How the FDA forgot the evidence: the case of donepezil 23 mg | BMJ

Posted on February 19, 2013 by Maurice Preter MD

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How the FDA forgot the evidence: the case of donepezil 23 mg

BMJ 2012; 344 doi: http://dx.doi.org.ezproxy.cul.columbia.edu/10.1136/bmj.e1086 (Published 22 March 2012)

Cite this as: BMJ 2012;344:e1086
  1. Lisa M Schwartz, professor12,
  2. Steven Woloshin, professor12

Author Affiliations

  1. Steven.Woloshin@dartmouth.edu

In the first of a new occasional series highlighting the exaggerations, distortions, and selective reporting that make some news stories, advertising, and medical journal articles “not so,” Lisa M Schwartz and Steven Woloshin challenge the claims made for the new 23 mg dose of donepezil

What is the difference between 20 and 23? If you said three, you are off by millions—of dollars in sales, that is—at least from the perspective of Eisai, the manufacturer of donepezil (marketed as Aricept by Pfizer).

A little context helps make the maths clearer. Donepezil, the biggest player in the lucrative market for Alzheimer’s disease treatments, was a blockbuster, with over $2bn in annual sales in the United States alone. But the drug, first approved in 1996, had reached the end of the road: the patent expired in November 2010. Investors call this “going over the cliff,” an anxious reference to plummeting sales as market share is lost to generic competitors. Necessity, however, is the mother of invention. Just four months before the expiry of the patent, the US Food and Drug Administration (FDA) approved a new dose for moderate to severe Alzheimer’s disease: donepezil 23 mg. Is 23 an odd number? Not really, when you consider that you cannot get to 23 mg using the 5 mg and 10 mg doses that were going generic. The “new” 23 mg product would be patent protected for three more years.

via How the FDA forgot the evidence: the case of donepezil 23 mg | BMJ.

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The nervous system and metabolic dysregulation: emerging evidence converges on ketogenic diet therapy.

Posted on February 11, 2013 by Maurice Preter MD

Front Neurosci. 2012;6:33. doi: 10.3389/fnins.2012.00033. Epub 2012 Mar 26.

The nervous system and metabolic dysregulation: emerging evidence converges on ketogenic diet therapy.

Ruskin DN, Masino SA.

Source

Neuroscience Program, Department of Psychology, Trinity College Hartford, CT, USA.

Abstract

A link between metabolism and brain function is clear. Since ancient times, epileptic seizures were noted as treatable with fasting, and historical observations of the therapeutic benefits of fasting on epilepsy were confirmed nearly 100 years ago. Shortly thereafter a high fat, low-carbohydrate ketogenic diet (KD) debuted as a therapy to reduce seizures. This strict regimen could mimic the metabolic effects of fasting while allowing adequate caloric intake for ongoing energy demands. Today, KD therapy, which forces predominantly ketone-based rather than glucose-based metabolism, is now well-established as highly successful in reducing seizures. Cellular metabolic dysfunction in the nervous system has been recognized as existing side-by-side with nervous system disorders – although often with much less obvious cause-and-effect as the relationship between fasting and seizures. Rekindled interest in metabolic and dietary therapies for brain disorders complements new insight into their mechanisms and broader implications. Here we describe the emerging relationship between a KD and adenosine as a way to reset brain metabolism and neuronal activity and disrupt a cycle of dysfunction. We also provide an overview of the effects of a KD on cognition and recent data on the effects of a KD on pain, and explore the relative time course quantified among hallmark metabolic changes, altered neuron function and altered animal behavior assessed after diet administration. We predict continued applications of metabolic therapies in treating dysfunction including and beyond the nervous system.

PMID:

22470316

[PubMed]

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Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet.

Posted on February 11, 2013 by Maurice Preter MD

PLoS One. 2009 Dec 23;4(12):e8349. doi: 10.1371/journal.pone.0008349.

Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet.

Ruskin DN, Kawamura M, Masino SA.

Source

Department of Psychology and Neuroscience Program, Trinity College, Hartford, Connecticut, United States of America.

