Candy Crush Saga: The Science Behind Our Addiction.


A year after the game’s mobile launch, we still can’t stop playing. The app’s designer and psychology experts weigh in on exactly what makes it so irresistible

If you haven’t heard of Candy Crush, it’s the mobile game that’s so addictive, players say they have left their children stranded at school, abandoned housework and even injured themselves as they try to reach new levels of the game.

Candy Crush

Candy Crush has been played 151 billion times since it launched as an app on mobile devices exactly year ago. And it’s the first game to ever be No. 1 on iOS, Android and Facebook at the same time. Candy Crush’s creator, King, a Stockholm-based company, says 1 in every 23 Facebook users plays it. And while Candy Crush is free, the in-game purchases that some players choose to make add up. Think Gaming, which releases gaming analytics, estimates that it takes in $875,382 per day. (By comparison, another insanely popular mobile game, Angry Birds, takes in an estimated $6,381 daily.)

All that adds up to some seriously distracted users. A survey by Ask Your Target Market polled 1,000 players and found that 32% of them ignored friends or family to play the game, 28% played during work, 10% got into arguments with significant others over how long they played, and 30% said they were “addicted.”

But there are lots of amusing games out there, so what’s so addictive about this one?

We asked Tommy Palm, one of the game’s designers, what the King team did to get us hooked. We also called a few psychology experts and players to understand the backstory on why their tactics worked so well. Here are the nine reasons they say Candy Crush is so irresistible:

1. It Makes You Wait

Perhaps the most genius element of Candy Crush is its ability to make you long for it. You get five chances (lives) to line up the requisite number of candy icons. Once you run out of lives, you have to wait in 30-minute increments to continue play. Or, if you’re impatient, you can pay to get back in the game — which is why it’s bringing in so much revenue. “You can’t just play all the time. You run out of lives,” says Andy Jarc, 22, one of the few players to reach level 440 in the game. “So the fact that they kind of constrain you — the whole mantra, ‘You always want what you can’t have.’ I can’t have more lives and I want them.”

“I think it makes the game more fun long term,” says designer Palm. “If you have a game that consumes a lot of mental bandwidth, you will continue playing it without noticing that you’re hungry or need to go to the bathroom. But then you binge and eventually you stop playing. It’s much better from an entertainment point of view to create a more balanced experience where you have natural breaks.”

2. We’re All Suckers for Sweet Talk

You flick four candies in a row, and they zap away. Candies above begin to cascade down, making even more matches. At the end words pop up on your screen, accompanied by a voice that says “Sweet” or “Delicious.” This feedback is essential for player immersion. “Positive rewards are the main reason people become addicted to things,” says Dr. Kimberly Young, a pioneering expert on Internet and gaming addiction who treats those addicted to the cyberworld. “When you play the game, you feel better about yourself.”

3. You Can Play With One Hand 

According to Palm, the icons and setup were created so players could multitask. You can play Candy Crush while carrying a drink, toting a purse or bag, clinging to a subway pole, or hiding your phone under the table. That’s a huge advantage and makes this game perfect for a train ride, a distraction while you’re waiting to see a doctor, or something to get you through boring meetings. Plus, you can play offline as well — so even if you’re stuck in a tunnel, you can be “crushing.”

4. There’s Always More

According to Palm, the Candy Crush team updates the game constantly and creates new levels every two weeks. Right now there are 544 levels. “Just three years ago, a game with 30 levels would be astonishing,” King says. “And now with this game, it has raised the bar with how much content a mobile game should and will have.”

Plus, on any single level, there’s no way to fail. If you run out of options on a board — and that happens once in a blue moon — the board immediately resets. You never get stuck. You can’t lose. “I believe this is part of the reinforcing pattern which keeps you playing,” says Dr. Dinah Miller, a psychiatrist who has written about the addicting elements of another popular game, Angry Birds. The game only ends when you’ve run out of your allotted number of moves “and you can end that frustration by buying your way out.”

5. You Don’t Have to Pay – but if You Want to, It’s Easy

King reports that of all the players on its last level — 544 — more than 60% of them didn’t pay a cent to buy extra lives or chances to get there. But if you want to pay, it’s easy. Connected to Facebook or the app store? Just click to pay.

6. It Taps Into Our Inner Child

“Many people have had a very positive feeling about candy since they were kids,” says Palm. “And it makes for a really nice visual game board with a lot of color and interesting shapes.” In fact, when you play you feel as if you’re transported into an entire Candy Land experience. The game pieces are candy, and the homepage for the game looks like the traditional Candy Land board, with your Facebook friends’ pictures displayed as pieces on that board, sitting at whatever level they’re stuck on.

7. It’s Social

Social games — any game that allows you to connect with your friends through a social-media platform like Facebook — have taken off. Whether it’s Words With Friends, Kingdoms of Camelot or Candy Crush, the ability to play with, or compete against, friends is irresistible. “Look, nobody’s coming to me because they have a clinical addiction to Candy Crush,” says Young. “It’s more of a social addiction, if you will.”

8. It’s an Escape

“When you read the research about gaming,” Young says, “you’re often looking at people who are distracting themselves from something in their lives.” The relaxing exercise of lining up candies to the tune of upbeat music is a perfect stress reliever.

9.  It Grows on You

This isn’t your average “line up three” game. “I started playing, and at first I was like whatever, it’s just bejeweled,” says Jarc. “But as I played more and more, it became addicting.”

King’s high-level of attentiveness toward updating gameplay has made it better quality than most casual games that are out there. When players took to Facebook to express their frustration with level 65 — notoriously one of the hardest levels in the game — King went into the game and altered the level to make it easier (though not too easy) multiple times.

 

 

Playing Pop and Rock Music Boosts Performance of Solar Cells.


Playing pop and rock music improves the performance of solar cells, according to new research from scientists at Queen Mary University of London and Imperial College London.

The high frequencies and pitch found in pop and rock music cause vibrations that enhanced energy generation in solar cells containing a cluster of ‘nanorods’, leading to a 40 per cent increase in efficiency of the solar cells.

The study has implications for improving energy generation from sunlight, particularly for the development of new, lower cost, printed solar cells.

The researchers grew billions of tiny rods (nanorods) made from zinc oxide, then covered them with an active polymer to form a device that converts sunlight into electricity.

