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THE LANCET Neurology Vol 2 May 2003 http://neurology.thelancet.com264

On March 12, 2003, 7 years after he filed a lawsuit relating to themarketing of the epilepsy drugNeurontin (gabapentin) by Parke-Davis, whistle-blower David Franklingranted his first in-depth interviewwith the media. In an interview withthe Boston Globe and New York Times,Franklin claimed: “I was trained to dothings and did things that wereblatantly illegal.” These includedpersuading physicians to prescribe the drug for unapproved uses, healleges. “I knew my job was to falselygain physicians’ trust and trade on my postgraduate degree [inmicrobiology]”, he claimed. In 1996Franklin resigned from Parke-Davis—a unit of Warner Lambert thatwas acquired by Pfizer in2000—having worked there for just 4months.

Larry Sasich of Public Citizen hasbeen closely following the case, whichis still ongoing. 200 000 documents aresaid to be involved in the lawsuit,along with a database of about 3000 physicians who are alleged to

have accepted around $60 million toprescribe gabapentin for 11 off-label uses (http://www.citizen.org/ELETTER/ARTICLES/neurontin.htm).The lawsuit (http://www.citizen.org/documents/1638attach.pdf) claims to“carefully lay out the industry’spromotional practices, including theperversion of the peer-reviewedliterature”.

Because of the ongoing litigation,Pfizer is unable to comment on the specific allegations in the lawsuit.“But what I can tell you”, Pfizerspokeswoman, Mariann Caprino toldThe Lancet Neurology, “is that it is aclear and longstanding Pfizer policythat we do not promote our medicinesfor uses for which they are notapproved. That’s very clear toeveryone throughout the company.”Caprino was also keen to emphasisethe distinction between Pfizer andWarner Lambert (the parent companyof Parke-Davis): “We certainly cannotspeak for Warner Lambert at a timewhen we were not responsible for thecompany”, she said

Public Citizen recommends that“people who write and make decisionsabout drugs need to review the FDAreview documents for a new drugapproval before forming an opinionabout the drug”, says Sasich. “This isthe only way to form an independentview of the drug’s therapeutic value,because there are studies in thosedocuments that never get published.”Neurontin is approved for moreindications in the UK than the USA,which, says Saisich “raises questionsabout what the Medicines ControlAgency uses as the basis of approval”.

Epilepsy expert Josemir Sander(UCL Institute of Neurology, London,UK) notes that “it is well known thatgabapentin has been very aggressivelymarketed for neuropathic pain andother indications” in the UK.“Nowadays, we make jokes about itbecause it never really caught on as anepilepsy drug—I wouldn’t even use itas a second-line treatment—but itsuddenly took off on the back of off-licence indications, and became a hit.”Marilynn Larkin

Parke-Davis whistle-blower speaks at last

Newsdesk

Organophosphate neurotoxicity: a new theoryCharacterisation of Nte, the gene thatencodes neuropathy target esterase(NTE), has opened up a new theory ofhow organophosphates, present ineither pesticides or chemical-warfareagents, may cause delayed chronicneurotoxic syndromes. Previously, itwas proposed that a gain in function of NTE was associated with greaterorganophosphate toxicity. But nowCarrolee Barlow’s group in Californiareveal that genetic or chemicalreduction of Nte activity may be themain factor underlying the molecularmechanism of nerve damage.

Christopher Winrow (The SalkInstitute for Biological Studies, LaJolla, CA, USA) and colleaguesgenerated mutant mice and found thatmice lacking NTE (Nte-/-) diedduring embryogenesis. Heterozygousmice (Nte+/-) survived but had lowerconcentrations of NTE protein andlower NTE activity, but normal levelsof acetylcholinesterase, an enzyme

that is inhibited in acute organo-phosphate toxicity. Surprisingly,Nte+/- mice were more susceptible tothe effects of ethyl octylphosphono-fluoridate, a potent organophosphateinhibitor of NTE (Nat Genet 2003; 33:477–85).

“This turns our old theory of how organophosphates cause delayedneurotoxicity completely on its head”,says James O’Callaghan, author of theaccompanying editorial (Nat Genet2003; 33: 437–38). Lower concentra-tions or lower activity of NTE, ratherthan a gain in function of NTE, lead toorganophosphate toxicity through amechanism that is not yet understood,he explains. Although Gulf WarSyndrome is the most publicisedexample of delayed neurotoxicitycaused by organophosphate exposure,the most well studied example is organophosphate-induced delayedneuropathy (OPIDN). “To date, about30 000 human cases have been studied

and the most common animal modelof the disease is the hen”, explainsBarlow.

O’Callaghan observes that some willcriticise the current results because theyhave not been obtained in the species ofchoice, but stresses that the mousemodel provides a useful tool for futurestudies aimed at uncovering targetsdownstream of, or in addition to, NTE,that may be involved in OPIDN. “Theuse of Nte-deficient mice may alsohasten the development of therapies for OPIDN and related conditions”,comments Barlow. “It is alwaysrewarding when experiments are donethat allow us to look at a process in anew light. We hope these results and themouse model can be used to help usbetter understand the diseasephysiology related to low and high doseorganophosphate exposure and thecontribution of NTE to diseases linkedto exposure”, she adds.Kathryn Senior