Review article: diagnosis and management of night-time reflux.

Symptoms of gastro-oesophageal reflux disease (GERD) range from mild to severe and, when they occur during night-time hours, can interfere with sleep patterns and reduce overall quality of life. The clinical presentation of GERD is characterized by oesophageal as well as supra-oesophageal symptoms, including otolaryngologic and pulmonary complications. However, GERD may be overlooked as the cause of a patient's supra-oesophageal symptoms because these complaints can occur in the absence of oesophageal symptoms or endoscopic changes. The role of available tools used for GERD diagnosis, including endoscopy, oesophageal pH monitoring and an empirical course of proton pump inhibitor therapy, is discussed. Interventions available to achieve the therapeutic goals of symptom relief and prevention include specific lifestyle modifications and over-the-counter as well as prescription pharmacological agents. Patient-initiated, as-needed treatment may not be the best choice for managing persistent night-time reflux because it requires patient arousal from sleep. Proton pump inhibitor therapy remains the treatment of choice for patients with more severe symptoms and those with erosive oesophagitis. Few studies have specifically evaluated the role of pharmacological agents in the management of night-time reflux and comparisons are difficult due to the variability in study design and endpoints assessed.

Comparison of 3 vancomycin dosage regimens during hemodialysis with cellulose triacetate dialyzers: post-dialysis versus intradialytic administration.

AIMS: Traditionally, vancomycin is administered following dialysis to minimize drug loss when high-flux membranes are employed. Unfortunately, this approach is extremely inconvenient for patients and staff, requiring the patients to remain in the unit for at least 1 hour following dialysis. This study was designed to evaluate the feasibility of administering vancomycin during hemodialysis. Specifically, this study was designed to compare the pharmacokinetics of vancomycin when administered during the last 1-2 hours of dialysis (i.e. intra-dialytic administration) to that administered after completion of dialysis. MATERIALS AND METHODS: In a randomized, 3-way crossover trial, the pharmacokinetics of vancomycin were evaluated in 9 hemodialysis patients, comparing vancomycin 15 mg/kg following dialysis (Phase I), vancomycin 15 mg/kg during the last hour of hemodialysis (Phase II) or vancomycin 30 mg/kg during the last 2 hours of hemodialysis (Phase III). Vancomycin plasma concentrations were obtained over an 8-day period and subsequent comparisons between the treatment approaches were made with paired t-tests or ANOVA, as appropriate. Dialysate vancomycin concentrations determined on Day 1 and Day 3 of Phases II and III were used to calculate the fraction of vancomycin dose removed, and were compared to plasma data using paired t-tests. RESULTS: Vancomycin was significantly removed (33.4 to 39.5%) during a 3- to 4-hour high-flux dialysis session occurring on Day 3 after vancomycin administration. Mean serum concentrations immediately following intradialytic vancomycin administration of 15 mg/kg over the last hour of dialysis or 30 mg/kg over the last 2 hours of dialysis were initially high (77.7 and 95.5 mcg/ml respectively), but fell to 25.9 and 40.5 mcg/ml, respectively, by 4 hours post-dialysis. Predialysis concentrations on Days 3, 5 and 8 were similar for vancomycin 30 mg/kg administered over the last 2 hours of dialysis as compared with a 15 mg/kg dose given after dialysis. Vancomycin 15 mg/kg over the last hour of dialysis resulted in significantly lower subsequent predialysis concentrations than the other dosing schemes. CONCLUSIONS: Vancomycin administration of 30 mg/kg over the last 2 hours of dialysis achieves serum concentrations similar to conventional dosing of 15 mg/kg after dialysis and would allow dosing on a weekly basis.

Novel method to assess gastric emptying in humans: the Pellet Gastric Emptying Test.