Abstract

The ketogenic diet is a high-fat, low-carbohydrate regimen that forces ketone-based rather than glucose-based cellular metabolism. Clinically, maintenance on a ketogenic diet has been proven effective in treating pediatric epilepsy and type II diabetes, and recent basic research provides evidence that ketogenic strategies offer promise in reducing brain injury. Cellular mechanisms hypothesized to be mobilized by ketone metabolism and underlying the success of ketogenic diet therapy, such as reduced reactive oxygen species and increased central adenosine, suggest that the ketolytic metabolism induced by the diet could reduce pain and inflammation. To test the effects of a ketone-based metabolism on pain and inflammation directly, we fed juvenile and adult rats a control diet (standard rodent chow) or ketogenic diet (79% fat) ad libitum for 3-4 weeks. We then quantified hindpaw thermal nociception as a pain measure and complete Freund’s adjuvant-induced local hindpaw swelling and plasma extravasation (fluid movement from the vasculature) as inflammation measures. Independent of age, maintenance on a ketogenic diet reduced the peripheral inflammatory response significantly as measured by paw swelling and plasma extravasation. The ketogenic diet also induced significant thermal hypoalgesia independent of age, shown by increased hindpaw withdrawal latency in the hotplate nociception test. Anti-inflammatory and hypoalgesic diet effects were generally more robust in juveniles. The ketogenic diet elevated plasma ketones similarly in both age groups, but caused slowed body growth only in juveniles. These data suggest that applying a ketogenic diet or exploiting cellular mechanisms associated with ketone-based metabolism offers new therapeutic opportunities for controlling pain and peripheral inflammation, and that such a metabolic strategy may offer significant benefits for children and adults.

PMID:

20041135

[PubMed – indexed for MEDLINE]

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Panic Developments – An Interesting Editorial by Donald F. Klein in the Revista Brasileira de Psiquiatria

Posted on February 4, 2013 by Maurice Preter MD

Revista Brasileira de Psiquiatria 2012;34(Supl1):S01-S04

Panic Developments

This editorial permits personal conclusions and questions, hoping to stimulate relevant research. Klein, in 1959, serendipitously found that imipramine blocked the apparently spontaneous panic attack in non-depressed inpatients, later considered agoraphobic.Later it was found that these specific anti-panic drugs blocked lactate challenges, although low potency benzodiazepines and beta-blockers did not. Also, panic patients with early onset, frequently had a history of severe separation anxiety disorder, often manifested as school phobia. A series of usually post-pubertal panics led to severe chronic distress marked by fearful anticipation that the next panic would cause death or insanity. Avoiding situations (bridges, tunnels, freeways etc.) where help could not be readily obtained if panic reoccurred led to extensive travel restrictions and demands to be accompanied. These avoidances were misinterpreted as phobias, since there was no fear of cars or bridges per se. Family exhaustion led to psychoanalytic psychiatric hospitalization.1 In 1967, Pitts found, in placebo-controlled studies that intravenous sodium lactate in patients with spontaneous panics, then considered anxiety neurosis, could regularly cause such attacks. Further, other stressful infusions, such as EDTA, did not elicit panics, ruling out conditioning as a feasible alternative view. Later studies found inhaled 5%-7% carbon dioxide was similar to IV lactate as a panicogen, while willful room air hyperventilation was an uncommon panicogen. This contradicted the hyperventilation theory of panic disorder. Such panic reactions rarely occurred in patients with other anxiety disorders, other psychopathological states or normal subjects, except strangely, in women with severe chronic premenstrual syndrome.Groundbreaking therapies derived from this program. Panic disorder and agoraphobia were now quite treatable outpatient conditions, although unfortunately DSM-III distorted agoraphobia’s definition by simply choosing six frequent avoidances as criteria, while ignoring their common role in preventing flight to help, as well as the utility of a companion for travel.

The lactate study initiated by Jean Endicott and Wilma Harrison led to SSRI treatment for PMS. Rachel Klein demon- strated the value of imipramine and counseling in the treatment of refractory Separation Anxious Disorder (mislabeled school phobia), laying the groundwork for SSRI treatment of children.

Since panic disorder and agoraphobia were stipulated in DSM-III, an enormous proliferation of studies attempted to clarify this area. Although the panic attack seemed fear like, there were incongruent features. Mandel Cohen (1940) showed such attacks were usually associated with marked air hunger, which was not characteristic of external danger induced fear. Further, remarkably, both clinical and challenge studies of panic disorder did not elicit the emergency reaction of hypothalamic-pituitary-adrenal (HPA) release. Thus, panic attack was not fear or due to a hypersensitive fear system.It was hypothesized that, rather than a generalized HPA alarm system responsive to all dangers, many separate alarm/ response mechanisms had evolved, over evolutionary time, to deal with recurrent distinct dangers. Such an alarm/response system dealt with the recurrent danger of suffocation, whose affective and behavioral response system must act quickly to prevent anoxic brain damage. Hypersensitivity of that system to signals of possible suffocation could result in panic and escape. Conversely, carbon dioxide insensitivity existed in congenital central hypoventilation syndrome. Preter and Klein’s controlled lactate study in normal subjects found a panic like tidal volume increase if naloxone anteceded intravenous lactate. This was consonant with the hypothesis that an inhibited endogenous opioidergic system caused hypersensitivity of the suffocation alarm/response system.2,3
[Full text here]
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Ben Goldacre: What doctors don’t know about the drugs they prescribe | Video on TED.com

Posted on January 19, 2013 by Maurice Preter MD

Ben Goldacre: What doctors don’t know about the drugs they prescribe | Video on TED.com

via Ben Goldacre: What doctors don’t know about the drugs they prescribe | Video on TED.com.

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