Adverse drug reactions detection systems

Strieker BH, Psaty BM. Detection, verification, and quantification of adverse drug reactions. Br Med J 2004 329(7456) 44-7. Thomsen HS, Marckmann P, Logager VB. Nephrogenic systemic fibrosis (NSF) a late adverse reaction to some of the gadolinium based contrast agents. Cancer Imaging 2007 7 130-7. 

One of the most important aspects of the UK regulatory system is the scheme that provided for the voluntary reporting of adverse reactions to a marketed drug. Because most serious adverse drug reactions (ADRs) are rare events, they are unlikely to be detected in early clinical trials. The problem is essentially one of numbers, as relatively few patients are exposed to a new drug before it is released on to the market. Marketing, therefore, may be the first adequate safety trial. 

Despite important progress in evaluating adverse drug reactions, there is still no reliable method to identify potential delayed events that might occur well after the original course of therapy. For example Medwatch system did not detect the identification of diethyl stilbesterol (DES) associated clear-cell adenocarcinoma in female fetuses exposed in utero [3]. 

The ramifications of the thalidomide tragedy were many-fold but the key lesson for the development of pharmacovigilance was that active systems for detecting hazards are needed. Within a few years this had been taken forward with the introduction of voluntary (or spontaneous ) schemes for reporting of suspected adverse drug reactions (ADRs). These have stood the test of time as an alerting mechanism or early warning system and wiU be covered in more detail in Chapter 3. 

Given the perceived failure of spontaneous reporting systems and the paucity of ADR reports/ some institutions have instituted more active methods of ADR detection to supplement spontaneous reports. Medication order screening has become a common practice in U.S. hospitals. Manual chart reviews and audits and computer programs are used for retrospective/ concurrent/ and prospective medication utilization evaluation. Certain events often prompt an evaluation of a suspected adverse reaction. These include abrupt discontinuation of a medication/ abrupt dosage reduction/ orders for antidotes and emergency medications/ orders for special tests or serum drug concentration measurements/ and abnormal results from laboratory tests and medical procedures. 

Nabumetone is a naproxen derivative, whose efficacy is related to its active metabolite, 6-methoxy-2-naphthyla-cetic acid. Not unexpectedly, a study in 2000 patients, mostly treated for more than 6 months, ehcited an adverse events pattern similar to the other derivatives of this class of NSAIDs (SEDA-13, 81). Adverse effects were reported in 18% of patients and 10% stopped taking the drug because of adverse reactions. Diarrhea was the most common problem (13%) followed by abdominal pain (9.9%), dyspepsia (9.3%), nausea (7.8%), and flatulence (4.7%). Ten ulcers were detected. Nervous system reactions, skin rashes, edema, unspecified eye disorders, and liver function test abnormahties aU occur (1). 

As a consequence of the toxicity related to the presence of aristolochic acid in plant preparations, several health institutions, such as the US Food and Drug Administration, Therapeutic Goods Administration have recently published safety information to prevent further cases of intoxication (information available at web address http //www.cfsan.fda. gov/ dms/ds-bot.html) [471], So detecting aristolochic acids in plant species that could be used in herbal remedies, and also in herbal preparations of uncertain composition, has attracted great priority in recent years to help prevent future adverse reactions. Aristolochic acids present in medicinal plants or herbs are analyzed by soxhlet extraction followed by TLC in the Chinese pharmacopoeia [412]. Another report used multiple ultrasonic extraction followed by HPLC analysis [472]. Ong s laboratory reported a method using a home made pressurized liquid extraction (PLE) system in dynamic mode to extract aristolochic acid in medicinal plants, followed by gradient elution HPLC [473]. Several scientific communities described various analytical methods for... 

However, there is also evidence that adverse reactions may be more common when this combination is used. During a pharmacokinetic study in healthy volunteers a 68-year-old woman developed severe thrombocytopenia after taking the combination, and no other drug therapy, for 2 weeks [266 j. Her platelet count fell from 200 to 15 X 10 /1. The two drugs were discontinued and her platelet count returned to normal within 1 week. In a review of the FDA s Adverse Event Reporting System database there were 93 cases of reduced platelet counts associated with oseltamivir and 24 associated with probenecid. Signal detection analyses were significant for oseltamivir but not probenecid. 

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