Using the special properties of the zinc oxide material, the team was able to show that sound levels as low as 75 decibels (equivalent to a typical roadside noise or a printer in an office) could significantly improve the solar cell performance.

“After investigating systems for converting vibrations into electricity this is a really exciting development that shows a similar set of physical properties can also enhance the performance of a photovoltaic,” said Dr Steve Dunn, Reader in Nanoscale Materials from Queen Mary’s School of Engineering and Materials Science and co-author of the paper.

Scientists had previously shown that applying pressure or strain to zinc oxide materials could result in voltage outputs, known as the piezoelectric effect. However, the effect of these piezoelectric voltages on solar cell efficiency had not received significant attention before.

“We thought the soundwaves, which produce random fluctuations, would cancel each other out and so didn’t expect to see any significant overall effect on the power output,” said James Durrant, Professor of Photochemistry at Imperial College London, who co-led the study.

“We tried playing music instead of dull flat sounds, as this helped us explore the effect of different pitches. The biggest difference we found was when we played pop music rather than classical, which we now realise is because our acoustic solar cells respond best to the higher pitched sounds present in pop music,” he concluded.

The discovery could be used to power devices that are exposed to acoustic vibrations, such as air conditioning units or within cars and other vehicles.

Co-author Dr Joe Briscoe also from Queen Mary’s School of Engineering and Materials Science, commented: “The whole device extremely simple and inexpensive to produce as the zinc oxide was grown using a simple, chemical solution technique and the polymer was also deposited from a solution.”

Dr Dunn added: “The work highlights the benefits of collaboration to develop new and interesting systems and scientific understanding.”

CLOTBUST-Hands Free.


Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke

Background and Purpose—The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion.

Methods—All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days.

Results—Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5–29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%–64%) complete and 2 of 20 (10%; 95% confidence interval, 1%–32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%–82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%–49) patients had a modified Rankin scale of 0 to 1.

Conclusions—Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial.

Source: Stroke

Active Versus Passive Cooling During Neonatal Transport.


BACKGROUND AND OBJECTIVE: Therapeutic hypothermia is now the standard of care for hypoxic-ischemic encephalopathy. Treatment should be started early, and it is often necessary to transfer the infant to a regional NICU for ongoing care. There are no large studies reporting outcomes from infants cooled passively compared with active (servo-controlled) cooling during transfer. Our goal was to review data from a regional transport service, comparing both methods of cooling.

METHODS: This was a retrospective observational study of 143 infants referred to a regional NICU for ongoing therapeutic hypothermia. Of the 134 infants transferred, the first 64 were cooled passively, and 70 were subsequently cooled after purchase of a servo-controlled mattress. Key outcome measures were time to arrival at the regional unit, temperature at referral and arrival at the regional unit, and temperature stability during transfer.

RESULTS: The age cooling was started was significantly shorter in the actively cooled group (46 [0–352] minutes vs 120 [0–502] minutes; P <.01). The median (range) stabilization time (153 [60–385] minutes vs 133 [45–505] minutes; P = .04) and age at arrival at the regional unit (504 [191–924] minutes vs 452 [225–1265]) minutes; P = .01) were significantly shorter in the actively cooled group. Only 39% of infants passively cooled were within the target temperature range at arrival to the regional unit compared with 100% actively cooled.

CONCLUSIONS: Servo-controlled active cooling has been shown to improve temperature stability and is associated with a reduction in transfer time.

Source: http://pediatrics.aappublications.org

Narrow-Spectrum Antibiotics Effective for Pediatric Pneumonia.


Narrow-spectrum antibiotics have similar efficacy and cost-effectiveness as broad-spectrum antibiotics in the treatment of pediatric community-acquired pneumonia (CAP), according to the findings of a retrospective study.

Derek J Williams, MD, MPH, from Vanderbilt University School of Medicine in Nashville, Tennessee, and colleagues published their findings online October 28 in Pediatrics.

“The 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America…guideline for the management of children with [CAP] recommends narrow-spectrum antimicrobial therapy for most hospitalized children,” the authors write. “Nevertheless, few studies have directly compared the effectiveness of narrow-spectrum agents to the broader spectrum third-generation cephalosporins commonly used among hospitalized children with CAP.”

Therefore, the researchers used the Pediatric Health Information System database to assess the hospital length of stay (LOS) and associated healthcare costs of children aged 6 months to 18 years who were diagnosed with pneumonia between July 2005 and June 2011 and treated with either narrow-spectrum or broad-spectrum antibiotics. The authors excluded children with potentially severe pneumonia, those at risk for healthcare-associated infections, and those with mild disease requiring less than 2 days of hospitalization.

Narrow-spectrum therapy consisted of the exclusive use of penicillin or ampicillin, whereas broad-spectrum treatment was defined as the exclusive use of parenteral ceftriaxone or cefotaxime.

The median LOS for the entire study population (n = 15,564) was 3 days (interquartile range, 3 – 4 days), and LOS was not significantly different between the narrow-spectrum and broad-spectrum treatment groups (adjusted difference [aD], 0.12 days; P = .11), after adjustments for covariates including age, sex, and ethnicity.

Similarly, the investigators found no differences in the proportion of children requiring intensive care unit admission in the first 2 days of hospitalization (adjusted odds ratio [aOR], 0.85; 95% CI, 0.25 – 2.73) or hospital readmission within 14 days (aOR, 0.85; 95% CI, 0.45 – 1.63) were noted between the groups.

Narrow-spectrum treatment was also linked to a similar cost of hospitalization (aD, −$14.4; 95% CI, −$177.1 to $148.3) and cost per episode of illness (aD, −$18.6; 95% CI, −$194 to $156.9) as broad-spectrum therapy.

The researchers note that the limitations of the study were mostly related to its retrospective nature, including potential confounding by indication, the absence of etiologic and other clinical data, and a relative lack of objective outcome measures.

“Clinical outcomes and costs for children hospitalized with CAP are not different when empirical treatment is with narrow-spectrum compared with broad-spectrum therapy,” the authors write. “Programs promoting guideline implementation and targeting judicious antibiotic selection for CAP are needed to optimize management of childhood CAP in the United States.”

Major Bleed Risk Falls with Bivalirudin vs Heparin en Route to PCI for STEMI: EUROMAX.


