FDA Warns of Potential Heart Failure Risk With Pramipexol

September 19, 2012 — The US Food and Drug Administration (FDA) has notified healthcare professionals about a possible risk for heart failure with pramipexole (Mirapex, Boehringer Ingelheim), a dopamine agonist used for the management of Parkinson's disease and moderate to severe restless legs syndrome.
"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," a statement from the FDA notes. "Because of the study limitations, FDA is not able to determine whether Mirapex increases the risk of heart failure. FDA is continuing to work with the manufacturer to clarify further the risk of heart failure with Mirapex, and will update the public when more information is available."
The FDA notes that it evaluated a pooled analysis of randomized clinical trials and found that heart failure was more frequent with pramipexole than placebo; however, the increase did not reach statistical significance. They also evaluated 2 epidemiologic studies that also suggested an increased risk for new-onset heart failure with treatment. Limitations of the studies, however, make it difficult to determine whether the excess in heart failure was due to pramipexole or other factors.
More information on the specific studies and the relative risks are included in the safety communication.
"At this time, FDA has not concluded that Mirapex increases the risk of heart failure," the FDA notification states. "Healthcare professionals should continue to follow the recommendations in the drug label when prescribing Mirapex." The benefits and risks of the drug should be discussed with patients, and patients should be encouraged to seek medical attention if they experience signs or symptoms of heart failure on treatment, the safety communication adds.
Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of this product to the FDA's MedWatch Safety Information and Adverse Event Reporting Program by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville,source medscape

 

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Are Brand-Name and Generic Drugs Really the Same? The Prescriber Perspective

Brand-Name vs Generic Agents: The Prescriber Experience

Prescribers and patients often voice concerns about the safety and efficacy of generic drugs that are substituted for brand-name drug products. Love 'em or hate 'em, they are with us to stay. The US Food and Drug Administration (FDA) approves a generic substitute if it has proven to be "identical, or bioequivalent, to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use."^[1]
The FDA's Orange Book provides the latest information on generic approvals. Approved generic agents have been demonstrated to have therapeutic equivalence -- although many providers have questioned whether that equivalence extends to all patients and all clinical scenarios. Jenny Van Amburgh, PharmD, an associate clinical professor of pharmacy at Northeastern University in Boston, Massachusetts, reminded prescribers in a previous discussion on Medscape that generic products are only compared with their brand-name products and not with generics made by other manufacturers.
Drugs that are known to exhibit a narrow therapeutic index (NTI), including levothyroxine, warfarin, phenytoin, and digoxin, are of greatest concern. Switching between generic NTI products made by different manufacturers may require particular vigilance to recommended monitoring.
James Lindon, PharmD, PhD, JD, in an earlier article on Medscape, noted that the product liability law applied to prescription drug products usually only requires the manufacturer to disclose "adequate warning and instruction" to the prescriber or dispenser. There may be no duty for the drug product manufacturer to warn the patient.^[2] In contrast, the prescriber and pharmacist may have a duty to counsel the patient when a particular generic product is prescribed or selected by the pharmacy. Laws regarding substitution vary by state.
What if the generic substitution is required by a patient's insurance carrier? Or the switch to a generic drug from a different manufacturer is made at the pharmacy and the prescriber is not aware of it? Is the prescriber liable? Prescribers may not know which generic product was dispensed at the pharmacy or why that agent was chosen. They may not be aware of any concerns about the product selected.
We asked our prescribing readers to participate in a survey describing their experience with generic agents and their opinions on the appropriateness of their use. Here is what they had to say.

Who Participated?

Over 1400 physicians (64% of the sample), nurse practitioners (32%), and physician assistants (4%) completed the survey. Respondents were fairly equally divided in their practice settings. Approximately 27% indicated that they practiced in a private primary care practice, 27% in a private specialty practice, and 27% in a nonprivate clinic (hospital, federally qualified health center, or public health); the remaining 19% were hospital-based (emergency medicine or hospitalist). The respondents were an experienced bunch: More than one half -- 56% -- had been in practice for over 16 years. An additional 16% reported 6-15 years' experience. Only 8% reported practicing for 2 years or less.source medscape.com

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Ασφαλέστερο το ηλεκτρονικό τσιγάρο σε σχέση με το συμβατικό

Ασφαλέστερο το ηλεκτρονικό τσιγάρο σε σχέση με το συμβατικό

 

Στο συμπέρασμα ότι το ηλεκτρονικό τσιγάρο ίσως ν’ αποτελεί μία πιο ασφαλή μέθοδο καπνίσματος σε σχέση με το κανονικό τσιγάρο, η οποία μπορεί να μειώσει τον κίνδυνο που προκαλεί η επιδημία του καπνίσματος κανονικών τσιγάρων, καταλήγει μελέτη του πραγματοποιήθηκε σε συνεργασία των Πανεπιστημίων Θεσσαλίας και Κρήτης και των τμημάτων ΤΕΦΑΑ και Βιοχημείας (Θεσσαλίας) και Ιατρικής (Κρήτης).