To further validate the Pellet Gastric Emptying Test (PGET) as a marker of gastric emptying, a randomized, four-way crossover study was conducted with 12 healthy subjects. The study consisted of oral co-administration of enteric coated caffeine (CAFF) and acetaminophen (APAP) pellets in four treatment phases: Same Size (100 kcal), Fasted, Small Liquid Meal (100 kcal), and Standard Meal (847 kcal). The time of first appearance of measurable drug marker in plasma, t(initial), was taken as the emptying time for the markers. Co-administration of same size enteric coated pellets of CAFF and APAP (0.7 mm in diameter) revealed no statistically significant differences in t(initial) values indicating that emptying was dependent only on size and not on chemical make-up of the pellets. Co-administration of different size pellets indicated that the smaller 0.7-mm diameter (CAFF) pellets were emptied and absorbed significantly earlier than the larger 3.6-mm diameter (APAP) pellets with both the Small Liquid Meal (by 35 min) and the Standard Meal (by 33 min) (P<0.05). The differences in emptying of the pellets were not significant in the Fasted Phase. The results suggest that the pellet gastric emptying test could prove useful in monitoring changes in transit times in the fasted and fed states and their impact on drug absorption.

Historical overview of generic medication policy.

OBJECTIVE: To provide a historical perspective on controversies surrounding the use of generic drugs. DATA SOURCES: Articles were indexed initially using terms such as generic medications, generic drugs, multisource medications, and multisource drugs. These terms were used to search indexing services such as MEDLINE, International Pharmaceutical Abstracts, CINAHL (a database of nursing and allied health literature), Science Citation Index, Psychological Abstracts, and Wilson Indexes to Journal Articles. STUDY SELECTION: Performed by the authors, with preference given to events from 1951 to the present. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: The history of generic drug use is a history of conflict from a variety of perspectives. The primary conflict is economic, in which manufacturers of brandname pharmaceuticals aggressively seek to protect their patents from a variety of groups (e.g., the federal government, managed care organizations, consumer groups) that want access to less expensive medications. Another conflict is professional, especially for the members of the pharmacy profession who view drug product selection as an important opportunity for pharmacists to use their professional judgment. The most confusing conflict is the scientific discussion of bioequivalence and product quality. The brand manufacturers suggest that not all products are bioequivalent and of the same quality. This position has been opposed by the pharmacy profession, generic drug manufacturers, health care institutions, and the Food and Drug Administration. CONCLUSION: Generic drug use has increased dramatically during the past 50 years and is an accepted part of health care. However, the economic consequences of generic drug use are sufficiently high for this activity to continue as a source of controversy in the future.

Economics and structure of the generic pharmaceutical industry.

OBJECTIVE: To review key economic trends of the generic medication market and analyze the changing structure of the generic medication industry. DATA SOURCES: Articles were indexed initially using terms such as generic medications, generic drugs, multisource medications, and multisource drugs. These terms were used to search indexing services such as MEDLINE, International Pharmaceutical Abstracts, CINAHL (a database of nursing and allied health literature), Science Citation Index, Psychological Abstracts, and Wilson Indexes to Journal Articles. STUDY SELECTION: Performed by the authors. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: The generic pharmaceutical market has the potential to play an important role in containing drug costs, although the amount that could be saved through the use of generic medications is not easy to measure. If estimates for the future growth in the use of generic products prove correct, the proportion of pharmaceutical sales attributable to generic products will remain in the 9% to 10% range through the first decade of the 21st century. The generic pharmaceutical industry includes several categories of companies based on business strategies. Further consolidation is expected as more resources are needed to address patent challenges stimulated by the Drug Price Competition and Patent Restoration Act. Companies are also entering into partnerships with research manufacturers to share profits from proprietary products. Future growth of the generic market will require more than increased use of generic products. Therapeutic interchange, involving switching from single-source, patent-protected products to products within the therapeutic class for which there are generic equivalents, represents a major growth opportunity for generic drug manufacturers because the savings potential is more significant than that for straightforward substitution of generic for brandname products. CONCLUSION: As it responds to challenges and opportunities, the generic pharmaceutical industry will continue to be a major force shaping the economics of medication use.

Human jejunal permeability of two polar drugs: cimetidine and ranitidine.