The 30-day risk of death or major bleeding fell significantly in ST-elevation MI (STEMI) patients treated with bivalirudin (Angiomax, the Medicines Company) compared with heparin-based management, both initiated prior to arrival at a hospital for primary PCI, in a large randomized but open-label study[1].

The bivalirudin benefit for that composite end point in the European Ambulance Acute Coronary Syndrome Angiography(EUROMAX) trial was driven by a significant drop in major bleeding, the definition of which excluded bleeding related to CABG surgery.

The heparin-based strategy consisted of either unfractionated heparin (UFH) or the low-molecular-weight heparin enoxaparin(Lovenox, Sanofi). Both groups could receive a GP IIb/IIIa inhibitor provisionally.

EUROMAX was published today in the New England Journal of Medicine with lead author Dr Philippe Gabriel Steg (Hôpital Bichat, Paris, France) to coincide with his presentation of the trial here at TCT 2013 .

http://img.medscape.com/news/2013/ih_131030_Steg_Philippe_Gabriel_TCT2013_120x156.jpg

Dr Philippe Gabriel Steg

Bivalirudin’s 40% primary-end-point relative risk reduction included a >50% drop in risk for non-CABG major bleeding. On the other hand, the relative risk of stent thrombosis with bivalirudin was nearly threefold what was seen in the heparin group, although absolute rates were very low.

At a media briefing on the trial, Steg said the excess stent thromboses with bivalirudin were driven by events in the acute phase, within 24 hours of PCI. And, he observed, they didn’t translate into more reinfarctions or ischemia-driven revascularization.

Still, “acute stent thrombosis . . . while rarely fatal and not outweighing the advantages of bivalirudin, is the only troubling issue with bivalirudin in STEMI, and we do need strategies to reduce this complication,” according to Dr Gregg W Stone (New York-Presbyterian Hospital/Columbia University Medical Center New York, NY), the assigned discussant following Steg’s formal presentation of EUROMAX.

Shades of HORIZONS AMI

The trial’s findings are reminiscent of the HORIZONS AMI trial 30-day outcomes reported about six years ago and covered then by heartwire . That trial, Steg et al observe, preceded some important changes in STEMI management and PCI technique that likely affected bleeding risk, changes that were a part of EUROMAX. These included the expansion of radial-artery PCI access, newer antiplatelet agents, reduced GP-IIb/IIIa-inhibitor use, and progressively earlier initiation of IV anticoagulants.

In the >3600-patient HORIZONS AMI, anticoagulation wasn’t started early during transport. But both it and EUROMAX with its nearly 2200 patients saw a decreased bleeding risk and increased stent-thrombosis risk with bivalirudin compared with heparin. But in contrast to EUROMAX, the earlier trial also showed a reduced risk of cardiac death in bivalirudin patients.

The two studies taken together have more to say than either alone. “I think the results of EUROMAX will heavily impact clinical use of bivalirudin in Europe,” Steg said to heartwire . “The results are very consistent wih HORIZONS AMI, even to the point of the stent-thrombosis signal” and are “reassuring enough to embrace [bivalirudin] in the prehospital setting.” That is, he added, “If you want to. [The EUROMAX results] are not mind-blowing because we don’t see a mortality reduction. But they suggest that the benefits seen in HORIZONS AMI can be extended to the contemporary prehospital setting. “

At the media briefing, Dr Bernard Gersh (Mayo Clinic, Rochester, MN), who wasn’t involved in the trial, said, “It’s not that often that you see trials that really will change clinical practice, and I think this will.”

The Role of Prehospital Diagnosis and Treatment

Gersh also said, “I’ve never seen really anything that suggests that prehospital administration [of anticoagulants] and [STEMI] diagnosis is not beneficial.”

But whether they are achievable in the field varies by country, even within Europe. Interviewed, Steg pointed out that at most participating centers, there were no physicians in the ambulances. It does take some expertise to interpret the ECGs, unless the tracings can be transmitted to a center for remote reading. But, he said, “It’s been shown in other trials if you have good trained paramedics, they do just as well if not better than physicians.”

Also speaking at the briefing as a EUROMAX observer, Dr Philippe Généreux (NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY) said prehospital STEMI diagnosis and treatment initiation could make the most difference in countries like Canada, “where there aren’t cath labs on every corner” and it might take 45 to 60 minutes for an ambulance to reach a PCI center.

Prospects for prehospital management in the US seem more remote, observers agreed. Dr James B Hermiller, Jr (St Vincent Hospital/The Heart Center of Indiana, Indianapolis,) said at the briefing, “The barrier to this in the US is very great. It’s difficult just to  get ECGs in the field, let alone administer anticoagulants, but we need to get there because this is very important.”

The Open-Label Randomization

EUROMAX randomized patients at centers in nine European countries presenting within 12 hours of onset of symptoms from electrocardiographically defined STEMI, on an open-label basis, to the bivalirudin or heparin strategies. Treatment was initiated in the ambulance or at a non-PCI hospital with subsequent transport to a PCI center.

For the 1089 patients who received bivalirudin, the drug was started as a 0.75-mg/kg bolus followed by an infusion of 1.75 mg/kg/h continued for at least four hours after PCI. The 1109 control patients received UFH at either 100 IU/g or 60 IU/kg with a GP IIb/IIIa inhibitor or were allowed to have enoxaparin at 0.5 mg/kg. Adjuvant GP IIb/IIIa inhibitors were allowed at physicians’ discretion. All patients received aspirin plus a P2Y12 inhibitor.

Relative Risk (95% CI) for Outcomes, Bivalirudin vs Heparin Strategies for STEMI Initiated During Emergency Transport to Primary PCI

End points

RR (95% CI)

p

30-day death from any cause or non-CABG major bleedinga

0.60 (0.43–0.82)

0.001

30-day death from any cause, reinfarction, or non-CABG major bleeding

0.72 (0.54–0.96)

0.02

Non-CABG major bleeding

0.43 (0.28–0.66)

<0.001

Major bleeding (TIMI definition)

0.62 (0.32–1.20)

0.15

Severe or life-threatening bleeding (GUSTO definition)

0.61 (0.22–1.68)

0.33

Definite stent thrombosisb

2.89 (1.14–7.29)

0.02

a. Primary end point 
b. Academic Research Consortium criteria

No significant differences were seen at 30 days for the composite of death, reinfarction, ischemia-driven revascularization, or stroke, or for any stroke or ischemic stroke. A committee blinded to treatment assignment adjudicated bleeding episodes and clinical events.