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Η μελέτη, η οποία δημοσιεύτηκε πριν από λίγες ημέρες στο επίσημο περιοδικό Τοξικολόγων της Ευρωπαϊκής Ένωσης «Food and Chemical Toxicology», προέβη σε σύγκριση της επίδρασης του κανονικού και του παθητικού καπνίσματος συμβατικού τσιγάρου με το κάπνισμα (κανονικό και παθητικό) ηλεκτρονικού τσιγάρου. Το ηλεκτρονικό τσιγάρο που επιλέχθηκε ήταν από τα πιο διαδεδομένα στην ελληνική αγορά, το δε υγρό γεμίσματος φίλτρων είχε γεύση καπνού και περιεκτικότητα νικοτίνης 11mg/ml. Αυτή είναι μια μέτρια περιεκτικότητα, καθώς τα υγρά γεμίσματος φίλτρων των ηλεκτρονικών τσιγάρων περιέχουν νικοτίνη από 0 έως 36 mg/ml. Εξετάστηκαν 15 καπνιστές και 15 μη καπνιστές άνδρες και γυναίκες. Όσον αφορά το κανονικό κάπνισμα, μελετήθηκαν οι επιπτώσεις καπνίσματος δύο τσιγάρων σε σχέση με την αντίστοιχη χρήση του ηλεκτρονικού τσιγάρου.
Σχετικά με το παθητικό κάπνισμα, μελετήθηκαν οι επιπτώσεις της έκθεσης για μία ώρα σε συνθήκες παθητικού καπνίσματος κοινού τσιγάρου και ηλεκτρονικού τσιγάρου. Χρησιμοποιήθηκε ένα ειδικά διαμορφωμένο εργαστήριο στο οποίο αναπαράχθηκαν οι συνθήκες που συνήθως απαντώνται σε κοινά μπαρ/εστιατόρια της χώρας. Βρέθηκε ότι μετά το κάπνισμα δύο κανονικών τσιγάρων, καθώς επίσης κι έπειτα από παθητικό κάπνισμα κανονικού τσιγάρου τα κύτταρα του αίματος που ενεργοποιούνται στη φλεγμονή αυξήθηκαν στατιστικά σημαντικά σε σχέση με τα άτομα που κάπνισαν (κανονικά και παθητικά) ηλεκτρονικό τσιγάρο.
Αυτό δείχνει ότι ενώ το κανονικό τσιγάρο ενεργοποιεί την διαδικασία της φλεγμονής, κάτι που είναι κύρια υπεύθυνο για την ανάπτυξη παθήσεων όπως ο καρκίνος και τα καρδιαγγειακά νοσήματα. Αντίθετα, το κανονικό και το παθητικό κάπνισμα ηλεκτρονικού τσιγάρου δεν έδειξαν ανάλογα αποτελέσματα. Τα αποτελέσματα αυτά συνάδουν με τη σκέψη ότι το ηλεκτρονικό τσιγάρο ίσως αποτελεί μια πιο ασφαλή μέθοδο καπνίσματος σε σχέση με το κανονικό τσιγάρο, η οποία μπορεί να μειώσει τον κίνδυνο που προκαλεί η επιδημία του καπνίσματος κανονικών τσιγάρων, επισημαίνεται στη σχετική μελέτη.
Το γεγονός ότι κάθε χρόνο πεθαίνουν 6 εκατ. άνθρωποι σε όλο τον κόσμο από το κάπνισμα έχει δημιουργήσει την ανάγκη για μεθόδους εναλλακτικού καπνίσματος για τη μείωση του κινδύνου στη δημόσια υγεία και μία τέτοια μέθοδος, για την οποία έχει γίνει παρουσίαση πληθώρας ερευνών, από διάφορα εργαστήρια ανά τον κόσμο, τον τελευταίο χρόνο, είναι το ηλεκτρονικό τσιγάρο.sourse medical news.gr

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Nonalcoholic Red Wine Reduces Blood Pressure

 

September 7, 2012 (Barcelona, Spain) — Nonalcoholic red wine was associated with a greater reduction in blood pressure than regular red wine in a new study [1].
The researchers, led by Dr Gemma Chiva-Blanch (University of Barcelona, Spain), conclude that the polyphenols found in red wine are the likely mediators of the blood-pressure reduction and that alcohol appears to weaken their antihypertensive effect.
They suggest that daily consumption of nonalcoholic red wine may be useful for the prevention of mild to moderate hypertension.
For the study, published online in Circulation Research on September 6, 2012, 67 men at high cardiovascular risk were randomized into three four-week treatment periods in a crossover clinical trial. Each participant followed a common background diet and also drank red wine (30 g alcohol/day), the equivalent amount of dealcoholized red wine, or gin (30 g alcohol/day). Blood pressure and plasma nitric-oxide (NO) concentration were measured at baseline and between each intervention. The men were moderate alcohol consumers before the study, but they abstained from drinking any alcohol for a two-week run-in period at the start of the study.
Results showed that both systolic and diastolic blood pressure decreased significantly after the dealcoholized red wine intervention, and these changes correlated with increases in plasma NO. During the red-wine phase, the men had a small reduction in blood pressure and a small increase in NO, while there was no change in blood pressure and a small reduction in NO while drinking gin.
Changes in blood pressure and nitric oxide with the different beverages

Change in BP/NO	Red wine	Nonalcoholic red wine	Gin
Systolic blood pressure (mm Hg)	-2.3	-5.8	-0.8
Diastolic blood pressure (mm Hg)	-1.0	-2.3	-0.1
Nitric oxide (µmol/L)	+0.6	+4.1	-1.4

The researchers note that although the blood-pressure reduction associated with nonalcoholic red wine was modest, reductions of this magnitude have been associated with a 14% decrease in coronary heart disease and 20% reduction in stroke risk.source medscape

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Latest From PURE: 40% of Adult Population Worldwide Has Hypertension

