RESUMEN
Unsolicited inquiries for off-label medical/product information are the focus of compliance monitoring programs as described in regulatory guidance published by the US Office of the Inspector General (OIG) and the US Food and Drug Administration (FDA). Pharmaceutical industry medical information departments (PIMIDs) are encouraged to monitor and report on patterns of activity, including the source and frequency and types of off-label inquiries received. Especially of interest are unsolicited off-label inquiries triaged via sales representatives. By tagging all response documents with "compliance topic" codes that reflect the type of off-label inquiry (eg, unapproved indications/uses, more detailed or extended data, adverse events, etc) and specifically tracking for the inquiry source route, our PIMID was able to analyze and compare customer inquiries including those triaged by sales representatives. In an analysis of all inquires (n = 20,213) received over a 2-year period (2010-2011), it was observed that inquires submitted by sales representatives after unsolicited health care worker (HCW) requests accounted for only 14.8% of requests overall. Questions related to "off-label indications/uses" (ie, compliance topic of most interest to regulatory agencies) accounted for 5.8% of all inquiries and were almost equally distributed in number between sales representative triage and HCW direct calls to the PIMID. For the set of sales representative triage submissions in 2010 and 2011, the "off-label indications/uses" category accounted for 15.3% to 20.5%, respectively, and was statistically significant ( P < .001) for the rate of 4.8% to 8.1% observed collectively for all customer sources. In most cases, there were similarities in questions asked (top 5 ranking) and their geographical source for sales representative triage versus customers directly.
RESUMEN
OBJECTIVE: L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. DESIGN: Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). SETTING: Laboratory. SUBJECTS: Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. INTERVENTIONS: The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. MEASUREMENTS AND MAIN RESULTS: The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. CONCLUSIONS: These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.