As discussant, Stone pointed out that PCI via the radial artery, rather than the femoral artery, was done in only 6% of cases in HORIZONS AMI but in 47% of EUROMAX patients. Some predicted that the greater proportion of radial procedures would lead to a much lower major bleeding rate and make it hard for bivalirudin to show an effect. A EUROMAX subgroup analysis found, however, that the benefits of bivalirudin over the heparin-based strategy were consistent for different kinds of patients, including whether their PCI was by the radial or femoral routes.

“Therefore, bivalirudin is beneficial regardless of the access site, and this is because most bleeding in the STEMI and ACS setting is not access-site related,” he said. It’s the non–access-site bleeds to pose the greater threat to later outcomes. So, he said, “the advantages of bivalirudin are present in patients undergoing radial as well as femoral intervention, and radialists should pay attention to this.”

Stone said EUROMAX raises the question of whether using cangrelor (the Medicines Company) as part of the accompanying antiplatelet therapy might help prevent stent thrombosis with bivalirudin, and that’s being addressed in HORIZONS-AMI-2, which is starting soon.

Many Children Killed by Influenza Were Not High Risk.


Nearly half of pediatric influenza deaths occur in otherwise healthy children, according to an 8-year Centers for Disease Control and Prevention study published online October 28 in Pediatrics.

“[T]hese data, which reveal that any child can be at risk of influenza-associated death regardless of age or high-risk medical conditions, support the recommendation that all children ≥6 months of age receive annual vaccination,” Karen K. Wong, MD, MPH, from the Epidemic Intelligence Service assigned to the Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, and colleagues write. They note that the national coverage rate (52% in 2011-2012) remains far below the Healthy People 2010 objective of 80%.

The investigators reviewed data for 830 pediatric influenza-related deaths that occurred between October 2004 and September 2012. Of the 794 children with an available medical record, 341 (43%) had no high-risk medical conditions such as neurologic disorders, asthma, or diseases of the heart, kidney, liver, or immune system, and 453 (57%) did. Among the entire study population, the median age of death was 7 years (interquartile range [IQR], 1 – 12 years), with 35% of cases occurring before hospital admission.

As expected, the study data confirmed the increased risk for complications, including mortality, among children with comorbidities: 33% of high-risk deaths occurred in children with neurologic disorders, and 12% had genetic or chromosomal disorders.

However, researchers also found that otherwise healthy children were almost twice as likely to die before hospital admission as their high-risk counterparts (relative risk [RR], 1.9; 95% confidence interval [CI], 1.6 – 2.4) and were 1.6 times more likely to die within 3 days of symptom onset (95% CI, 1.3 – 2.0).Although the cause remains unclear, a doubled prevalence of bacterial coinfection may have factored in the observed acceleration of clinical course (relative risk [RR], 2.0; 95% CI, 1.5 – 2.5), the authors write.

Otherwise healthy children were also more likely to be younger than 5 years (RR, 1.3; 95% CI, 1.1 – 1.6; P < .001), with a median age of 5 years (interquartile range [IQR], 1 – 11 years), compared with 8 years (IQR, 3 – 13 years) in the high-risk group.

According to the authors, the findings underscore the need for clinicians to be more aggressive with antiviral therapy.

“[I]influenza antiviral medications can reduce the severity of illness and complications associated with influenza virus infection…. [H]owever, antiviral treatment was reported in less than half of the children who died during the 2010-2011 and 2011-2012 seasons in this study,” the authors point out.

Children with signs or symptoms of severe or progressive illness and those who are hospitalized should be started on antivirals without waiting for laboratory results, even if they have no other risk factors for influenza-related complications, the authors write. Oseltamivir can be used in infants as young as 2 weeks, they note. In addition, antivirals are recommended regardless of illness severity for children younger than 2 years and for those with high-risk medical conditions.

“The potential for severe outcomes from influenza should be recognized in all children, both those with conditions that place them at higher risk of influenza-associated complications as well as healthy children,” the authors conclude.

Add-on Eslicarbazepine Reduces Partial-Onset Seizures.


Once-daily adjunctive therapy with eslicarbazepine significantly reduced the frequency of partial-onset seizures in adult patients compared with adding a placebo, and the effect was sustained out to 1 year. In an analysis of pooled data from 3 phase-3 pivotal trials, doses of 800 mg and 1200 mg were well tolerated.

Eslicarbazepine is an oral drug that stabilizes the inactive state of voltage-gated sodium channels and blocks T-type voltage-gated calcium channels.

Patrício Soares-da-Silva, MD, PhD, head of research and development at BIAL in S. Mamede do Coronado, Portugal, the developer of the drug, presented trial results here at the XXI World Congress of Neurology (WCN).

The 3 trials had slight variations in protocols, but in general involved an 8-week observation or single-blind drug period, 2 weeks of drug titration depending on dose, a 12-week double-blind maintenance period, 4 weeks of tapering of the drug or not, and an open-label extension period. Two trials (BIA-2093-301 and 302) tested the drug at 400 mg, 800 mg, or 1200 mg daily or placebo for the maintenance period, with about 100 patients in each group. Trial BIA-2093-303 dropped the 400-mg dose (about 84 patients per group).

The pooled groups were well matched for mean age (about 37 years), sex (half were men), seizure types, duration of epilepsy (22 years), and the number of concomitant antiepileptic drugs (AEDs) they were taking. About 70% of patients in each group were receiving 2 other AEDs besides the trial drug.

Dr. Soares-da-Silva said that eslicarbazepine significantly reduced the seizure frequency in each 4-week period of the 12-week double-blind maintenance phase from 8.17 ± 0.034 with placebo (n = 279) to 6.24 ± 0.034 with 800 mg (n = 262) and to 5.95 ± 0.035 with 1200 mg (n = 253) (both P < .001 vs placebo), the primary endpoint of the trials.

The responder rate, defined as a 50% or greater reduction in seizure frequency over the 12-week period, rose from 21.5% with placebo to 36.3% with 800 mg of eslicarbazepine and 43.5% with 1200 mg.