Hypertension is truly a global epidemic, being highly prevalent in all communities worldwide, according to new data from the Prospective Urban Rural Epidemiology (PURE) study. Other findings show that awareness is very low and that once patients are aware, most are treated, but control is very poor.
The hypertension cohort of the PURE study was presented at last week's European Society of Cardiology (ESC) 2012 Congress by Dr Rafael Diaz (Instituto Cardiovascular de Rosario, Argentina). The study aimed to assess the prevalence, awareness, and control of hypertension worldwide by measuring blood pressure in 153 000 individuals from 528 urban and rural communities in 17 countries from five continents.
The mean age of the participants was 50.4, 60% were female, and 46% were from rural communities.
The prevalence of hypertension was lowest in lowest-income countries (around 30%) and highest in upper-middle-income economies (around 50%), with high-income and low-middle-income economies having an intermediate level (around 40%).
Only 13% controlled
Only 30% of the population had optimal blood pressure, with another 30% found to be in the prehypertension range. Of the 40% with hypertension, 46% of these individuals were aware of their condition, 40% were treated, but only 13% were controlled.
In low-income countries, there were higher rates of hypertension in urban areas than in rural areas, but this was reversed in upper-income countries, where hypertension was more prevalent in rural communities.
Men were more likely to be hypertensive than women in high- and middle-income countries, but women were more likely to be hypertensive than men in low-income countries.
Low levels of education were association with increased prevalence of hypertension in high- and middle-income economies, but the reverse was true in low-income countries, where hypertension was actually more common in better-educated people.
Awareness, treatment, and control was higher in urban than in rural communities across all incomes, and women had higher rates of awareness, treatment, and control than men again across the board.
The use of multiple antihypertensive drugs was very low, at just 14%, and "practically nonexistent" in low-income countries, Diaz reported.
He concluded that better screening methods are required and increased use of combination medications is needed.
More cooperation needed
Designated discussant Dr Georg Ertl (Wurzburg University, Germany) said the study had the strengths of being very large and truly international, covering a wide spectrum of social and cultural backgrounds.
"For me, the most interesting data are those that show that awareness, treatment, and control are very low all over the world and are virtually absent in rural communities in low-income countries," Ertl commented. Noting that lessons learned in high-income countries may help low-income countries, he suggested that cooperation needs to be fostered between medical institutions in the two economies.sourse medscape

 

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Hot Cocoa May Boost Seniors' Brain Power

By Kristina Fiore, Staff Writer, MedPage Today

Action Points

• This double blind study tested the hypothesis that dietary flavanols might improve cognitive function in elderly subjects with mild cognitive impairment (MCI).
• Note that elderly patients with MCI who consumed high or moderate levels of cocoa flavanols for 2 months had significant improvements on certain cognitive assessment tests, as well as decreases in insulin resistance and blood pressure, compared with those who took in only small amounts.

Cocoa flavanols have shown some benefits for the heart, but they may also be good for cognitive function in older people, researchers found.
In a double-blind study, elderly patients with mild cognitive impairment who consumed high or moderate levels of cocoa flavanols for 2 months had significant improvements on certain cognitive assessment tests compared with those who took in only small amounts, Giovambattista Desideri, PhD, of the University of L'Aquila in Italy, and colleagues reported online in Hypertension.
"Although additional confirmatory studies are warranted, the findings...suggest that the regular dietary inclusion of flavanols could be one element of a dietary approach to the maintaining and improving not only cardiovascular health but also specifically brain health," they wrote.
Evidence suggests eating flavonoids, polyphenic compounds from plant-based foods, may confer cardiovascular benefits. Flavonols are a subclass of these compounds that are abundant in tea, grapes, red wine, apples, and cocoa products including chocolate.
So to assess whether cocoa flavanols could improve cognitive function in elderly patients with mild cognitive impairment (MCI), Desideri and colleagues assessed 90 elderly patients with MCI who were randomized to drink varying levels of a dairy-based cocoa containing flavanols per day for 8 weeks: 990 mg (high), 520 mg (intermediate), or 45 mg (low).
The researchers found that scores on the Mini Mental State Examination didn't change significantly in any of the groups ( P=0.13), a finding that was likely due to the low sensitivity of the test to detect small changes at the upper end of cognitive performance over time, they wrote.
There were, however, changes in the time required to complete Trail Making Tests A and B, with significantly greater improvements for those on high or intermediate doses of flavonols compared with those who had a low intake (P<0.05):

• High: -14.3 seconds for A, -29.2 seconds for B
• Intermediate: -8.8 seconds for A, -22.8 seconds for B
• Low: +1.1 second for A, +3.8 seconds for B

Scores on the verbal fluency test improved significantly for all groups, but, improvements were significantly greater for those who had a high versus low intake (P<0.05):

• High: +8.0 words per 60 seconds
• Intermediate: +5.1 words per 60 seconds
• Low: +1.2 words per 60 seconds

