A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

Opioids such as morphine are the cornerstone of pain treatment. The challenge of measuring the concentrations of morphine and its active metabolites in order to assess human pharmacokinetics and monitor therapeutic drugs in children requires assays with high sensitivity in small blood volumes. We developed and validated a semi-automated LC-MS/MS assay for the simultaneous quantification of morphine and its active metabolites morphine 3ß-glucuronide (M3G) and morphine 6ß-glucuronide (M6G) in human plasma and in dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the internal standards were the only manual steps. Morphine and its metabolites were separated on a Kinetex 2.6-µm PFP analytical column using an acetonitrile/0.1% formic acid gradient. The analytes were detected in the positive multiple reaction mode. In plasma, the assay had the following performance characteristics: range of reliable response of 0.25-1000 ng/mL (r(2) > 0.99) for morphine, 1-1,000 ng/mL (r(2) > 0.99) for M3G, and 2.5-1,000 ng/mL for M6G. In DBS, the assay had a range of reliable response of 1-1,000 ng/mL (r(2) > 0.99) for morphine and M3G, and of 2.5-1,000 ng/mL for M6G. For inter-day accuracy and precision for morphine, M3G and M6G were within 15% of the nominal values in both plasma and DBS. There was no carryover, ion suppression, or matrix interferences. The assay fulfilled all predefined acceptance criteria, and its sensitivity using DBS samples was adequate for the measurement of pediatric pharmacokinetic samples using a small blood of only 20-50 µL.

A low blood volume LC-MS/MS assay for the quantification of fentanyl and its major metabolites norfentanyl and despropionyl fentanyl in children.

Preterm and term neonates often require surgical procedures and analgesia. However, our knowledge about neonatal pharmacokinetics of fentanyl, the most commonly used drug for these procedures, and its metabolites is still incomplete. To facilitate pharmacokinetic studies of fentanyl and its metabolites in neonates and other children, we developed and validated an LC-MS/MS method based on minimally invasive, low blood volume sampling. LC-MS/MS was used for the simultaneous analysis of fentanyl, despropionyl fentanyl (DPF), and norfentanyl from dried blood samples (DBS) collected on filter paper. Positive ions were monitored using multiple reaction monitoring. Since the standard matrix for measuring fentanyl blood concentrations is plasma, the assay was developed and validated in plasma, whole blood, and then DBS. Our method was able to measure clinically relevant levels of fentanyl and its metabolites. In DBS, the lower limits of quantification were 100 pg/mL for fentanyl with a range of reliable response from 0.1 to 100 ng/mL (r(2)>0.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r(2)>0.99). In plasma and in DBS inter-day accuracy and precisions of fentanyl met predefined acceptance criteria and also indicated comparable assay performance in both matrices.

Minimally invasive colorectal resection is associated with a transient increase in plasma hepatocyte growth factor levels early after surgery for colon cancer.

INTRODUCTION: Surgery's impact on blood levels of hepatocyte growth factor (HGF), a potent angiogenic factor, is unknown. Preoperative (PreOp) HGF blood levels are elevated in patients with colorectal cancer (CRC) and correlate with disease stage and prognosis. This study's purpose was to determine plasma HGF levels after minimally invasive colorectal resection (MICR) in patients with CRC. METHODS: Clinical and operative data were collected. Blood samples were obtained in all patients PreOp and on postoperative day (POD) 1 and 3; in some, samples were taken during weeks 2 and 3 after MICR. Late samples were bundled into 7-day time blocks. HGF levels were determined via enzyme-linked immunosorbent assay in duplicate. Student's t test was used to analyze the data (significance, P < .0125 after Bonferroni correction). RESULTS: A total of 28 CRC patients who underwent MICR were studied. Most had right, sigmoid, or left segmental colectomy. The mean plasma HGF level was higher on POD 1 (2417 ± 1476 pg/mL, P < .001) and POD 3 (2081 ± 1048 pg/mL, P < .001) when compared with PreOp levels (1045 ± 406 pg/mL). Plasma levels were back to baseline by the second (1100 ± 474 pg/mL, P = .64) and third postoperative weeks (1010 ± 327 pg/mL, P = .51). CONCLUSION: MICR for CRC is associated with a 1.9- to 2.3-fold increase in plasma HGF levels during the first 3 PODs after which levels normalize. This transient increase may briefly promote angiogenesis and the growth of residual tumor cells.