Positive Results Continue to 1 Year

Of 857 patients completing the double-blind period, 833 entered the open-label extension phase, and 612 (73.5%) completed the full year, with a median daily dose of 800 mg. The maximum allowed dose was 1200 mg.

The drug maintained its efficacy during the open-label extension period and showed a slight rise in both the responder rate and the proportion of patients free of seizures.

Table. Eslicarbazepine Efficacy During 1-year Extension Period*

Time Period

Responder Rate (%)

Proportion of Seizure-Free Patients (%)

Weeks 5 to 16

46.1

6.3

Weeks 17 to 28

47.0

9.4

Weeks 29 to 40

48.2

10.1

Weeks 41 to 52

50.1

13.6

*Median eslicarbazepine dose was 800 mg.

 

Treatment with adjunctive eslicarbazepine was associated with improvements in mood and quality of life, as assessed by QOLIE-31 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Whether patients had mild, moderate, or severe symptoms, all those who improved had improved significantly at the final assessment compared with baseline (all P < .001).

On the basis of the results of the pivotal trials, Dr. Soares-da-Silva said the European Medicines Agency approved eslicarbazepine for use in Europe as adjunctive therapy for adults with partial-onset seizures. It has not been approved in the United States, but he noted it is now undergoing trials in the United States as monotherapy.

Monotherapy Trials

Topline results of 2 phase 3 monotherapy trials of eslicarbazepine were just reported by Sunovion Pharmaceuticals. In both trials the drug met the primary endpoints.

Treatment was well tolerated and demonstrated seizure control rates superior to those among historical controls in adult patients with partial-onset seizures with or without secondary generalization who were not well controlled with current antiepileptic drugs, a statement from Sunovion released September 17 notes.

The agent is under review by the US Food and Drug Administration (FDA) as a once-daily adjunctive therapy for partial-onset seizures in patients aged 18 years or older with epilepsy.

“Pending the outcome of FDA review of the current New Drug Application (NDA) resubmission for eslicarbazepine acetate as an adjunctive treatment, Sunovion plans to submit these data as part of a supplemental NDA in support of a monotherapy indication,” Fred Grossman, DO, senior vice president, clinical development and medical affairs at Sunovion, said in the company’s statement.

The phase 3 studies, dubbed 093-045 and 093-046, were double-blind, historical-controlled, randomized trials with identical designs. Study 093-045 included 193 patients from 67 study centers in North America, and study 093-046 included 172 patients from 41 centers in 5 countries.

The primary endpoint of both studies was the proportion of patients meeting predefined exit criteria, “signifying worsening seizure control,” the statement notes, 16 weeks after titration compared with historical controls.

In both studies, adults with partial-onset seizures that were not well controlled, defined as 4 or more partial-onset seizures in the 8 weeks before screening and no 4-week seizure-free period, with 1 to 2 AEDs, were gradually converted to monotherapy treatment with eslicarbazepine. They were then randomly assigned in a 1:2 ratio to receive 1200 or 1600 mg of eslicarbazepine daily.

Detailed results from the 2 monotherapy studies will be presented at upcoming scientific meetings, the company notes.

Difference Debated?

Asked to comment about what eslicarbazepine may add to the AED armamentarium as adjunctive therapy, session chair Reeta Kälviäinen, MD, from the Kuopio Epilepsy Center, and professor of clinical epileptology at the University of Eastern Finland in Kupio, told Medscape Medical News that it is something of a debate at the moment whether eslicarbazepine differs significantly from oxcarbazepine.

“It’s a metabolite of oxcarbazepine, and we think at the moment that it might have a little bit less adverse effects than oxcarbazepine, less hyponatremia and less idiosynchrous reactions,” she said. “And we hope that therefore it would be better tolerated, perhaps as carbamazepine, as effective as oxcarbazepine, and then you can dose it once daily, which is a benefit.”

She said that she was “a little bit disappointed” that the study did not show which AEDs eslicarbazepine might be best used with but that current studies and clinical practice may reveal the better combinations. But for now, “definitely you shouldn’t add it on top of other sodium channel blockers. That’s not the way to use it,” because of additive adverse effects.

Similarly, if a patient has problems while receiving carbamazepine or oxcarbazepine, switching to eslicarbazepine would be a bad idea. “It’s nearly the same drug, so that’s a dangerous situation. So that’s a contraindication,” Dr. Kälviäinen noted. She said clinicians are now “a little bit mixed up” in choosing among these similar drugs, and clearer studies on the differences among them are needed.

Otto Muzik, PhD, a professor of radiology and pediatrics at Wayne State Medical School in Detroit, Michigan, questioned the value of adding another drug in this same class.

“It’s still not approved in the States, and it appears to me that the FDA does not believe that there is added value,” he mentioned to Medscape Medical News. “So that means that…it’s probably going to do better than a placebo, but if you now say, ‘Give me the best combined therapy of drugs,’ and now we throw in this new drug, is it more efficacious or not, and the jury seems to be still out on that.”

Too Much Information? Geneticist Mark Robson Discusses Accidental Genetic Findings.


Genetic testing of tumors is becoming increasingly common in cancer care. The molecular alterations found in a tumor can provide critical information for making an accurate diagnosis and determining the best treatment.

Although current clinical testing usually focuses on a panel of specific mutations, cancer centers are developing programs to analyze entire cancer genomes routinely — an approach made possible by cheaper sequencing costs — in order to individualize care. This process raises a thorny issue: What happens when a genome analysis of a person’s tumor reveals that he or she is at risk for developing a different type of cancer or other disease?

Recently, Memorial Sloan-Kettering Clinical Genetics Service Chief Kenneth Offit, Clinical Genetics Service Clinic Director Mark E. Robson, and researcher Yvonne Bombardpublished a viewpoint in the Journal of the American Medical Association regarding this question of incidental genetic findings, which cancer researchers have dubbed the “incidentalome.”

We asked Dr. Robson to discuss some of the issues surrounding accidental genetic findings and what Memorial Sloan-Kettering is doing to address them.

What is an example of a genetic variation that might be discovered by accident while sequencing the genome of a patient’s tumor?