Also, the composite cognitive z-score significantly changed over the study period for the high and intermediate intake groups (P<0.0001), but did not change for those with the lowest intake, they reported.
Desideri and colleagues also observed improvements in several metabolic parameters, including blood pressure and insulin resistance, for those on high and intermediate doses of cocoa flavanols.
For blood pressure, the high flavanol group saw mean reductions of 10 mm Hg for systolic and 4.8 mm Hg for diastolic (P<0.0001) while the intermediate group saw a mean drop of 8.2 mm Hg for systolic and 3.4 mm Hg for diastolic pressures. There were no significant changes for those taking a low dose of flavanols.
Plasma glucose fell a mean 0.6 mmol/L for those in the highest group and by 0.5 mmol/L for those on the mid-level dose (P<0.0001) with no differences for low intake, and both the high and intermediate groups also had significant reductions in homeostasis model assessment–insulin resistance (HOMA-IR) scores (-1.7 and -0.9 points, respectively).
Changes in HOMA-IR were found to be the main determinant of changes in cognitive function, explaining about 40% of composite z-score variability through the study period, the researchers reported (P<0.0001).
Thus the effect on cognition appears to be mediated in part by improvement in insulin sensitivity, the researchers wrote.
They noted that there were no changes in cholesterol or triglycerides in any of the groups.
The study was limited because its short time-frame didn't allow for conclusions about the extent of cognitive benefits and their duration. Nor can it establish whether the observed benefits are a consequence of the cocoa itself or a secondary effect related to general improvements in cardiovascular function or health. Also, participants were in good health overall and without known cardiovascular disease, so the population may be representative of all subjects with MCI.
Still, the researchers concluded that the data "are suggestive of a possible clinical benefit derived from the regular dietary inclusion of cocoa flavanol-containing foods in subjects with MCI."

The study was supported by a grant from Mars, Inc., which supplied the standardized powdered cocoa drinks used in the study.
A co-author is an employee of Mars, Inc.

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Καταρρίπτεται ο μύθος για τα βιολογικά προϊόντα

Καταρρίπτεται ο μύθος για τα βιολογικά προϊόντα

 

Μια νέα αμερικανική έρευνα έρχεται να αλλάξει την ευρέως διαδεδομένη αντίληψη ότι τα βιολογικά προϊόντα είναι πιο υγιεινή από τα συμβατικά και τονίζει ότι είναι εξίσου πιθανό να είναι μολυσμένα με ορισμένα βακτήρια.

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Από την άλλη, όμως, σύμφωνα με τους επιστήμονες, τα βιολογικά αγροτικά και κτηνοτροφικά προϊόντα είναι λιγότερο πιθανό να περιέχουν υπολείμματα παρασιτοκτόνων ή να φιλοξενούν μικρόβια ανθεκτικά στα αντιβιοτικά. Αν και από τόπο σε τόπο διαφέρουν οι πρακτικές που εφαρμόζονται στις βιολογικές φάρμες, τα προϊόντα τους σε γενικές γραμμές αναπτύσσονται χωρίς τη χρήση χημικών φαρμάκων, αντιβιοτικών και ορμονών, ενώ δεν περιέχουν γενετικά τροποποιημένους οργανισμούς.
Όμως, η νέα έρευνα δείχνει ότι η αντίληψη των καταναλωτών πως τα βιολογικά προϊόντα είναι πάντα πιο θρεπτικά και ασφαλή για την υγεία, δεν είναι κατ’ ανάγκη σωστή. Έτσι, παραμένουν ασαφή τα συγκριτικά οφέλη για την υγεία από την κατανάλωσή τους, με δεδομένο μάλιστα ότι τα βιολογικά τρόφιμα είναι πολύ ακριβότερα από τα συμβατικά (συχνά έχουν έως διπλάσια τιμή), αναφέρει το Αθηναϊκό Πρακτορείο Ειδήσεων.
Η νέα μελέτη, με επικεφαλής την δρα Κρίσταλ Σμιθ- Σπάνγκλερ της Ιατρικής Σχολής του πανεπιστημίου Στάνφορντ, που δημοσιεύθηκε στο αμερικανικό ιατρικό περιοδικό «Annals of Internal Medicine», σύμφωνα με το πρακτορείο Reuters, αξιολόγησε τα δεδομένα από 237 σχετικές έρευνες που συνέκριναν τη διατροφική αξία των βιολογικών και των συμβατικών τροφών και τις τυχόν διαφορές στο επίπεδο μικροβίων που περιέχουν.
Από τη σύγκριση δεν προκύπτει κάποια αξιοσημείωτη διαφορά ανάμεσα στις δύο κατηγορίες προϊόντων όσον αφορά την περιεκτικότητά τους σε βιταμίνες (με εξαίρεση τον ελαφρώς περισσότερο φώσφορο στα βιολογικά). Επίσης δεν βρέθηκε κάποια διαφορά στην περιεκτικότητα σε πρωτεΐνες και λίπη, αν και υπάρχουν ενδείξεις ότι το βιολογικό γάλα περιέχει περισσότερα ωμέγα-3 λιπαρά οξέα.
Ειδικότερα στα φρούτα και τα λαχανικά, δεν διαπιστώθηκε ότι τα βιολογικά υπερτερούν σε θρεπτική αξία. «Παρά την ευρέως διαδεδομένη αντίληψη ότι τα βιολογικά προϊόντα είναι πιο θρεπτικά από τα συμβατικά, δεν βρήκαμε αξιόπιστα στοιχεία που να υποστηρίζουν αυτή την αντίληψη», όπως αναφέρουν οι ερευνητές.
Από την άλλη, διαπιστώθηκε ότι τα βιολογικά και τα συμβατικά τρόφιμα είναι εξίσου πιθανό να είναι μολυσμένα με παθογόνους μικροοργανισμούς, όπως κολοβακτηρίδια (E.coli) και σαλμονέλα. Περίπου το 7% των βιολογικών προϊόντων και το 6% των συμβατικών βρέθηκαν να περιέχουν κολοβακτηρίδια, ενώ τα αντίστοιχα ποσοστά για τη σαλμονέλα ήσαν 34% (τα βιολογικά) και 35% (τα συμβατικά).
Αντίθετα, υπήρχε αισθητή διαφορά στη μόλυνση με παρασιτοκτόνα- εντομοκτόνα (7% στα βιολογικά έναντι 38% στα συμβατικά) και στα μικρόβια που είναι ανθεκτικά σε αντιβιοτικά (το βιολογικό/οργανικό κρέας είχε κατά μέσο όρο 33% μικρότερη περιεκτικότητα σε αυτά τα βακτήρια σε σχέση με το συμβατικό κρέας). Πάντως, είναι αξιοσημείωτο ότι, αν και σε μικρότερο βαθμό, τα βιολογικά προϊόντα δεν είναι απαλλαγμένα τελείως (100%) από παρασιτοκτόνα- εντομοκτόνα.
«Είναι αδύνατο να πει κανείς, με βάση αυτήν τη μελέτη, αν η μία μέθοδος καλλιέργειας είναι καλύτερη από την άλλη», δήλωσε ο ερευνητής Τζιν Λέστερ, ειδικός στη φυσιολογία των φυτών στην Υπηρεσία Αγροτικών Ερευνών του υπουργείου Γεωργίας των ΗΠΑ. Όπως είπε, αν και τα νέα ευρήματα είναι ενδιαφέροντα, δεν μπορούν να θεωρηθούν οριστικά, με δεδομένη τη μεγάλη ποικιλομορφία στις βιολογικές/ οργανικές πρακτικές και στην υπάρχουσα δυσκολία να γίνουν διαχρονικές συγκρίσεις.
«Δεν υπάρχει μεγάλη διαφορά ανάμεσα στα βιολογικά και στα οργανικά τρόφιμα, όσον αφορά έναν ενήλικο που θέλει να επιλέξει με βάση μόνο την υγεία του», δήλωσε η ερευνήτρια Ντένα Μπραβάτα. Σημειωτέον ότι ακόμα δεν υπάρχουν μακρόχρονες έρευνες (διάρκειας άνω των δύο ετών) που να συγκρίνουν τις τυχόν διαφορές στις επιπτώσεις για την υγεία μεταξύ όσων τρώνε μόνο συμβατικά και όσων τρώνε μόνο βιολογικά προϊόντα.
Σύμφωνα πάντως με τους ερευνητές, πέρα από τα θέματα της υγείας, υπάρχουν άλλοι λόγοι που θα μπορούσε κανείς να προτιμήσει τα βιολογικά προϊόντα, όπως η (πιθανή) καλύτερη γεύση, το ενδιαφέρον του για το περιβάλλον και τα ζώα κ.α.sourse medicalnews.gr