Hospitals' health promotion services in their communities: findings from a literature review.

BACKGROUND: Hospitals have long had an important role in the health of communities and the nation. Health promotion (HP) has gained attention in American health and will become more important with the 2010 health reform legislation. Many U.S. hospitals provide HP services in their communities, and hospital leaders are accountable for HP. PURPOSES: This article uses a systematic review of research literature to answer three questions about U.S. hospitals' HP services in their communities: (a) What are the characteristics of hospitals that offer HP services? (b) What are the reasons that hospitals offer HP services? And (c) what are the implementation processes hospitals use to offer HP services? METHODOLOGY/APPROACH: Authors used search criteria and found 255 articles published between 1985 and 2009. Inclusion/exclusion criteria were applied to screen and select articles, and 25 articles were kept and reviewed. Authors independently completed a standard data extraction form for each article, combined and reconciled their data, and created a database of findings. FINDINGS: Hospital size was positively associated with HP, as were participation in systems, alliances, and networks. Communities' median income, existing HP, population younger than 65 years, population above poverty, and employment levels were positively related to hospitals' HP. Relationships with hospital ownership, managed care, and competition were less clear. External norms, HP diffusion, and mimetic behavior were reasons for hospitals' HP; community benefit laws were less important. To implement HP, hospitals applied management methods, shared resources, collaborated with community organizations, and used a variety of HP methods. PRACTICE IMPLICATIONS: Collaboration and linkages with other organizations enable hospitals to expand HP. Hospitals should apply management methods (not just HP methods) to effectively offer HP services. Support for small hospitals' HP is needed.

Increased utilization of flexible endoscopic methods during colorectal resection over a 3-year period.

INTRODUCTION: Intraoperative endoscopy (IE) is performed during some colorectal resections (CRR) mainly to inspect circular stapled anastomoses (CSA) and to locate small neoplasms. This study's purpose was to determine how often rigid and flexible lower endoscopic methods were used during CRR by one colorectal surgeon over three 1-year periods. METHODS: Data concerning the indication for surgery and IE, type of resection, and the use of rigid and flexible methods were obtained from a prospective database and from hospital charts during Period 1 (P1), 1/1/05 to 12/31/05; P2, 7/1/06 to 6/31/07; and P3, 7/01/07 to 6/30/08. The endoscopic CO2 insufflation device was introduced during P2. The utilization rates (UR) for rigid and flexible methods and the overall UR in each time period were compared. The chi(2) and Fisher exact test were used for analysis. RESULTS: No significant differences were found in overall endoscopy UR between periods (94-109/per period.) A significantly higher flexible UR was noted during P3 (43.1% of all CRR) than during P1 (18.6%, P < .001) or P2 (28.7%, P < .03). There was a concomitant significant drop in the rigid UR during Period 3 (1.8% of all CRR) when compared with P1 (24.5%, P < .001) or P2 (27.7%, P < .001). CONCLUSION: The overall UR did not significantly vary; however, during P3 the flexible UR increased whereas the rigid UR decreased (vs P1, P2; P < .05). The addition of extra endoscopes and an endoscopic CO2 insufflation device to the operating room coincided with increased flexible UR.

Serious Cardiovascular Adverse Events Reported with Intravenous Sedatives: A Retrospective Analysis of the MedWatch Adverse Event Reporting System.