For instance, you could be sequencing a lung cancer tumor in search of an EGFR mutation to target with an anticancer drug, and find a mutation in BRCA1, which is associated with increased risk for breast and ovarian cancer. Since most of a tumor’s DNA sequence is identical to the sequence of a normal cell from that same patient, this additional variation is probably inherited — and is what is called a germline mutation.

In that situation, are you obligated to inform the patient? It’s a very complex question. There are many variables to consider, such as individual preference, whether anything can be done to control risk, and whether other people — such as close relatives — may be affected.

Has this actually become a problem for doctors and researchers, or is it still a hypothetical situation for now?

Right now, most clinical testing of tumors is for a relatively limited number of specific mutations, not the full genome. But soon we’re going to be testing for a much broader panel of genes, increasing the chances of incidental findings.

On the research side, it’s quickly becoming an issue. Many tumor samples that have been stored in tissue banks for years or decades are now being fully sequenced. If incidental discoveries are made during that process, is there an obligation to try to find those patients and inform them? This has not been established, and there are obvious practical barriers. We need to lay the intellectual groundwork now for how we’re going to respond to these questions.

What steps have been taken at Memorial Sloan-Kettering to address the issue?

This summer, our Institutional Review Board (IRB), which oversees all of our patient-related research, updated part of our patient consent policy. When patients agree to have a tissue sample taken, they are asked whether they are open to being re-contacted if an investigator finds something that might affect their health.

Under the new procedure, if a researcher finds something that might be important to communicate to the patient, the specific question will be put before the IRB and carefully considered. If there is agreement the information should be conveyed, and the patient has indicated that he or she wants to be re-contacted, we’ll reach out to that person. We think this protects the people participating in our studies without restricting important research.

With all the genetic research taking place at Memorial Sloan-Kettering, is the IRB facing a deluge of these cases?

So far, no. The way the analyses are being conducted is that the computer looks for mutations in specific spots and subtracts all other information about the inherited genetic sequence before the investigator sees it. In other words, if you have genetic variants present in the tumor that are also in the normal cells, they are being filtered out by the software. The investigator ends up seeing variants that are only in the tumor.

As we pointed out in the JAMA paper, this is one way of limiting potential incidentalome issues.

But some researchers don’t have the germline DNA sequence available for comparison purposes, so while sequencing the tumor they see potentially relevant variations. For example, they could be sequencing a prostate cancer genome and see a mutation in theBRCA1 gene, which increases risk of other cancers.

The question becomes, under what circumstances do you tell the patient, and what about the patient’s siblings or children who may carry the mutation as well? In addition, sometimes multiple variants associated with disease risk may be found — and how do we provide counseling for all of them at once?

Have you gotten a sense from patients about what their preference usually is regarding being informed of these incidental genetic discoveries?

Commonly, people say, “I want to know everything,” but the devil’s in the details when you start considering the risk for diseases that can’t be prevented or treated. We are setting up focus groups of patients and unaffected people to try to understand how people think when they are confronted with these situations and how they prioritize different types of genetic information. We also have an active IRB protocol in which we are giving people who had their sequence determined as part of research studies the opportunity to learn their results.

Right now, it’s not clear what the dividing lines are. We want to reach a point where mutations are sorted into different categories, where certain incidental findings are nearly always appropriate to communicate to patients, others almost never so, and some require more context to determine.

We’re moving from the traditional model of asking patients if they would like to hear the results of a specific test before that test is performed, to this brave new world where we’re trying to help people make decisions about genetic information revealed by accident that is not possible to fully anticipate. It’s a very complicated issue, but it also offers a tremendous opportunity to benefit patients.

If you are interested in participating in the focus group, call 646-888-4867. Everyone is welcome, including patients, relatives, Memorial Sloan-Kettering employees, and the general public. No sequencing is provided.

Source: MSKCC

 

 

 

Florbetapir Approved: Now How Do We Use It?


April 19, 2012 — Florbetapir (Amyvid, Eli Lilly/Avid Radiopharmaceuticals), a new agent to detect beta-amyloid plaques in living patients with possible Alzheimer’s disease (AD), has just been approved by the US Food and Drug Administration (FDA). The question now is how this imaging option will be used in practice.

Although they are for the most part enthusiastically awaiting access to this new agent, expected to be available by June, many neurologists are also striking a cautionary note. Cost, availability, the need for expert interpretation of scans using the florbetapir tracer, and what it really means for a diagnosis of AD are a few of the concerns being raised.

Medscape Medical News polled experts in the field of AD to see how they view the approval and how they see this diagnostic tool may fit into their clinical practice.

Diagnostic Dilemmas

Florbetapir is a diagnostic agent tagged with a radioisotope, fluorine-18. Used with positron emission tomography (PET), it binds to amyloid plaques in the brain. Approved by the FDA on April 9, florbetapir is 1 of 3 imaging agents in various stages of development; others are florbetaben (Bayer/Piramal Imaging SA) and flutemetamol (GE Healthcare). All are reported to detect amyloid deposition in the living brain.

 
 

Although the presence of amyloid on the scan doesn’t necessarily mean the patient has AD, a scan showing little amyloid deposition, “is inconsistent with a neuropathological diagnosis,” of AD, a press release from the company at the time of approval notes. The statement added that the safety and effectiveness of florbetapir have not been established for predicting development of dementia or other neurologic conditions, or for monitoring responses to therapies.

Still, the use of florbetapir may clear up some diagnostic dilemmas, said Sandra Black, MD, professor, Department of Medicine, Division of Neurology, University of Toronto, Ontario, Canada. “It might help in situations where you’re not quite sure what’s going on — when you don’t know whether this is aphasia due to AD or a frontal temporal dementia-type thing.”

Pedro Rosa-Neto, MD, assistant professor, neurology, neurosurgery and psychiatry, McGill University, Montreal, Quebec, Canada, felt that the new tracer could be informative in the investigation of patients with early onset or atypical presentations of dementia to rule out AD, and in cases of rapidly progressive dementia.

“Rapidly progressive Alzheimer’s disease is a highly neglected condition, frequently misdiagnosed as Creutzfeldt-Jakob disease,” Dr. Rosa-Neto noted. For these selected cases, he sees PET using florbetapir adding to the information gained from the clinical history, various magnetic resonance imaging (MRI) modalities, including fluid-attenuated inversion recovery and diffusion-weighted imaging, cerebrospinal fluid sampling, and neuropsychological and genetic evaluations.