PURPOSE: To determine the human jejunal permeability of cimetidine and ranitidine using a regional jejunal perfusion approach, and to integrate such determinations with previous efforts to establish a baseline correlation between permeability and fraction dose absorbed in humans for soluble drugs. METHODS: A sterile multi-channel perfusion tube, Loc-I-Gut, was inserted orally and positioned in the proximal region of the jejunum. A solution containing cimetidine or ranitidine and phenylalanine, propranolol, PEG 400, and PEG 4000 was perfused through a 10 cm jejunal segment in 6 and 8 subjects, respectively. RESULTS: The mean Peff (+/- se) of cimetidine and ranitidine averaged over both phases were 0.30 (0.045) and 0.27 (0.062) x 10(-4) cm/s, respectively, and the differences between the two were found to be statistically insignificant. The mean permeabilities for propranolol, phenylalanine, and PEG 400 averaged over both phases and studies were 3.88 (0.72), 3.36 (0.50), and 0.56 (0.08) x 10(-4) cm/s, respectively. The differences in permeability for a given marker were not significant between phases or between the two studies. CONCLUSIONS: The 10-fold lower permeabilities found for cimetidine and ranitidine in this study, compared to propranolol and phenylalanine, appear to be consistent with their less than complete absorption in humans.

Drug product selection: legal issues.

OBJECTIVE: To review the potential legal liability of the pharmacist in the drug product selection process. DATA SOURCES: Published articles identified through MEDLINE, published law reviews identified through InfoTrac, and appellate court decisions. Search terms used included pharmacist liability, drug product selection, and generic substitution. Additional articles, books, and appellate court decisions were identified from the bibliographies of retrieved articles and citations in appellate court decisions. DATA SYNTHESIS: Pharmacists engaging in drug product selection are civilly liable under three legal theories: negligence, express or implied warranties, and strict product liability. Potential criminal liability includes prosecution for insurance fraud, deceptive business practices, and violation of state drug product selection laws and regulation. CONCLUSION: Pharmacists increase their liability when engaging in drug product selection, but the increase is small. Still, the law continues to evolve as pharmacists seek expanded roles and responsibilities. When courts give closer examination to pharmacists' expanded role, it is likely that pharmacists' liability will increase.

Understanding the scientific issues embedded in the generic drug approval process.

OBJECTIVE: To review the major scientific issues embedded in the generic drug approval process. DATA SOURCES: Articles indexed initially under terms such as generic medications, generic drugs, bioequivalence, and bioinequivalence. These terms were used to search indexing services such as MEDLINE, International Pharmaceutical Abstracts, CINAHL (a database of nursing and allied health literature), and Science Citation Index. Additional data sources included the Code of Federal Regulations and regulatory guidances from the Food and Drug Administration (FDA) Center for Drug Evaluation and Research. STUDY SELECTION: Performed by the authors. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Despite the fact that regulations regarding bioequivalence have been in place for more than 20 years, controversies over bioequivalence continue to arise. Consensus on many of these issues is driving the development of new FDA guidances regarding bioequivalence. Still, despite the issuance of new guidance and consensus building among scientists, many clinicians and consumers remain uninformed regarding the scientific basis for establishing bioequivalence and the generic drug approval process in general. Although some have suggested that the generic drug approval process is flawed, overall, it appears that the process works. CONCLUSION: Understanding the generic drug approval process and the issues surrounding bioequivalence is of paramount importance to both clinicians and scientists.

Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases.

OBJECTIVE: To review the comparative efficacy and safety of the proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole, and rabeprazole--in the management of acid-related diseases. DATA SOURCES: English-language journal articles retrieved from a MEDLINE search from 1990 to the present using these index terms: proton pump inhibitors, omeprazole, lansoprazole, pantoprazole, rebeprazole, and each of the acid-related diseases. STUDY SELECTION: Clinical trials and pertinent review articles that discussed the pharmacology, pharmacokinetics, efficacy, and safety of PPIs in the management of acid-related disease. DATA EXTRACTION: By the authors. DATA SYNTHESIS: PPIs are substituted benzimidazoles that inhibit gastric acid secretion by covalently binding to the proton pump (H+/K+ ATPase). All undergo extensive hepatic metabolism and conjugation. The four agents differ in their metabolism by and effects on specific hepatic enzymes and thus in their ability to interact with other medications. PPIs are important agents used for eradicating Helicobacter pylori, in treating peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison syndrome, and upper gastrointestinal bleeding, and for preventing acid aspiration. Short-term side effects of the four agents are similar. The long-term safety of pantoprazole and rabeprazole appears similar to that of omeprazole and lansoprazole. Pantoprazole, which is in the final stages of approval for marketing in the United States, will be available in both an oral and injectable formulation. CONCLUSION: Based on superior efficacy profiles, PPIs are the drugs of choice in managing patients with peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. The decision to select one PPI versus another is most likely to be based on the agents' acquisition costs, formulations, FDA-labeled indications, and overall safety profiles. Intravenous or parenteral pantoprazole may become the preferred antisecretory agent for patients unable to take oral medications (e.g., critically ill patients and those with Zollinger-Ellison syndrome).

