April 2010 Archives

Intermission (2003): I believe that Colin Farrell and America got off on the wrong foot. The actor's bad-boy antics could hardly be excused by his clumsy work in Spielberg's Minority Report (2002) or Oliver Stone's Alexander (2004). Dude should have adhered to his Irish roots if In Bruges (2008) and Intermission are any indication. Farrell is vastly better in both Irish films than in any Hollywood vehicle to date.* And he proves himself to be, not a leading man, but an exceptional ensemble player—particularly in Intermission, a 9-plus character jumble of what goes down whan a young couple breaks up.

* With the possible exception of Crazy Heart.

An ungrounded tenet in the practice of neurology is to avoid, if possible, the use of generic antiepileptic drugs (AEDs) in patients with epilepsy. 

The fear: Even small changes in the drug's makeup, from branded pill to unbranded pill and from generic company to generic company, can lead to inconsistent bioavailability, variable drug levels, and, consequently, breakthrough seizures.

A new study published in an advanced online issue of Neurology appears to substantiate the fear; however, caveats are necessary.

Investigators at the University of Arizona examined insurance claims of more than 33,000 continuously treated adults with epilepsy during 6-year period and found that the use of generic AEDs was associated with

1. an increased use of all prescription drugs;
2. higher epilepsy-related medical utilization (ie, hospitalizations, outpatient visits, length of hospital stays); and
3. an increased risk of injury. 

Their findings applied to both clinically stable and unstable patients.

However, in an accompanying editorial, UK neuropsychiatrist Frank Besag warns that an observed association does not indicate causation. Moreover the Arizona study was open and unblinded—an important point, because many physicians and patients have a negative view of generic AEDs. Last epilepsy is known to be a variable and fickle condition; often the cause of seizure breakthrough cannot be identified.

To better answer the question of whether generic AEDs alter the cost of epilepsy care, Besag advocates a study that uses a randomized, double-blind, and double-dummy design (meaning, in both treatment arms, patients take 2 pills, one placebo and one active or 2 placebo pills). He suggests that pharma companies would be motivated to fund such studies, if they believed that their branded AEDs were superior to generic versions.

In the meantime, Besage chastises the Neurology editors for printing the uncontrolled analysis. "It is time for journals to stop publishing open studies and to insist on rigorous scientific studies," he concludes.

First: Donald Trump is "dealing with" Bret Michaels's absence from "The Apprentice" reality show.

[Pause for universal brow mop.]

Second: The latest on the Poison singer is that he's suffered a "minor setback" while hospitalized with a subarachnoid hemorrhage (SAH). The 47-year-old Michaels reportedly has a "lack of sodium," or hyponatremia, reports the BBC News. The cause of Michaels's SAH, which occurred almost 1 week ago, is evidently still unknown.*

Hyponatremia occurs in 10%-30% of patients with SAH, according to the latest AHA guidelines on the management of the condition, and is more common in patients with a poor clinical status or hydrocephalus. The condition appears to be related to the inappropriate urinary excretion of sodium. The major concern with hyponatremia in SAH is that it is associated with reduced intravascular volume, which is linked to cerebral vasospasm (see below).

To reduce the risk of hyponatremia in SAH, the guidelines recommend that large volumes of hypotonic fluids and volume contraction should be avoided. Intensive-care monitoring of the circulatory volume is also advised. When hyponatremia occurs, the administration of hypertonic saline and fludrocortisone (Florinef) is "reasonable" to achieve euvolemia.

Other issues to concern Michaels's treating doctors are cerebral vasospasm and rebleeding—both major contributors to SAH-associated death.

Cerebral vasospasm, seen in 30%-70% of patients with SAH, typically occurs 3-5 days after the initial bleed and gradually resolves during the next 2-4 weeks. The calcium-channel blocker nimodipine (Nimotop; Bayer) has been shown to reduce the risk of poor outcomes associated with post-SAH vasospasm.

Efforts to reduce the risk of rebleeding in SAH include bed rest and the control of circulatory volume and blood pressure to some sort of equilibrium that avoids both hypertension and volume contraction. There are data suggesting that the risk of rebleeding is reduced with an early, short course of antifibrinolytic therapy (Amicar).

Among survivors of SAH, persistent deficits—including cognitive impairment—are common. The 3 strongest predictors of death or disability are impaired consciousness on admission, advancing age, and a large bleed.

AHA = American Heart Association.

* In about 75% of cases, subarachnoid bleeding is caused by a ruptured (eg, berry) cerebral aneurysm; and in about 20% of cases, there is not an identifiable cause. According to a 2006 review, a substantial percentage of the cases with an unidentified bleeding source are defined as idiopathic in nature. The remainder, 5%, are caused by vascular malformations, arterial dissection, sympathomimetic drugs (eg, cocaine, phenylpropanolamine), tumors, or vasculitis. Notably diabetes, which Michaels reportedly has, does not increase the risk of SAH.