Although the tracer could be of assistance in patients with dementia in whom it’s unclear whether amyloid is a cause of cognitive deterioration, it would not be as useful an addition in cases where all clinical, cognitive, and imaging findings strongly point to the presence of AD, said Liana Apostolova, MD, Alzheimer’s Disease Research Center, University of California, Los Angeles.

“While the test could be useful to confirm that presumption, dementia specialists can already diagnose AD under these circumstances with high sensitivity,” she said. “This is when I might say, ‘I’m pretty certain what’s going on at this point; I don’t need to subject the patient to this expensive diagnostic procedure.”

Role in Mild Cognitive Impairment?

Some clinicians agreed that there is a place for the new biomarker in patients with mild cognitive impairment (MCI). Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, Rochester, Minnesota, credited with developing the concept of MCI, said the tracer “will be helpful” to see whether amyloid can explain memory problems experienced by these patients. “It will not make the diagnosis, but it will help the clinician sort out the cause of the symptoms.”

Dr. Petersen pointed out that many patients with MCI — perhaps up to 40% — don’t have AD as the underlying cause of their cognitive problems.

For Steven T. DeKosky, MD, vice president and dean, University of Virginia School of Medicine, Charlottesville, the new biomarker “seems like a reasonably accurate detector” of whether MCI is AD in development or whether it relates to some other cause.

Other physicians said they wanted to avoid using the new tracer in cases of MCI.

“Although I think a positive amyloid imaging study would increase the likelihood that the person will decline, that is not known for certain,” said David Knopman, MD, Department of Neurology, also at Mayo Clinic Rochester, Minnesota. “So, I would definitely not do an amyloid scan routinely.”

Doctors stressed that a positive scan does not necessarily mean an asymptomatic patient will develop AD. “Many cognitively normal elderly will show amyloid deposition in their brains as the disease is believed to have an asymptomatic stage that lasts up to 20 years,” pointed out Dr. Apostolova.

“I don’t think we know enough about the prognostic factors of a positive amyloid scan,” said Adam S. Fleisher MD, director of brain imaging, Banner Alzheimer Institute, Phoenix, Arizona, during a Web-based debate on the role of neuroimaging in the diagnosis of AD earlier this year.

On the other hand, a negative scan may not mean a patient is out of the woods because there could be another explanation for their cognitive problems, such as vascular dementia.

“We will have to be very careful using amyloid imaging and making sure patients understand that a negative scan is not necessarily a cause to celebrate,” said James B. Brewer, MD, PhD, associate professor, radiology and neurosciences, Human Memory Laboratory, University of California at San Diego, who also participated in the Webinar.

Possible other causes of cognitive decline could include stroke, thyroid problems, drug interactions, chronic alcoholism, and vitamin deficiencies. Psychiatric disorders such as depression can masquerade as dementia as well.

The Alzheimer’s Association acknowledged that FDA approval of florbetapir is a “double-edged sword,” although it supports the move.

…the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm.

In a statement, the Association said that although the approval will expand the clinical and research opportunities for amyloid imaging, “the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm.” Additional research is needed to clarify the role of florbetapir-PET imaging in Alzheimer’s, it added.

Worried Well

Physicians weighing in agreed that amyloid measurements alone are not enough — that other imaging tests, including MRI, should also be part of the diagnostic equation. Many talked about the “multi-modal use” of this and other emerging amyloid biomarkers.

And, as Dr. Brewer pointed out, the new amyloid tracer does not measure tau, which some experts believe plays a crucial role in AD. Another agent under development by researchers at the University of California, Los Angeles, called FDDNP, images both tau and amyloid on PET.

All doctors also emphasized the importance of patient counseling before ordering an amyloid test.

“You have to have a good understanding of how that’s going to influence discussions with the patient, and your treatment and prognostic decision-making,” said Dr. Fleisher. He added that the test results could be quite anxiety provoking for a patient.

Doctors who spoke to Medscape Medical News also expressed a concern about “direct to patient” advertising and about “worried well” patients asking for this test. Many called for caution about using this new biomarker in cognitively normal patients who are anxious about their amyloid status.

The Alzheimer’s Association, too, warns of “less than scrupulous” imaging operators who make unrealistic promises to such patients about the value of florbetapir imaging. It recommends that the test be accessible only in the context of a complete evaluation of medical/neurologic status and with appropriate expert consultation.

Cost Issues

Cost may be a significant issue in determining whom to scan using this new biomarker, doctors agreed. The price tag for the radioactive compound alone appears to be in the neighborhood of $1600, said Dr. Apostolova.

“Then there will be the added cost of getting the PET scan which in most places will be between $1000 and $1500. So I think we are looking at a cost of about $2500 to $3000 per scan here.”

Because the tracer will be costly, “we have to use it with caution and only when it’s really necessary,’ said Dr. Apostolova, “Is it going to tell me anything beyond what I already know?”

As for insurance coverage, Dr. Petersen said that it’s unclear at this time who will pay for this new agent when it becomes available in June. Dr. Knopman commented that that “to start with, no insurer will pay for it.” The agent is also not currently eligible for coverage by the Centers for Medicare and Medicaid Services (CMS) because of its specific policy on reimbursement for PET procedures.

During a press conference after approval of the agent, Stephanie Prodouz, manager of Eli Lilly Bio-Medicines Communications, said that, “Although Amyvid will not be eligible for coverage, it’s important to note that Lilly is working with a broad group of stakeholders to explore and collaborate with CMS to find a new policy for PET coverage.”

Treatment Lacking

Although there is palpable excitement among some neurologists about the diagnostic possibilities of this new tracer, their enthusiasm is also tempered by the lack of available AD treatments.

“From a scientific viewpoint, the development of amyloid imaging was huge [but] the commercial availability is less so, unless it can be tied to finding better therapeutics,” said Dr. Knopman. “Until there are better therapeutics for AD, amyloid imaging does not change the landscape in clinical practice.”

Until there are better therapeutics for AD, amyloid imaging does not change the landscape in clinical practice.

But new treatments are on the horizon, according to Marwan Sabbagh, MD, director, Banner Sun Health Research institute, Sun City, Arizona. “Later this year, you will see 2 large immunotherapy studies — bapineuzumab and solanezumab — reporting their data to the world on their phase 3 trials, so the game changing elements here are perfectly timed in anticipation of these potential disease modifying agents.”