Pharmacokinetics of torsemide in patients with decompensated and compensated congestive heart failure.

Plasma pharmacokinetics of oral furosemide have been shown to be influenced by degree of decompensation in patients with congestive heart failure (CHF). This open-label, sequential comparison trial was conducted to determine whether CHF decompensation also alters the pharmacokinetics and pharmacodynamics of torsemide. Twelve patients with CHF, defined by either hemodynamic parameters or clinical signs and symptoms, were enrolled. On admission for treatment of their CHF, the patients were given 100 mg oral torsemide (phase A). A second dose of oral torsemide 100 mg was administered after hemodynamic parameters and clinical signs and symptoms of decompensated CHF resolved (phase B). Plasma and urine samples were collected over a 24-hour period for determination of torsemide concentrations and urine sodium. Hemodynamic measurements and physical signs and symptoms also were evaluated. During phase A, patients had significantly greater urine output and fractional sodium excretion compared with phase B. A significant increase in the area under the plasma concentration-time curve (AUC) was observed during phase B compared with phase A. However, no significant differences in maximal excretion rate of torsemide were noted between phase A and phase B. Heart failure status slightly affects the plasma pharmacokinetics of torsemide; however, this does not significantly alter the maximal urinary excretion rate of torsemide.

Determination of fluoxetine and norfluoxetine concentrations in cadaveric allograft skin.

Fluoxetine hydrochloride is the sixth most prescribed drug in the United States and is administered to treat major depression. A cadaveric skin donation was obtained from a 46-year-old woman who died as a result of a fluoxetine overdose. Due to the potential penetration of the drug and its major metabolite, norfluoxetine, into skin, the safety of using the skin as an allograft was questioned. Our evaluation showed that mean concentrations in skin were 2304+/-175 and 1353+/-102 ng/g of skin, respectively. The skin:plasma ratio was 0.41. Clinically, the amount of fluoxetine that can be transferred to an allograft recipient depends on many factors. Based on penetration of drug and metabolite into skin, one would have to evaluate carefully the risk:benefit ratio of using allografts from a donor who died from a fluoxetine overdose.

Drug marker absorption in relation to pellet size, gastric motility and viscous meals in humans.

PURPOSE: The objective of this study was to evaluate drug marker absorption in relation to the gastric emptying (GE) of 0.7 mm and 3.6 mm enteric coated pellets as a function of viscosity and the underlying gastric motility. METHODS: Twelve subjects were evaluated in a 3-way crossover study. 0.7 mm caffeine and 3.6 mm acetaminophen enteric coated pellets were concurrently administered with a viscous caloric meal at the levels of 4000, 6000 and 8000 cP. Gastric motility was simultaneously measured with antral manometry and compared to time events in the plasma profiles of the drug markers. RESULTS: Caffeine, from the 0.7 mm pellets, was observed significantly earlier in the plasma than acetaminophen, from the 3.6 mm pellets, at all levels of viscosity. Motility related size differentiated GE was consistently observed at all viscosity levels, however, less variability was observed with the 4000 cP meal. Specifically, the onset of absorption from the of 3.6 mm pellets correlated with the onset of Phase II fasted state contractions (r = 0.929, p < 0.01). CONCLUSIONS: The timeframe of drug marker absorption and the onset of motility events were not altered within the range of viscosities evaluated. Rather, the differences in drug marker profiles from the non-digestible solids were most likely the result of the interaction between viscosity and motility influencing antral flow dynamics. The administration of the two sizes of pellets and a viscous caloric meal with subsequent monitoring of drug marker profiles is useful as a reference to assess the influence of motility patterns on the absorption profile of orally administered agents.

Human intestinal permeability of piroxicam, propranolol, phenylalanine, and PEG 400 determined by jejunal perfusion.