From Wikipedia: Horizontal cut of CT image showing hyperdense subarachnoid blood in the basal cistern. To my knowledge, this is not Bret Michaels's scan.

05/06/10 addendum: Although today's FOXNews story of Bret Michaels's release from the hospital makes it sound like the rocker was discharged to home, Michaels was actually released to a physical rehab facility, according to USA Today. The latter story makes a whole lot more sense.

Michaels SAH occurred almost 2 weeks ago, and other than the report of hyponatremia, he did not suffer any of the usual SAH-related complications—like cerebral vasospasm or rebleeding. The cause of Michaels's SAH was evidently never identified, and he apparently has not experienced any significant neurologic deficits. In the setting of being really unlucky, Michaels is a very, very lucky guy. So is Donald Trump, who must be peeing himself, given the possibility that Michaels may rejoin "The Apprentice." 

From heartwire: Reported ambivalence about enrolling patients in the TIDE trial, a head-to-head study of rosiglitazone (Avandia; GSK) and pioglitazone (Actos; Takeda) in patients with type 2 diabetes, endangers the assessment of vitamin D supplementation.

That's because the GSK-funded and FDA-commissioned trial uses a 2-by-2 factorial design to answer 2 questions.

• Does long-term treatment with rosiglitazone or pioglitazone reduce the risk of vascular events?
• Does even longer-term treatment with vitamin D reduce the risk of death or serious cancer?

Quoted by heartwire, US principal investigator Jeffrey Probstfield said, "...I can tell you that probably at least half of the investigators in the US who signed up to do this [trial] find the vitamin D question more compelling and interesting than the rosiglitazone-vs-pioglitazone-vs-placebo issue."

If the trial is sidelined over enrollment problems (because of the controversy about rosiglitazone's safety), GSK is unlikely to support a trial assessing only vitamin D, Probstfield reasonably concluded.

A search of the NIH database reveals that, while there are several other studies assessing the possible health benefits of vitamin D, TIDE is the only trial examining the supplement's death- or cancer-preventing potential.

TIDE = Thiazolidinedione Intervention With Vitamin D Evaluation.

Although the primary endpoint was not achieved in a recent phase 2 study, high-dose atorvastatin (Lipitor; Pfizer), like the interferon betas, may reduce the likelihood of full-blown multiple sclerosis after a first attack.*

The results of the placebo-controlled trial (N = 81), which were reported last week at the annual meeting of the American Academy of Neurology in Toronto, showed that atorvastatin 80 mg/d significantly reduced the odds of new T2 lesions on brain MR images at 12 months. However, the percentages of patients developing 3 or more new T2 lesions or 1 or more clinical relapses (the combined primary endpoint) were not significantly different between atorvastatin and placebo treatment (49% vs 56%; P = .65).** And while the odds of remaining free of active (ie, gadolinium-enhancing) MR lesions were higher with atorvastatin, this finding also did not reach statistical significance.

The study was originally designed to enroll 150 patients; however, because of slow recruitment, it was stopped after treatments were randomized to 81 patients. The study was sponsored by the NIAID and managed by the Immune Tolerance Network, which receives support from Pfizer and Biogen Idec.

The rationale for assessing atorvastatin in MS relates to its ability to modulate immune reactions and reverse disease in rodent models (ie, experimental autoimmune encephalomyelitis). Open-label studies also suggested clinical benefit with atorvastatin in relapsing-remitting MS.

At MedPage Today, the lead investigator, UCSF's Emmanuelle Waubant, indicated that the results are hypothesis generating—meaning that they warrant phase 3 study.

* AKA clinically isolated syndrome (CIS) manifesting, for example, as optic neuritis, spinal cord syndrome, or brainstem dysfunction.

** Those patients who experienced the primary endpoint were offered weekly IM interferon beta (Avonex; Biogen Idec).

T2-weighted supraventricular horizontal MR image from Harvard's Whole Brain Atlas. Multiple subcortical MS lesions are evident, including a very prominent lesion in the patient's right (left to the viewer) frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.

The Informant

(2009): Steven Soderbergh's farcical take on the price-fixing scandal of the Archer Daniels Midland company and whistleblower Mark Whitacre would have been a whole lot better (and funnier) without the overbearing score by Marvin Hamlisch. (Marvin to viewers: Yes, yes, audience! This is comical! And this here! And oh yes, this, also!) Too bad: It detracts from a really compelling character study and some fine performances by virtually every cast member, including Damon, Scott Bakula, and that "Talk Soup" guy, Joe McHale.

