose an oral contraceptive as their method of birth control, Beyaz is also approved for raising folate levels to reduce the risk for neural tube defects in offspring.

Beyaz increased folate levels in women who participated in a multicenter, double-blind, randomized, controlled US trial designed to determine product efficacy. In a Germany study, folate levels remained elevated for several weeks after Beyaz was discontinued.

Beyaz safety and efficacy data for the contraception, PMDD, and acne indications came from previous clinical trials of Yaz.

The FDA said that the clinical trials of Beyaz did not yield any findings that would suggest it differs from Yaz in terms of its overall safety profile. The agency expects that the most common adverse events for Beyaz will be the same as those for Yaz. Adverse effects most frequently reported by users of combined oral contraceptives are irregular uterine bleeding, nausea, breast tenderness, and headaches.

As with other oral contraceptives, Beyaz is not intended for use in women older than 35 years who smoke.

Ropivacaine Versus Bupivacaine For Epidural Labor Analgesia

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Ropivacaine is too expensive to merit its routine use in epidural labor analgesia, especially when bupivacaine is more potent, much cheaper, and no different with respect to toxicity or maternal or neonatal outcomes. In addition, the clinical preparations of ropivacaine in glass bottles and hard plastic vials severely limit the flexibility of concentrations and opioid additives that can be prepared for epidural infusions, whereas concentrated bupivacaine preparations in stoppered glass vials allow dilutions to an infinite spectrum of concentrations and additives. Bupivacaine is a long-acting local anesthetic no longer under patent protection that has a long history of safe use in epidural anesthesia for both obstetric labor anesthesia and for intraoperative anesthesia and postoperative analgesia for a wide variety of cardiac, thoracic, orthopedic, and general abdominal surgeries. Like all local anesthetics, excess administration intravenously may produce neurotoxicity and cardiotoxicity. The refractory nature of racemic bupivacaine cardiotoxicity led to the separation and clinical testing of its L-enantiomer, ropivacaine. Unfortunately, this research was biased by funding sources, and led to the misleading conclusion that ropivacaine was safer than bupivacaine. Drs Beilin and Halpern review some of the main comparative studies and conclude that no significant difference exists. I have long argued that the studies lack clinical relevance because they compared equal concentrations of ropivacaine and bupivacaine administered intravenously to volunteers, when epidural ropivacaine is routinely used at a significantly higher concentration (0.2%) than epidural bupivacaine (0.0625-0.125%). In these routine clinical circumstances, ropivacaine would be more likely to cause toxicity than bupivacaine, and review of recent case reports supports this hypothesis. Furthermore, the use of intravenous intralipid as an antidote to bupivacaine cardiotoxicity has further enhanced its safety profile. Ropivacaine is popular because it is new and touted as better and safer, but because it is under patent protection it is much more expensive than bupivacaine, without any significant added benefit or decreased risk. If ropivacaine is the great new local anesthetic, then why not advocate its use in epidural anesthesia for cesarean delivery as well as for labor analgesia? I only had to use it once to understand why. My patient was completely comfortable during testing and initial skin incision but the obstetrician would not proceed further because the patient kept moving her legs up and down during the surgery. Lack of significant motor blockade with epidural ropivacaine has never been shown to translate into a greater incidence of vaginal delivery compared to bupivacaine, yet an immobile surgical field is a nearly absolute requirement for obstetricians performing cesarean delivery. I am delighted that Dr Beilin and Dr Halpern advocate the use of epidural bupivacaine over ropivacaine because it concurs with both my review of the literature and my clinical experiences.

Management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid Vascular Health and Risk Management 

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Moutzouri E et al. – Fibrates are well known for their beneficial effects in triglycerides, high–density lipoprotein cholesterol, and LDL–C subspecies modulation. Fenofibrate is the most commonly used fibric acid derivative, exerts beneficial effects in several lipid and nonlipid parameters, and is considered the most suitable fibrate to combine with a statin. However, in clinical practice this combination raises concerns about safety. ABT–335 is the newest formulation designed to overcome the drawbacks of older fibrates, particularly in terms of pharmacokinetic properties. It has been extensively evaluated both as monotherapy and in combination with atorvastatin, rosuvastatin, and simvastatin in a large number of patients with mixed dyslipidemia for up to 2 years and appears to be a safe and effective option in the management of dyslipidemia.