PURPOSE: To determine the human jejunal permeabilities of compounds utilizing different transport mechanisms using a regional perfusion approach and to establish a standard procedure for determining drug permeability class to be used for the establishment of drug product bioequivalence standards. METHODS: Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and positioned in the proximal region of the jejunum. A solution containing piroxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate samples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and intersubject variation. RESULTS: The mean P(eff) (+/-SD) of piroxicam, phenylalanine, propranolol, and PEG 400 were 10.40 +/- 5.93, 6.67 +/- 3.42, 3.59 +/- 1.60, 0.80 0.46 x 10(-4) cm/sec, respectively. The coefficient of variation for the intersubject variability, first and second perfusion periods were: piroxicam, 60.5% and 57.1%; phenylalanine, 52.8% and 57.8%; propranolol, 62.1% and 44.6%; and PEG 400, 81.7% and 42.3%, indicating a slightly lower CV for the second perfusion period in the same subject. The intrasubject CV's between the two perfusion periods were: 19.4%, 21.3%, 23.6% and 41.0% respectively, indicating a smaller intraindividual variation for all compounds studied. CONCLUSIONS: Piroxicam, a nonpolar drug exhibited the highest permeability of the compounds studied. The intrasubject CV was lower than the intersubject CV, indicating consistent permeability estimation within subjects. The methodology is useful for permeability estimation regardless of absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption and for establishing the biopharmaceutic permeability class of drugs.

Alterations in gastric acidity in patients infected with human immunodeficiency virus.

In a randomized crossover trial, gastric acidity and gastric microbial colonization in 19 men infected with human immunodeficiency virus (HIV) (of whom nine had AIDS) were assessed. Gastric acidity was assessed during a baseline period and following pentagastrin or glutamic acid administration. Only two (22.2%) of the nine patients with AIDS and none of the non-AIDS patients were hypochlorhydric, as determined by maximal acid output. However, 60% and 67% of patients in the HIV-infected and AIDS groups, respectively, had persistently elevated gastric pH values during the baseline period. Both pentagastrin and glutamic acid significantly increased gastric acidity. Gastric colonization with Candida albicans and gram-positive mouth flora was common. Overall, this study demonstrates that many HIV-infected patients have elevated gastric pH values that may lead to alteration in drug absorption. The large degree of intrasubject and intersubject variability observed in gastric pH suggests that, unfortunately, one cannot predict which patients will have elevated gastric pH values.

Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients.

STUDY OBJECTIVE: To determine the variation of prothrombin times and international normalized ratio (INR) over 24 hours in humans. DESIGN: Prospective, parallel study. SETTING: University-affiliated general clinical research center. PATIENTS: Six patients receiving long-term warfarin therapy and six sex-matched controls. INTERVENTIONS: Warfarin was administered to the patients at 6:00 P.M. MEASUREMENTS AND MAIN RESULTS: Prothrombin times and INR were determined every 2 hours over 24 hours. Time of study entry, meals, and sleep cycles were controlled. A significant cosinor rhythm for prothrombin times and INR (p < or = 0.03) occurred in warfarin-treated patients, suggesting that diurnal variation occurs. The mean difference between the peak and trough prothrombin times was 1.8 +/- 0.9 seconds (range 0.8-3 sec) with a mean change of 9.3% +/- 3.7%. The peak prothrombin time and INR values occurred between 4:00 A.M. and 8:00 A.M. in five patients, and trough values between 6:00 P.M. and midnight in five. No significant cosinor rhythm was noted for controls (p > 0.5). CONCLUSION: Significant variations in prothrombin time and INR occurred in patients receiving warfarin therapy, with the highest values occurring in the morning and the lowest in the evening. These results may have clinical implications for patients receiving either high- or low-intensity warfarin therapy.

Influence of cellulose triacetate hemodialyzers on vancomycin pharmacokinetics.