Last month

, an Orange County jury found that Botox maker Allergan was not liable for the death of Kristen Spears, a girl with severe cerebral palsy. The girl had received a series of high-dose botulinum toxin injections for spasticity from her Allergan-trained pediatrician. Spears's mother, Dee, brought a civil suit against Allergan, asking for $60 million (for more background, go here). The legal crux of the case appeared to be whether Allergan provided sufficient warning about Botox injections. The jury, in a 10-to-2 vote, decided that the company did.

Now Allergan, in perhaps a tone-deaf move, is suing Kristen's mom for legal fees, to the tune of $460,000, reports the OC Register. The company is likely sending a harsh message to existing or would-be plaintiffs and their attorneys. Among 14 other pending civil lawsuits against Allergan is that of physician Sharla Helton, who alleges that cosmetic Botox caused a multitude of neurologic problems, presumably due to the migration of toxin (which seems, BTW, highly unlikely at cosmetic dosages). The trial began this week in Oklahoma City. The physician is represented by Ray Chester of the Texas-based firm McGinnis, Lochridge, and Kilgore. Chester also represented Dee Spears.

In the meantime, Allergan's lawyers are consumed with the company's free-speech case against the government (Allergan v the United States of America). A motion hearing was scheduled for April 26; however, today's search of the court calendar reveals nothing on the schedule for the remainder of the year.

So who uses the web to find health information—or should I say, health misinformation?

According to a National Health Interview Survey...

• nearly one half of adults (46%);
• women (51%) more than men (40%); and
• younger adults.

Here's the age-sex breakdown:

Yesterday the Council of Medical Specialty Societies, a nonprofit umbrella group of 32 medical groups, announced its guidelines for interacting with industry. There's nothing particularly new here to shake up the established movement that emphasizes independence from pharma influence and the full disclosure of industry ties. For instance (yawn), the code stresses a distinction between certified continuing medical education (CME) activities and non-CME activities and prohibits ghostwritten articles in society journals.

In its entirety, the code, currently endorsed by 13 member societies,* addresses charitable contributions, corporate sponsorships, educational grants, exhibits and advertising, licensing, research grants, and editorial standards for society journals. The other 19 member societies, including CMSS President James Scully's American Psychiatric Association, have until the end of the year to sign on.

* American Academy of Family Physicians (AAFP)
  American Academy of Neurology (AAN)
  American Academy of Ophthalmology (AAO)
  American Academy of Pediatrics (AAP)
  American College of Cardiology (ACC)
  Accreditation Council for Continuing Medical Education (ACCME)
  American College of Emergency Physicians (ACEP)
  American College of Obstetricians and Gynecologists (ACOG)
  American College of Physicians (ACP)
  American College of Preventive Medicine (ACPM)
  American College of Radiology (ACR)
  American Society for Radiation Oncology (ASTRO)
  American Society of Clinical Oncology (ASCO)

From Pediatrics: a study of tobacco poisonings in young American children.

• From 2006 to 2008, 13,705 cases of tobacco poisoning were reported.
• About 70% of cases occurred in kids younger than 1 year of age.
• Nearly 80% of poisonings were due to the ingestion of cigarettes and (or?) filter tips (vs smokeless tobacco or cigars).

Plus there's commentary on a charming, new Tic Tac-like product from RJ Reynolds: cinnamon- or mint-flavored Camel Orbs, which contain 1 mg of nicotine per pellet. Although the product is new to the market, there has been at least 1 reported case of tobacco poisoning due to the ingestion of Camel Orbs (by a 3-year-old child).

RJ Reynolds also markets flavored Camel Sticks and Camel Strips.

Last year, the FDA was given the authority to regulate flavored cigarettes (but not other flavored tobacco products), thanks to the Family Smoking Prevention and Tobacco Control Act. The agency was quick to ban candy-, fruit-, and clove-flavored smokes in the United States.

Image of Camel Orbs from dissolvables.tobaccopleasure.com.

A lot more obscure than the "seven-fourteen" slang for Quaalude, "420," as a code for Mary Jane, is exhaustively mined by Ryan Grim of the HuffPo. (And God help me, I'm linking to the HuffPo).

HT: KPB, my (what else) college roommate.

Photo of growing marijuana plant from the Department of Justice.

Wow. A drug company actually downplaying its phase 2 data?

That's the charge of child neurologist Brenda Wong, an on-site investigator of PTC Therapeutic's ataluren (or PTC124) in muscular dystrophy, according to a report at MedPage Today.