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Q: Will an Inhaler Enhance My Performance?

Q: Will an Inhaler Enhance My Performance?

Until recently, the World Anti-Doping Association (WADA) considered the asthma medication salbutamol (a.k.a. albuterol) a banned substance requiring medical proof of need because it was thought the medication might provide a competitive advantage, likely in the form of increased oxygen consumption (VO2 max). But late in 2009, WADA announced that salbutamol would be allowed in doses recommended for asthmatics. And starting in 2012, WADA took another asthma medication called formoterol off of the prohibited list.
Why would notoriously strict WADA downgrade these meds? Because several studies over the past few years concluded that asthma medications, also referred to as beta-2 agonists, had no significant, positive effects on performance. For example, a 2011 review of 26 studies on the effects of inhaled beta-2 agonists found that the medications did not improve “endurance, strength or sprint performance in healthy athletes.” In another study published in 2011, Belgian researchers wrote that taking salbutamol “does not affect exercise capacity in normal subjects.”
Leading up to the Beijing Olympics, news outlets suggested that the large number of elite athletes using inhalers, including silver medalist swimmer Dara Torres and gold medalist triathlete Emma Snowsill, signaled a potential abuse of asthma meds to get ahead. Amateur athletes, it seemed, were following suit, leaving a record numbers of inhalers behind at triathlon start lines.
Now, however, it’s speculated that the intense training Olympic athletes do might actually cause asthma symptoms. Olympic athletes with asthma regularly beat their non-asthmatic competitors, redorbit.com reports—not because they’re using inhalers, but possibly because the athletes that trained the most did the most damage to their lungs. Or because asthmatic athletes train harder to make up for their pulmonary deficit.
BOTTOM LINE: If you don’t have asthma, don’t use an inhaler. It won’t make you faster, stronger, or last longer, and you could unnecessarily subject yourself to performance-hindering side effects including dizziness, headaches, and nausea. source outside

                                        

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Apixaban: A Good Choice for AF Patients With Renal Dysfunction?