This study was designed to evaluate the pharmacokinetics of vancomycin during hemodialysis with cellulose triacetate (CT) high-flux dialyzers and to assess the influence of membrane surface area on intradialytic clearance. In a randomized crossover fashion, the pharmacokinetics of vancomycin were evaluated during dialysis with the CT 110 and CT 190 membranes. Six hemodialysis patients received 1 g of vancomycin immediately after the completion of a dialysis session, and subsequently, blood samples were obtained over a 5-day study period. On Day 3 subjects were dialyzed with CT 110 or CT 190 membranes. The mean intradialytic clearance of vancomycin was 56.7 +/- 7.5 and 100.70 +/- 10.7 mL/min with the CT 110 and CT 190 membranes, respectively (P < 0.05). Significant rebound in vancomycin serum concentrations occurred after dialysis; this rebound appeared to be complete 3 h postdialysis. On the basis of postrebound concentrations, the apparent percent removal of vancomycin was 23.6 +/- 1.2 and 25.2 +/- 8.6% for CT 110 and CT 190 membranes, respectively (not significant). Vancomycin is significantly cleared during dialysis with cellulose triacetate membranes, and its clearance is dependent on membrane surface area. Although a small supplemental dose of vancomycin could be administered after dialysis to replace drug lost during dialysis, it may be more efficient to give a larger dose of vancomycin after several dialysis periods. The determination of vancomycin removal can be used to estimate vancomycin serum concentrations as well as dosage requirements. This in conjunction with serum concentration monitoring can be used to optimize vancomycin dosing.

The effect of dosage release formulations on the pharmacokinetics of propranolol stereoisomers in humans.

Recent studies in dogs have suggested that the disposition of S- and R-propranolol may depend on the input rate of drug delivered to the liver. Therefore, this study was designed to determine whether differences in the disposition of S- and R-propranolol occur in humans when altering the input rate of propranolol by giving different dosage forms of the drug. Twelve healthy subjects were enrolled in a single-dose, 4-way crossover pharmacokinetic study in which racemic propranolol was given according to 1 of 4 treatments: one 80-mg immediate-release (IR) tablet, phase A; two 80-mg IR tablets, phase B; a 160-mg controlled-release capsule, phase C; or a 10-mg IV bolus, phase D. The results showed no significant differences in the ratios of S/R-propranolol for AUC, clearance, or overall mean concentration among the oral dosage groups. Significant differences in these parameters including Cmax S/R ratio were seen between the oral phases and the IV phase. These differences appear to be related more to the route of administration than to the low input rate. However, at high concentrations there may be input-rate alteration in S/R ratios. Specifically, for phase B, which had the highest Cmax concentrations, the Cmax S/R ratio was significantly lower than the other oral dosage groups A and C (Cmax S/R ratios: 1.44 versus 1.54 and 1.54, respectively; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse drug reaction reporting in a multicenter surveillance study.

OBJECTIVE: To evaluate the performance of a multicenter, prospective surveillance program in identifying adverse events, and to seek explanations for misclassification bias. DESIGN: The design was a prospective observational study of patients with documented or suspected bacterial pneumonia. SETTING: Data were collected in 74 acute care hospitals across the US. PATIENTS: This evaluation was based on a consecutive sample of 1822 adult patients (> 18 years of age) with documented or suspected bacterial pneumonia who were being treated with a cephalosporin, a penicillin, or an aminoglycoside over a 3-month period. Patients were followed for the duration of antibiotic therapy and were excluded if antibiotic therapy was < 3 days or if the pneumonia was judged to be nonbacterial. INTERVENTIONS: Clinical pharmacists documented patient demographics, concurrent illnesses and medications, antibiotic administration, relevant laboratory data, and the occurrence of nephrotoxicity and neutropenia. MAIN OUTCOME MEASURES: Validity of investigators' identification of neutropenia and nephrotoxicity as compared with objective laboratory data was assessed by using sensitivity, specificity, and positive and negative predictive value measures. RESULTS: Among the 1502 patients with sufficient data to evaluate neutropenia, there was agreement in 1270 patients (84.6%); likewise, among 1291 patients with sufficient data to evaluate nephrotoxicity there was agreement in 1186 patients (91.9%). Sensitivity of the researchers' assessments was 50.9% and 71.0% for neutropenia and nephrotoxicity, respectively. The negative predictive value was > 95% for both events. CONCLUSIONS: Overall, this evaluation demonstrated that the Drug Surveillance Network can successfully identify targeted adverse events. Moreover, this study highlights the importance of validation for all types of outcomes-oriented research studies.