Last month, PTC Therapeutics and its collaborator Genzyme announced that a treatment-related change in the primary endpoint, the 6-minute walk test, of a phase 2b trial of ataluren in Duchenne or Becker muscular dystrophy* (nmDBMD) did not reach statistical significance at 48 weeks. However, Wong, speaking at the just-completed annual meeting of the American Academy of Neurology in Toronto, said that patients treated with ataluren in the phase 2 trial experienced a mean improvement of 29 meters in the 6-minute walk test—which was just shy of the trial's prespecified target of 30 meters. This detail and others were not provided by PTC in its official communication.

Wong also said that the endpoint difference between ataluren- and placebo-treated patients was significant, when a different statistical test (a ranked analysis of covariance) was used, instead of what was prespecified (a simple analysis). Another important outcome: low-dose ataluren was more effective at delaying a deterioration in mobility than high-dose ataluren—which was no better than placebo. Wong proposed that low-dose ataluren may be more effective, because it has a relatively moderate effect on ribosomal activity. (Ataluren is designed to cause ribosomes to ignore a premature stop codon during protein translation.)

It's speculation here, but PTC may be reticent to broadcast details of its trial results, owing to the legal troubles it encountered in Gunvalson v. PTC Therapeutics in 2008 and the resultant threat to its clinical-trial program. In this legal case, which was correctly reversed on appeal (in favor of the company), a boy with nmDBMD demanded compassionate access to the drug outside of an ongoing clinical trial.

According to the NIH database, ataluren is currently being studied at the phase 2/3 level in cystic fibrosis and hemophilia A and B (in cases on nonsense mutations). Phase 3 trials in muscular dystrophy are not listed.

* Due to a nonsense (or premature stop codon) mutation, not a more common deletion mutation.

That Hamilton Woman

(1941): Winston Churchill reportedly saw this heavily embellished weepie about Lord Nelson (Laurence Olivier) and his striking mistress, Lady Hamilton (Vivien Leigh), more than 80 times. Must have been on Betamax.

The closing line, ostensibly written by Walter Reisch or playwright R. C. Sheriff, is a kicker.

And the tired can-kicking game continues.

Last night, the House, in a 289-to-112 vote, passed a bill that will again delay the SGR-mandated 21% cut in Medicare reimbursement to physicians. But the new deadline, June 1, echoes the same old brevity of previous stop-gap measures.*

The House voted almost immediately after the Senate approved the Democrat-favored bill in a 59-to-34 vote. The bill also contains provisions to extend unemployment benefits, COBRA subsidies, and state funding through the American Recovery and Reinvestment Act of 2009. An earlier version of the bill, passed by the Senate in March, would have extended the Medicare cut to October 1st.

If my count is correct, this is the 4th time in 5 months that Congress has acted to delay the mandated cut in the Medicare reimbursement rate. Unfortunately the current 45-day postponement gives Congress little time to produce a permanent (and commonsensical) fix to the perpetually looming drop in Medicare reimbursement.

For more coverage, visit Medscape.

COBRA = Consolidated Omnibus Budget Reconciliation Act; SGR = sustainable growth rate.

* The 21% cut officially began April 1st, but Medicare again stepped in to delay the processing of physicians' claims for 2 weeks.

Photo of weathered can from magannie at Flickr.

Worries about a rise in Guillain-Barre syndrome during the 2009 H1N1 vaccination campaign were unfounded. Only 35 cases of the acute autoimmune neuropathy were reported to the CDC or the FDA's voluntary reporting system, VAERS, at the end of last year, say researchers at the ongoing annual meeting of the American Academy of Neurology in Toronto.

The 2009 H1N1 (or swine flu) vaccination campaign began in earnest in mid-October of last year, and approximately 100 million vaccinations were administered in the United States. Consequently the rate of GBS associated with vaccination was 3.5 per 10 million. All but 1 case occurred within 6 months of vaccination; 23 cases occurred within 2 weeks of inoculation. The annual background rate of GBS is about 1-4 cases per 100,000. (The 2009 H1N1 vaccine protects against GBS, anyone?)

Original worries about a vaccine-associated increase in GBS stemmed from the observed rise in the condition during the 1976 swine-flu vaccination program.

VAERS = Vaccine Adverse Event Reporting System.

Yesterday's favorable news of Baxter's Gammagard (IV Ig) in Alzheimer disease (and the obligatory buzz) should be approached cautiously. Here's why.

First: The results are from a phase 2 study, not an all-important phase 3 study (two of which are typically required for FDA approval). As is common in a phase 2 study, different doses of the study drug were assessed.

Second: The study was small, enrolling only 21 subjects (14 with AD).

Third: The study was placebo controlled for a relatively limited time—6 months. Afterward all patients received IV Ig at various doses for 12 months.