Bapineuzumab and solanezumab are both monoclonal antibodies that bind to and clear beta amyloid. Dr. Sabbagh is an investigator on both trials and serves on the steering committee for the bapineuzumab study.

Still, it’s unclear what role the amyloid plays and whether clearing it will result in any change in cognitive status. However, if safe and effective treatments become available, “that changes the whole ball game,” commented Dr. Brewer.

Dr. Apostolova agreed. “If we can find an agent that can halt the disease progression, before symptoms occur, this [florbetapir] will become the single most useful diagnostic and prognostic test out there,” she added.

For his part, Dr. DeKosky said that if an effective AD drug were available, the amyloid test could be used not necessarily to rule out AD but to determine that the cognitive impairment a patient experiences is indeed AD, so that drug could be administered.

Still, even in the absence of more effective amyloid treatments, many doctors felt that the test could nevertheless be useful. For example, said Dr. Brewer, it provides physicians with an opportunity to educate patients, help them manage risk factors and perhaps get them enrolled in a clinical trial.

As well, said Dr. Apostolova, the test results may spur patients to make necessary work-related arrangements or put their personal affairs in order. “Knowledge is power,” she said.

Clinical Studies

According to Eli Lilly, the information on scans using the new tracer correlates highly with what is seen on autopsy. In a study that used the majority interpretation of 5 readers, there were 96% sensitivity and 100% specificity in patients who underwent scanning within a year of death.

Dr. Black called this autopsy correlation research “elegant.” “It showed that indeed they were really picking up the amyloid” prior to death in these patients, she said.

The clinical studies also showed that the new diagnostic tracer appears to be very safe. The most common adverse reactions reported in these trials were headache (1.8%), musculoskeletal pain (0.8%), fatigue (0.6%), nausea (0.6%), anxiety (0.4%), back pain (0.4%), increased blood pressure (0.4%), claustrophobia (0.4%), feeling cold (0.4%), insomnia (0.4%), and neck pain (0.4%).

The studies are outlined in more detail in the product prescribing information.

But although the new imaging agent is safe and promises to be helpful diagnostically, training of interpreters will be key. Florbetapir was approved only with the proviso that Eli Lilly improve education initiatives for readers of the images. In January 2011, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 13 to 3 against recommending approval for the tracer, but in a second unofficial vote, the committee voted 16 to 0 in favor of approval if the company would agree to structured training for those reading the scans.

“There was a fear that radiologists would not know how to interpret the scans, as well as a concern about what would be an appropriate use of this agent,” said Dr. Black.

After working with the FDA and nuclear medicine experts, Eli Lilly developed both an online and an in-person training program for physicians. According to the company, images should be interpreted only by readers who have successfully completed a training course. The company cautions that errors may occur in the estimation of plaque density during image interpretation.

“This is a new kid on the block; it’s a new technique” that requires training, commented Dr. Apostolova, who carries out imaging research. “It’s not the case that one day, all of a sudden, one’s brain’s tissue becomes full of amyloid. It’s a slow protracted continuous build up.”

Patients will fall on a continuum, with some having minimal amyloid binding and others moderate or severe amounts, she added. “The last ones would be the easiest to call, but there will be many intermediate cases where we have to decide on a threshold that we will be using to call a scan positive versus calling it negative.”

Not Straightforward

The lack of familiarity in reading scans could pose “a big problem” for clinicians since “it’s not straightforward,” commented Dr. Petersen.

Dr. Knopman agreed, saying he’s “very concerned” about the scan interpretation issues. “I am dubious that radiologists who don’t do a lot of them will misinterpret them,” he said. “Even after nuclear medicine physicians have taken the course provided by Lilly, if they have low instances of contact with the test, they are likely to make mistakes in interpretation.”

He added that he’s particularly worried about the risk for overdiagnosis of Alzheimer’s, especially when the amyloid imaging is not interpreted in light of the clinical history.

“For example, up to 30% of cognitively normal people over age 70 years are expected to have a ‘positive’ scan,” he said. “I’m worried that a normalperson will hear that their amyloid scan shows ‘Alzheimer’s disease’ and will conclude that they have the disease and are at imminent risk of losing their memories. In fact, an abnormal amyloid scan should be interpreted as showing amyloidosis, not Alzheimer’s.”

Dr. Black said her “hunch” is that florbetapir will be more likely to be used in specialty memory clinics that have access to experts who can properly interpret the scans than in general family practices.

Longer Half-Life

One of the advantages of the new agent is its versatility. Florbetapir has a half-life of almost 2 hours, compared to a half-life of 20 minutes for the currently available amyloid imaging agent, carbon 11–labeled Pittsburgh compound B (C-PiB).

The discovery of PiB was truly ground-breaking and set the stage for the current series of amyloid tracers now hitting the market, said Dr. DeKosky, who led the clinical trials of PiB.

“PiB was 7 years ahead of all these others,” he said. “We were able to find a way to non-invasively detect amyloid in living people harmlessly, and then several people found a way to develop different compounds. They are all to be congratulated, but the first one is always the one for which there’s romance,” he says wryly.

But because even florbetapir still loses over half of its radioactivity every 2 hours, it must be distributed in a timely fashion from a radiopharmacy to an imaging center. To address this problem, Siemens PETNET Solutions, a subsidiary of Siemens Medical Solutions USA Inc, announced last week a manufacturing and distribution agreement with Eli Lilly.

Beginning in June, Siemens will supply florbetapir to imaging centers in limited US markets. By the end of the year, the company anticipates having 25 manufacturing centers and co-located radiopharmacies offering the compound.

Dr. Apostolova pointed out that to administer florbetapir, a center must also have a PET scanner. In addition to the manufacturing and distribution of florbetapir, Siemens announced its new Biograph mCT PET/CT (computed tomography) scanner, and related software.

Many neurologists said they have faith that the distribution network used by Lilly/Avid will make the agent widely available to clinicians.

“Now we have PET scanners everywhere, which we didn’t have maybe 7 or 8 years ago,” Dr. Black noted. “And now we have an 18-fluorine compound and there are others that should be emerging soon.”

This widening and promising landscape, she said, “is very exciting.”