August 29, 2012 (Munich, Germany) — A new prespecified analysis of the ARISTOTLE study has shown that the new oral anticoagulant apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) was better than warfarin at preventing the primary outcome, stroke or systemic embolism, in atrial-fibrillation patients, regardless of renal function [1]. And patients with kidney disease seemed to have the greatest reduction in major bleeding with apixaban.
These findings are important, because patients with renal insufficiency pose a problem for any kind of anticoagulant treatment due to their increased risk for both thromboembolic and bleeding events. Up to 20% of those with AF have some renal dysfunction, making treatment decisions difficult in this patient group.
These new results suggest that "apixaban may be particularly suited to address the unmet need for more effective and safer stroke prevention in patients with AF and renal dysfunction," say Dr Stefan H Höhnloser (JW Goethe University, Frankfurt, Germany) and colleagues in their paper published online August 29, 2012 in the European Heart Journal. Höhnloser also reported the results today in a clinical trial and registry update session at the European Society of Cardiology (ESC) 2012 Congress.
In a commentary accompanying the paper [2], Dr Jan Steffel (University Hospital Zurich, Switzerland) and Dr Gerhard Hindricks (University of Leipzig–Heart Center, Germany) concur. "This new substudy of ARISTOTLE provides solid evidence for the superiority of apixaban in patients with atrial fibrillation and chronic kidney disease. In the light of these data, apixaban appears to be a very appealing option for these individuals." However, they caution that this conclusion does not necessarily extend to those with severe renal disease (estimated glomerular filtration rate [eGFR] of <30 mL/min), since they made up only 1.5% of the study population.
And discussant of the trial at the ESC meeting, Dr Keith AA Fox (University of Edinburgh, Scotland), agrees: "In my view, ARISTOTLE provides a treatment option and advantages over warfarin in patients with moderate renal dysfunction, a group that is currently suboptimally treated."
Doctors Torn Deciding on Anticoagulation in AF With Renal Impairment
The main ARISTOTLE results were first reported at the ESC meeting last year and published simultaneously in the New England Journal of Medicine; they were widely viewed as the "most positive" data among the major randomized trials comparing new oral anticoagulants with warfarin for prevention of stroke in AF. Despite this, the US FDA has failed to yet approve apixaban for this indication for reasons that remain unclear. Apixaban is not approved for AF in the European Union, either, although it was cleared for marketing there for prevention of venous thromboembolism.
Steffel and Hindricks say doctors are torn when having to decide whether or not--and if so, how--to anticoagulate patients with atrial fibrillation and renal insufficiency. A recent study has even shown, for instance, that the net clinical benefit of warfarin is unclear in patients with AF and renal disease.

ARISTOTLE provides a treatment option and advantages over warfarin in patients with moderate renal dysfunction, a group that is currently suboptimally treated.

And the initial enthusiasm associated with the novel anticoagulants--such as dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson)--"was dampened shortly after their introduction, when reports of major hemorrhages surfaced," they note. "Indeed, it quickly became clear that especially dabigatran, which is 80% renally cleared, has a significant potential for severe bleeding in patients with reduced renal function."
To try to address this problem, Höhnloser and colleagues evaluated the ARISTOTLE data, comparing apixaban--which is partially excreted by the renal system--with warfarin in relation to renal function. They note that a reduced dose of apixaban (2.5 mg twice daily instead of the usual 5 mg twice daily) was given to patients with two of the following criteria: age >80 years, weight <60 kg, and serum creatinine >133 mmol/L (1.5 mg/dL).
There were 7518 patients (42%) with no renal dysfunction (eGFR of >80 mL/min), 7587 (42%) with eGFR between 50 and 80 mL/min, and 3017 (15%) with an eGFR of <50 mL/min.
The rate of cardiovascular events and bleeding was higher in those with impaired renal function (<80 mL/min), as would be expected.
"The present analysis represents the largest experience of anticoagulation therapy in patients with AF and impaired renal function, and the superiority of apixaban relative to warfarin for preventing stroke or systemic embolism was consistent, irrespective of degree of renal impairment," say the researchers.
Those With Worse Kidney Function Had the Least Major Bleeding on Apixaban
Apixaban was also associated with fewer major bleeding events across all ranges of eGFR, with the relative risk reduction in major bleeding being greater in patients with an eGFR of <50 mL/min (hazard ratio 0.50; 95% CI 0.38–0.66' interaction p=0.005].
To examine whether the reduction in bleeding in patients with impaired renal function was due to the more frequent use of the lower apixaban dose (2.5 mg twice daily), two sensitivity analyses were conducted, first by adjusting for dose and second by excluding all patients on low-dose apixaban and repeating the analysis only in the patients on the standard dose. In both, the interaction between treatment and renal function remained statistically significant for major bleeding.
Steffel and Hindricks seem convinced by this analysis: "The finding of a statistically significant greater reduction in major bleeding in patients with impaired renal function implies a particularly pronounced benefit of apixaban compared with warfarin in this patient population," they observe.
Further Analysis Of Existing Studies Will Provide More Guidance
They then wonder, "Should every patient with atrial fibrillation and renal insufficiency hence be anticoagulated with apixaban?" and "How does apixaban compare with rivaroxaban and dabigatran in these patients?"
Unfortunately, comprehensive cross-trial comparisons with the other novel anticoagulants are impossible to perform, given--among other factors--the different study designs, different patient populations, and (partly)

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different bleeding definitions, they state. But as all three trials compared the respective novel agent with warfarin, it would be interesting to compare matched subsets of patients from each trial; "such data, however, are not yet available."
Nevertheless, data from large registries and from real-world use will provide additional evidence for further guidance, they note.
Höhnloser has served as a consultant, member of steering committee, or speaker for Bayer Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cardiome, Forest RI, Johnson & Johnson, Medtronic, Pfizer, Portola, Sanofi, and St Jude Medical. Disclosures for the coauthors are listed in the paper. Steffel has received consulting and/or speaker's fees from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer and research support from Bayer Healthcare. Hindricks declared no conflicts of interest. Fox has received grant funding and honoraria from Sanofi, Lilly, Bayer, Johnson & Johnson, AstraZeneca and Boehringer Ingelheim.source medscape

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Choosing Oral Contraceptives With Lowest Thrombotic Risk

Oral Contraceptive Pills

The most widely used form of contraception is the combined oral contraceptive pill. However, progestin-only pills, implants, depot medroxyprogesterone acetate (DMPA) injections, and medicated intrauterine devices are other contraceptive options, along with combined preparations available as transdermal patches and vaginal rings.
The combined pill contains 20-50 µg of ethinylestradiol and a progestin. Norethisterone was the first active progestin used in oral contraceptive pills and is classified as a first-generation progestin. Norgestrel and levonorgestrel are second-generation progestins, and desogestrel, gestodene, and norgestimate are the newer, third-generation progestins. Drospirenone is the latest progestogen component (fourth-generation) used in combined pills.
The combination pill works through multiple mechanisms: Negative feedback lowers follicle-stimulating and luteinizing hormone levels and prevents ovulation. The progestin component affects the cervical mucus, endometrium, and tubal motility and contributes significantly to the pill's contraceptive properties. The overall efficacy of the combination pill is user-dependent, but even with less-than-perfect use, it is among the most effective contraceptive options.