Fourth: The difference in the ADCS-CGIC score change between treatment groups, while statistically significant, was not huge—1.36 points (-0.64 vs -2.0).

Fourth: The significant difference between the mean ADAS-cog scores at endpoint may be due to the substantial change in the mean score of control patients—15 points. It'd be nice to know when the bulk of this 15-point change in the control patients occurred: during placebo treatment or during IV Ig treatment?

Fifth: The results have not been peer reviewed.*

Perhaps the most intriguing result of Baxter's phase 2 AD study is the statistically significant associations among IV Ig treatment, brain atrophy on MR images, and clinical scores. Again, however, the study was small, and the outcome warrants confirmation in phase 3 investigations, which are ongoing or planned.

The rationale for administering IV Ig in AD is to provide nonspecific anti-amyloid antibodies. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; ADCS-CGIC = Alzheimer's Disease Cooperative Study, Clinical Global Impression of Change.

* While the Baxter press release indicates that these data were presented yesterday at the ongoing annual meeting of the American Academy of Neurology, I--for the life of me--cannot find the related abstract. The closest presentation from the same investigators is "Neuropsychological outcomes following 18-months of uninterrupted intravenous immunoglubulin (IVIg) treatment in patients with Alzheimer's disease (AD)." The data from this related trial are to be presented this evening.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

Addendum: D'oh! Here's the AAN abstract (found in late-breaking science, which—Hmm—is to be presented as a poster this evening. It is Wednesday, isn't it?). Relkin N et al. Intravenous immunoglobulin treatment decreases rates of ventricular enlargement and cognitive decline in Alzheimer's disease. P03.294.

The 6-month data were presented at the 2008 annual meeting of the AAN. Among 23 completers, 19 had "fully evaluable data." The difference between the change in the ADCS-CGIC score of IV Ig-treated patients and that of placebo-treated patients was statistically significant (IV Ig, +0.25; placebo, -1.25; absolute difference, 1.50); however, the mean change in the ADAS-cog score was not (IV Ig, -0.38; placebo, +2.61). 

So most of the change in the ADAS-cog score of control patients at 18 months occurred while they were receiving IV Ig. It seems flukish that 6 months of upfront IV Ig therapy would provide that much neuroprotection in the treated group, whose ADAS-cog score changed by only 5 points at 18 months.

The small drop in pressure, 2-3 mm Hg, occurring after jugular-vein angioplasty in patients with multiple sclerosis is unlikely to be pathologically significant. The implication was made in Sunday's review of the procedure by US neurologist John Corboy at the ongoing annual meeting of the American Academy of Neurology in Toronto, Canada.

Corboy assessed the clinical data of Italian vascular surgeon Paolo Zamboni, who first proposed that MS is caused by an insufficiency of the cerebral veins. Consequently Zamboni performed angioplasty in 65 patients with MS (including his wife) and claimed clinical and radiographic improvement in an uncontrolled trial.

Among Zamboni's rationales for addressing venous insuffiency in MS is to reduce perivenular iron deposits, a known pathologic feature of MS. (Although no causative link has been established between these deposits and MS, to my knowledge.) Pathologists consulted by Corboy implied that the small drop in pressure due to jugular-vein angioplasty or stenting is unlikely to purge these deposits—or anything else, for that matter.

A much larger follow-up blinded study at the University of Buffalo reaffirmed reduced blood flow in the extracranial veins of patients with MS and correlated these data with iron deposits on MR images. These data are scheduled to be presented tomorrow in a poster session at the AAN meeting (P03.126).

Last December, Stanford correctly shut down the jugular-vein stent program of surgeon Michael Dake, who had performed the procedure in 40 patients with MS. One died of cerebral hemorrhage, and the stent of another became dislodged and found its way to the patient's heart. Dake's interest in the procedure was indirectly sparked by chat-room enthusiasm for Zamboni's work.

Corboy concluded his review by advising that he would not recommend jugular-vein angioplasty or stenting in patients with MS "until we had a much better idea whether this approach has any merit whatsoever."

News source: MedPage Today.

Image of neck veins from Gray's Anatomy (1918).

Last month, physicians at Bagram Airfield in Afghanistan removed a 14.5-mm explosive round, containing about 5 g of explosive, from the scalp of an Afghan National Army soldier. The 2 1/2-inch round was lodged into the soldier's scalp after he was involved in a roadside bomb attack, revealed a recent Air Force press release. Friday's NYT picked up the story, adding more details.

Seems that the medical staff first believed that the Afghani merely sustained a shrapnel wound to the head; however, on closer inspection, thanks to CT images, the radiologist realized that the foreign object was an explosive round, "primed to go off." Nice pick up.

The discovery, which prompted the bomb squad, led to the evacuation of the operating suite, and the remaining operating personnel had to wear body armor. Electronic monitoring machines also had to be turned off, for fear of triggering the device. Because the bomb squad suspected that the live round probably had an impact detonator in the tip, instructions to the lead surgeon were, "Just don't drop it."

A frontal skull image provided by the Air Force shows the round lodged in the right frontal area of the patient's scalp, evidently resting on the skull.

However, a horizontal CT image shows that the round is lodged between 2 skull fragments in the right frontal area. This image suggests (to me) that the device impacted the head sideways, probably blasting into the Afghani's head from his left and grazing his brow before burying itself under a created skull fragment.

The round was removed successfully, and the Afghan soldier reportedly continues to recover.

The Long Goodbye

(1973): Robert Altman's take on film noir and Raymond Chandler, with all the signature amorphousness of a Robert Altman movie. Chandler's story from the 1950s, however, takes place in the 70s—with Elliott Gould, perpetually suited and chain-smoking, as the throwback PI Philip Marlowe in sunny, EST-loving Los Angeles.

Altman's love of overlapping dialogue, extraneous audio, and distracting visuals is in full bloom, as Marlowe investigates the apparent suicide of a buddy whose wife was just murdered. Renowned DP Vilmos Zsigmond (Close Encounters of the Third Kind) effectively contrasts dark, cool interiors with blinding beachscapes in numerous single shots, and underachiever John Williams takes partial credit for the title song, which is heard repeatedly in various incarnations—like torch cabaret, uptempo jazz, and Mexican funeral march.

Featuring Sterling Hayden, Henry Gibson, and a mute Governator in an uncredited bit role.

(With apologies for "Repurposing.")

Largely because of a controversial 2007 meta-analysis by the controversial and controversy-stirring Steve Nissen, sales of the antidiabetic drug Avandia (rosiglitazone) dropped more than 50%, from about $3 billion in 2006 to $1.2 billion in 2009. As an apparent consequence, the drug's manufacturer, GlaxoSmithKline, has been searching for an alternative indication for the product, especially given that the drug is at risk of being pulled from the market. In addition, the use patent for Avandia in type 2 diabetes (the drug's primary indication) expires in 2 years.

Unfortunately for GSK and people with Alzheimer disease, trials of an extended-release version of the drug (the REFLECT studies) failed to show any cognitive benefits with Avandia when added to or compared with the standard treatment of donepezil (Aricept; Pfizer) or placebo. Last year, GSK announced that it was abandoning its development of Avandia for AD.

But plenty of other GSK-sponsored and non-GSK trials of Avandia have been conducted or are ongoing. These include studies in asthmatic smokers,* ulcerative colitis,* HIV-related lipoatrophy, and chronic kidney disease. Avandia's effects on preventing or treating certain types of solid tumors also have been or are under investigation.

* In addition to mitigating insulin resistance, Avandia appears to have anti-inflammatory properties.

A big HT to the DCMB for citing the latest Calvalcade of Risk roundup at Political Contributions. Yesterday's edition provides an intriguing online calculator—based on income and the cost of and need for health insurance—to determine whether it's cheaper to buy coverage or suffer the IRS penalty* for not having it.

The big question answered (sort of): Should I retain or drop health insurance under "ObamaCare"?

Because the new act prohibits insurance companies from denying coverage to anyone with a preexisting illness, an essential loophole is created that allows some citizens to game the system. In these cases, the cheaper option—to purchase insurance or to suffer the tax—can be determined.

For instance, for a person with an annual income of $40,000 who pays $4824 annually for an individual policy and has a 1-in-4 chance of being hospitalized, the formula spits out the following like a carnival fortune teller: "It makes more sense to drop your health insurance, buying it only when you need it, then drop it again if your health allows."

That's because the annual penalty for not being insured,** $1000, is much lower than the likely accumulated savings from dropping coverage over 3 years, $11,472 ([$4824 x 3] – $3000). However, if someone loses the gamble (meaning that she fails to get health insurance and then find that she needs it, the basic cost is $5824—or the tax penalty plus the cost of insurance for 1 year).

Major caveats to the formula must be noted, however. Insurance premiums are based on current rates (eg, the average annual premium for an individual in 2009 was $4824, according to USA Today). The hospitalization odds provided are for Australia (see table below); it is assumed that the odds are similar for Americans. Also the odds of needing outpatient and prescription coverage, which are much more likely than hospitalization, are not considered. Another big caveat: out-of-pocket costs for necessary hospitalization, whether insured or not, are ignored.