Risk for Venous Thromboembolism

In addition to providing effective contraception, use of the combined oral contraceptive pill is associated with multiple noncontraceptive benefits (including decreased blood loss, reduced dysmenorrhea, less cyst formation, and lower risk for ovarian/endometrial cancer). It is not, however, without adverse effects. It was recognized early on that the risk for venous thromboembolism (VTE) was increased among combination pill users.^[1] This risk was attributed to its estrogen component, which affects the synthesis of clotting factors.
To mitigate this risk, the dose of the estrogen component was reduced, and later, new progestins were incorporated into the pill. Although the new progestins may be associated with a more favorable clinical profile, reports suggest a higher risk for VTE with these agents.
Many factors influence the risk for VTE. The incidence of VTE increases with age and body mass index. Family history, hematologic problems, immobilization, varicose veins, and pregnancy all affect a woman's risk for VTE. Therefore, these factors need to be controlled for when assessing the risk associated with different forms of hormonal contraception and generations of combination pills. Nonusers of hormonal contraception have a baseline risk for VTE of 1-3 per 10,000 woman-years.
A universal finding of existing research is an increased risk for VTE with the combination pill. The risk was somewhat reduced when the dose of ethinylestradiol was lowered. Most studies that compared pills from various generations found a higher risk with the third- and fourth-generation combined pills compared with the second-generation pills. Studies that failed to find a difference typically drew conclusions on the basis of a small number of VTE events.

Article Summary

This review by Lidegaard and colleagues summarizes the latest findings on VTE risk associated with hormonal contraceptives. In previous research, the investigators found the risk for VTE to be the highest (8 times the baseline risk) during the first year of contraceptive use compared with that of nonusers.^[2] The risk, however, was still 3 times higher after 4 years of pill use. On the basis of findings from studies performed in different countries, the risk for VTE is 3 times higher with second-generation pills and 6-7 times higher with third- and fourth-generation pills. The absolute risk is small but cannot be ignored.
The investigators recommended the use of second-generation pills with the lowest estrogen content as the first choice of contraceptive pills. If adverse effects occur, a switch can be made to a third- or fourth-generation pill. Patients at risk for VTE should use a progestin-only pill, DMPA injections, or an intrauterine device. Older women, who have a higher risk for VTE as a result of age, also should use second-generation pills.

Viewpoint

Under normal physiologic conditions, the mechanisms responsible for clotting and spontaneous bleeding are controlled, and the risks for both are low. However, many factors can disrupt this equilibrium. Vascular problems, inherited risk for thrombosis, immobility, obesity, and hormones, in addition to contraceptive pill use, all can influence the clotting cascade and increase the risk for VTE.
Combined oral contraceptive pills containing newer progestins are associated with a doubling of the risk for VTE compared with second-generation pills. Lidegaard and colleagues explain this finding as a differential effect on sex-hormone-binding globulin levels. Newer progestins induce much higher levels, and this affects the total estrogenicity of the pill.
However, other possible explanations exist. Newer preparations are more likely to be prescribed to new users of hormonal contraception. Most VTE occurs during the first year of use, so new users are at higher risk. Newer medications are considered safer overall, and therefore newer-generation pills may be prescribed preferentially to women who are at higher risk for VTE.
Drospirenone has antiandrogenic properties and is commonly prescribed to take advantage of this noncontraceptive benefit. Women with hyperandrogenemia (mainly polycystic ovary syndrome) are more likely to have underlying vascular problems and are at a higher baseline risk for VTE.
The message of this review is that care must be taken in the selection of a combined oral contraceptive pill and the choice has to be individualized, taking into account age, body mass index, family history, and other risk factors. The combined pill carries about the same risk for VTE as the pregnancy it is designed to prevent. Patients should be counseled about the signs of VTE to avoid more severe complications.sourse medscape

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The Pathophysiology of Atrial Fibrillation (AF) and the Importance of Sinus Rhythm

Remodeling of the atria caused by atrial fibrillation makes it more difficult to return to sinus rhythm, more difficult to respond to treatment, and increases vulnerability to relapse.¹

Classification

• The American College of Cardiology (ACC), the American Heart Association Task Force (AHA), and the European Society of Cardiology Committee (ESC), in collaboration with the Heart Rhythm Society have established guidelines for the classification of AF²
• First-detected episode of AF – may or may not be symptomatic; the actual duration of the episode and previous undetected episodes may be uncertain²
• Recurrent AF - 2 or more episodes²
  • Paroxysmal AF - self-terminating, spontaneously converts to sinus rhythm²
  • Persistent AF - lasts longer than 7 days, is not self-terminating and usually requires medical intervention²
• Permanent AF – refractory to cardioversion or has persisted for a long period of time²
• Lone AF – occurring in a patient younger than 60 years who has no clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension²
• Valvular and nonvalvular AF – occurs in a patient who has evidence or history of rheumatic mitral valve disease, who has a prosthetic heart valve, or who has valve repair; all other forms of AF are classified as nonvalvular AF²