According to one report, gaming the system has already occurred in Massachusetts, where a health insurance mandate has been in effect since 2006. The consequence: soaring insurance rates. 

Age, years	Female	Male
<1	1 in 3	1 in 2
1-10	1 in 10	1 in 8
10-20	1 in 9	1 in 10
20-30	1 in 4	1 in 8
30-40	1 in 3	1 in 6
40-50	1 in 4	1 in 4
50-60	1 in 3	1 in 3
60-70	1 in 2	1 in 2
≥70	4 in 5	4 in 5

* Which goes into effect in 2016.

** In that income bracket.

While reviewing trials of novel agents for Alzheimer disease at the NIH database, one thing is readily apparent: There are few candidates in the late-stage pipeline.

With 2 drugs in phase 3 development, Lilly is the clear frontrunner. Its sole competition appears to be a green tea extract, sunphenon EGCg, which is being assessed in 1 actively recruiting, phase 2/3 AD trial in Germany.*

Lilly's drugs of promise are semagacestat (LY450139), a gamma-secretase inhibitor, and solanezumab (LY2062430), a monoclonal antibody. For what it's worth (and that may not be much), both are intended to disrupt or break up the amyloid plaques of AD (like the woebegone bapineuzumab).

Two phase 3 company-sponsored trials of semagacestat are listed in the NIH database (here and here). The first trial, called IDENTITY, will be completed in June of next year. And two phase 3 trials of solanezumab, EXPEDITION and EXPEDITION 2, are recruiting patients with mild-to-moderate AD (here and here). These trials will not be completed until 2012.

A phase 2 safety trial of semgacestat in 51 patients with mild-to-moderate AD revealed possible "concerns" about skin and hair reactions. Although plasma levels of amyloid beta dropped significantly with semagacestat, there were no treatment-related changes in CSF levels and no between-group differences in cognitive measures; however, the trial was too short (14 weeks) to adequately assess any cognitive benefits. A more recently published study showed that single doses of semgacestat reduce amyloid beta production, but not clearance, in a dose-dependent fashion.

* The trial is expected to be completed in April of 2011.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

In ALS, lithium carbonate is no better than placebo when added to riluzole (Rilutek; sanofi aventis) therapy. The conclusion is based on the fully reported results of a 6-month, multicenter North American study, the details of which are now available in an advanced online issue of the Lancet Neurology. The disappointing findings were originally reported in September of last year, after a planned interim analysis showed no added benefit with the compound.

On the basis of favorable results from a highly publicized Italian pilot study by Fornai et al, Canadian and US researchers randomized lithium and placebo treatment in double-blind fashion to 84 patients with ALS. By using a distinctive time-to-event trial design, researchers would continue the study only if the statistical significance (P value) between treatment-related events equaled .68 or less at an interim analysis.

At a mean treatment duration of 5.4 months,* 22 of 40 (55%) patients receiving lithium and 20 of 44 (45%) patients receiving placebo either died or demonstrated a 6-point score drop on the revised ALS Functional Rating Scale. The statistical significance between the treatment groups was .78—which, according to plan, necessitated discontinuation of the study.

Despite the inefficacy of lithium, which was dosed to achieve blood levels of 0.4-0.8 mEq/L, the drug was reasonably well tolerated. The most common treatment-related adverse events were falls and back pain.

According to the NIH database, there are 5 phase 3 survival trials currently recruiting patients with ALS. Investigated drugs include IM mecobalamin (ie, vitamin B12), the novel agents olesoxime and arimoclomol, and the antibiotic ceftriaxone. Information about active trials can also be found at the ALS Association web site.

ALS = amyotrophic lateral sclerosis.

* The first interim analysis occurred when 84 patients were allocated to treatment, at 6 months or after 55 events, and after 100 events.

Image of lithium carbonate powder from Wikipedia.

I don't get it. How does an employee with, by all appearances, an inherited illness prevail in litigation against a company for personal injury? At least the federal judge in the case of McClain v Pfizer threw out the issue of whether a Pfizer-bioengineered virus caused the plaintiff's recurrent paralytic illness.

Nevertheless, a jury awarded nearly $1.4 million to ex-Pfizer scientist Becky McClain, by ruling that the company had violated free-speech and whistle-blower laws. (The judge left the personal-injury issue to workers' compensation litigation.)

Coverage of the jury's decision is provided by the NYT, which also reveals that McClain, 52, suffers from "a potassium deficiency that causes sporadic and temporary paralysis"—in other words, hypokalemic periodic paralysis, a rare, genetically determined* disorder of ion channels in muscle (ie, a channelopathy). Unfortunately news coverage of the trial fails to stress the crucial genetic feature of McClain's reported illness. (They also fail to note that her OSHA complaint was evidently dismissed.)