Atrial Fibrillation Begets Atrial Fibrillation

• One of the main challenges of atrial fibrillation is the tendency of the disease to become chronic over time, during which a combination of molecular and structural changes make it difficult to achieve and maintain sinus rhythm³

Electrical Remodeling

• The concept that AF is self-perpetuating has been studied extensively in a goat model using an automatic atrial fibrillator that detected spontaneous termination of AF and reinduced AF by electrical stimulation. At first, the electrically induced AF terminated spontaneously. However, with repeated inductions, AF episodes became progressively more sustained until AF persisted and at a more rapid rate. The increasing propensity to AF was associated with progressive shortening of the effective refractory period as well as with increasing episode duration² (See Figure)
• Electrophysiological remodeling has led to the phrase “atrial fibrillation begets atrial fibrillation,” originally coined by Wijffels and colleagues^2,3
• In addition to remodeling and changes in electrical refractoriness, prolonged AF disturbs atrial contractile function. After a period of persistent AF, recovery of atrial contraction can be delayed for days or weeks following the restoration of sinus rhythm²

Figure. Posterior view of principal electrophysiological mechanisms of atrial fibrillation. A. Focal activation. The initiating focus (indicated by the star) often lies within the region of the pulmonary veins. The resulting wavelets represent fibrillatory conduction, as in multiple-wavelet reentry. B. Multiple wavelet reentry. Wavelets (indicated by arrows) randomly reenter tissue previously activated by the same or another wavelet. The routes the wavelets travel vary. LA indicates left atrium; PV, pulmonary vein; ICV, inferior vena cava; SCV, superior vena cava; and RA, right atrium. Adapted from Konings.^2,4

• Electrophysiological remodeling occurs on 2 time scales: rapid (seconds or minutes) and slower (days or weeks)³
  • Rapid electrophysiological remodeling involves translational modulation of I_ca and I_TO ionic currents by altered pH, intracellular Ca²⁺, phosphorylation and oxidation state, and metabolic regulation of pore forming alpha and beta subunits³
  • Slower changes are due to changes in the rate of translation, synthesis, and degradation of ion channel subunits in the myocyte membrane³

Structural Remodeling

• The most frequent structural changes in AF are atrial fibrosis and loss of atrial muscle mass²
• Atrial fibrosis may precede the onset of AF. Nonhomogeneity of conduction may result from the juxtaposition of patchy fibrosis with normal atrial fibers²
• Interstitial fibrosis may be triggered by atrial dilation in any type of heart disease associated with AF. Also, interstitial fibrosis may result from apoptosis leading to replacement of atrial myocytes, loss of myofibrils, disruption of cell coupling gap junctions and organelle aggregates, or accumulation of glycogen granules²
• Apoptosis, or programmed cell death, provides temporal and spatial control of a cell and determines the cell’s lifetime. Apoptosis may occur inappropriately under pathophysiological conditions. When this happens in the heart, myocytes die and contractile capacity as well as electrical activity is permanently lost. The pathways of electrical activation may be altered due to replacement fibrosis. The presence of apoptotic myocytes in the atrial tissues of patients with chronic AF was documented by Aime-Sempe and colleagues³
• Structural changes in AF occur at a slow rate, significantly slower than electrophysiological remodeling, and probably most structural changes are irreversible³

Molecular Changes in AF

• In atrial tissue specimens from a total of 53 explanted hearts of transplantation recipients with dilated cardiomyopathy, 18 had persistent, 19 had permanent, and 16 had no documented AF. Extracellular matrix remodeling including selective upregulation of matrix metalloproteinase 2 (MMP-2), type 1 collagen volume fraction (CVF-1) and downregulation of insulin-like growth factor II mRNA-binding protein 2 (IMP-2) were associated with sustained AF²
• The concentration of membrane-bound glycoproteins that regulate cell-cell and cell-matrix interactions (disintegrin and metalloproteinases) in human atrial myocardium has been reported to double during AF, potentially contributing to atrial dilation. Dilation of the atria activates several molecular pathways including the renin-angiotensin-aldosterone system (RAAS). Angiotensin II is upregulated in response to stretch, and atrial tissue from patients with persistent AF demonstrates increased expression in angiotensin-converting enzyme (ACE). Angiotensin inhibition and angiotensin II receptor blockage may prevent AF by reducing fibrosis²
• A genetic defect, such as mutations in lamin AC gene, has been associated with AF. Other triggers of fibrosis include inflammation as seen in cardiac sarcoidosis and autoimmune disorder²

Long-term Impact of AF

• A retrospective analysis demonstrated that 20% of patients with intermittent AF were in permanent AF after 4 years⁵
• 77% of patients with paroxysmal AF were in permanent AF after a mean of 14 years.⁵ Independent risk factors for early progression to permanent AF included age, dilated left atrium, MI, and valvular disease⁵
• The longer one waits to initiate a rhythm treatment strategy, the harder it is to regain sinus rhythm. Patients who converted to sinus rhythm within 3 months of onset of AF were more likely to remain in sinus rhythm at 6 months than patients who converted more than 12 months after onset of AF (67% versus 27%)⁶
• By shortening the atrial refractory period, reducing conduction velocity and provoking contractile and structural remodeling, AF sets the stage for self-perturbationSOURCE,MEDSCAPE

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