Approximately 60% of cases of Hypo PP are due to a mutation in CACNA1S (calcium channel) gene; 20% are caused by a mutation in the SCN4A (sodium channel) gene. The remainder are probably due to new dominant mutations, according to information cited in a review by Venance et al. These ion-channel mutations cause the aberrant depolarization of muscle fibers, which renders them inexcitable; the clinical result is periodic paralysis. It's not clear what kind of Hypo PP-related mutation, if known, is harbored by McClain.

The essential features of Hypo PP, beyond its genetically determined nature, are listed:

• Age at onset: 1st or 2nd decade
• Duration of paralytic attacks: hours to days (may be diffuse or focal)
• Usual triggers: rest after exercise, carb loading
• Ictal potassium level: low
• Cardiac arrhythmias or skeletal developmental abnormalities: no (unlike Anderson-Tawil syndrome**)
• Response to potassium: improvement of weakness

Hypo PP is diagnosed on the basis of episodic paralysis, low serum potassium levels during the paralysis, and EMG features (post-exercise features may be particularly helpful). For anybody presenting with Hypo PP-consistent symptoms after the age of 20 years or whose family history is nonexistent, thyroid function should be assessed to exclude thyrotoxic PP.

According to news reports, McClain—who has an MS degree—claims that her paralytic illness was triggered by infection with a genetically engineered lentivirus at Pfizer's Groton, CT, campus. The Connecticut Law Tribune reports that McClain left work in early 2004 after developing her alleged symptoms.

Though her doctor cleared her to resume working a few months later, her attorney instead negotiated with Pfizer over her work conditions. Unable to reach an agreement, McClain was terminated in May 2005; Pfizer said it was because she had abandoned her job.

By then, McClain had filed a complaint with OSHA. It was dismissed when investigators ruled that her complaints were without merit; the OSHA report cited Pfizer for making "substantial efforts" to address McClain's concerns.

Probably smelling the high possibility of litigation from McClain on whatever grounds, it seems reasonable to conclude that Pfizer would have bent over backwards to accommodate McClain and her safety concerns—at least on some kind of sensible level.

According to the Center for Public Awareness in Bioethics web site, McClain has a bachelor's degree from Indiana University and a Master of Science in Public Health from the University of Texas School of Public Health in Houston. She worked for Pfizer as an unspecified scientist from 1996 to 2005 and filed her suit against the company in 2006.

EMG = electromyography; OSHA = Occupational Safety and Health Administration.

* Prevalence is reported at 1 in 100,000. The disorder is inherited in autosomal dominant fashion, with reduced penetrance in women. Also sporadic mutations are reportedly common in Hypo PP.

** The triad of PP, ventricular ectopy, and skeletal anomalies.

Accepting the KBF duty this week is KTG. Take it away, KTG.

Franklyn

(2008): Go for the otherwordly cover art. Stay for the 4 seemingly disconnected storylines that eventually form a tidy, if slightly blood-spattered, bow.

This Brindie (that's Brit-indie) features Ryan Phillippe as a steampunk vigilante, Bernard Hill as a tormented father, and Eva Green* as a suicidal performance artist. Put that in your rolled-up, overwrought screenplay and smoke it. Meanwhile Sam Riley plays a jilted lover who stumbles into the middle of...things.

* You remember her as the Bond girl in Casino Royale (2006). 

Like GSK, Lilly, and Merck, Pfizer has begun to publicly disclose its payments to US docs for their advising and speaker services, as of yesterday.* However, unlike the other companies, Pfizer is revealing how much money it has given to fund US-based clinical trials (ie, research grants).

During the second half of 2009, the world's biggest drug firm shelled out $19.8 million to 4500 health care professionals ($4400, on average, per HCP) and $15.3 million to 250 academic or other research groups ($61,200, on average, per group). Pfizer provides a friendly graph (below) and also notes that it invests about $7 billion in R&D and spends about $1.3 billion to bring a drug to market.

Individual Pfizer payments are available here, with a database that is browsable and searchable. However, the payment information, like that from other companies, is not easily downloadable, as yesterday's NYT notes.

According to a Pfizer spokesperson, also by way of the NYT, the disclosures (or at least most of them) are mandated by an "integrity agreement" between Pfizer and the federal government. The agreement was struck as part of a settlement in re Pfizer's off-label promotion of drugs (like Wyeth's Neurontin [gabapentin]).

HCP = health care professional (including nurse practitioners and PAs).

* "Meals, business travel expenses and educational items that are greater than or equal to $25 in value, and where the aggregate amount paid to an individual health care professional is greater than or equal to $500 in a calendar year."