BACKGROUND: Serious cardiovascular adverse events (SCAEs) associated with intravenous sedatives remain poorly characterized. OBJECTIVE: The objective of this study was to compare SCAE incidence, types, and mortality between intravenous benzodiazepines (i.e., diazepam, lorazepam, and midazolam), dexmedetomidine, and propofol in the USA over 8 years regardless of the clinical setting where it was administered. METHODS: The Food and Drug Administration's MedWatch Adverse Event Reporting System was searched between 2004 and 2011 using the Evidex® platform from Advera Health Analytics, Inc. to identify all reports that included one or more of ten different SCAEs (package insert incidence ≥ 1%) and where an intravenous benzodiazepine, dexmedetomidine, or propofol was the primary suspected drug. RESULTS: Among the 2326 Food and Drug Administration's MedWatch Adverse Event Reporting System cases reported, 394 (16.9%) were related to a SCAE. The presence of a SCAE (vs. a non-SCAE) is associated with higher mortality (34 vs. 8%, p < 0.001). The percentage of cases with one or more SCAE, the case mortality rate (%), and the incidence of each SCAE (per 106 days of sedative exposure), respectively, were benzodiazepines (14, 26, 13) [diazepam (13, 23, 31); lorazepam (15, 43, 14); midazolam (14, 20, 11)]; dexmedetomidine (40, 15, 13); and propofol (17, 39, 7). Propofol (vs. either a benzodiazepine or dexmedetomidine) was associated with more total SCAEs (268 vs. 126, p < 0.001) but a lower incidence (per 106 days of sedative exposure) of SCAE (7 vs. 13, p = 0.0001) and cardiac arrest [6.3 (benzodiazepine) vs. 6.7 (dexmedetomidine) vs. 1.4 (propofol), p < 0.0001]. CONCLUSIONS: Serious cardiac adverse events account for nearly one-fifth of intravenous sedative Food and Drug Administration's MedWatch Adverse Event Reporting System reports. These SCAEs appear to be associated with greater mortality than non-cardiac serious adverse events. Serious cardiac events may be more prevalent with either benzodiazepines or dexmedetomidine than propofol.

Analysis of Spontaneous Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic Adverse Events and JAK Inhibitors.

INTRODUCTION: The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks. METHODS: Adverse event (AE) data for tofacitinib, tofacitinib extended-release (XR), and ruxolitinib were obtained from the FAERS. Reporting odds ratios (RORs) and the R package 'PhViD' to estimate the empirical Bayesian geometric mean (EBGM) were used to detect AEs with higher-than-expected reporting rates within the FAERS. RESULTS: We did not find evidence in the FAERS for elevated reporting rates for DVT and PE across the three JAK inhibitors we analyzed. However, multiple drug-AE combinations relating to thromboembolic events had both RORs and EBGM values above 1, indicating a trend toward higher-than-expected reporting rates. For pulmonary thrombosis, the ROR values for ruxolitinib, tofacitinib, and tofacitinib XR were 1.46 (95% confidence interval [CI] 0.76-2.80), 2.46 (1.55-3.91), and 2.48 (0.80-7.71), respectively, while the EBGM values were 1.25 (0.70), 2.46 (1.64), and 1.56 (0.57), respectively. Ruxolitinib had ROR values of 4.08 (2.25-7.38) and 1.22 (0.97-1.53) for portal vein thrombosis and thrombosis, respectively. The EBGM values for the same drug-AE combinations were 3.04 (1.79) and 1.16 (0.96). CONCLUSIONS: Our safety review of postmarketing FAERS reports associated with three FDA-approved JAK inhibitors did not find elevated reporting rates for DVT and PE specifically. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. Portal vein thrombosis may also be a potential risk for ruxolitinib. While these FAERS data add to a growing body of evidence that JAK inhibitors may be contraindicated in patients at risk of thromboembolic events, the data need to be confirmed by future AE reporting trends, analysis of electronic health records, and/or future clinical trials.

Amyotrophic Lateral Sclerosis Associated with Statin Use: A Disproportionality Analysis of the FDA's Adverse Event Reporting System.

INTRODUCTION: Apparent elevations in reporting of amyotrophic lateral sclerosis (ALS)-like conditions associated with statin use have been previously described from data obtained via US and European databases. OBJECTIVE: The aim of this study was to examine US FDA Adverse Event Reporting System (FAERS) data to compare reporting odds ratios (RORs) of ALS and ALS-like conditions between statins and other drugs, for each statin agent. METHODS: We assessed for disproportional rates of reported ALS and ALS-related conditions for each statin agent separately by using the ROR formula. FAERS data were analyzed through September 2015. RESULTS: RORs for ALS were elevated for all statins, with elevations possibly stronger for lipophilic statins. RORs ranged from 9.09 (6.57-12.6) and 16.2 (9.56-27.5) for rosuvastatin and pravastatin (hydrophilic) to 17.0 (14.1-20.4), 23.0 (18.3-29.1), and 107 (68.5-167) for atorvastatin, simvastatin, and lovastatin (lipophilic), respectively. For simvastatin, an ROR of 57.1 (39.5-82.7) was separately present for motor neuron disease. CONCLUSION: These findings extend previous evidence showing that significantly elevated ALS reporting extends to individual statin agents, and add to concerns about potential elevated occurrence of ALS-like conditions in association with statin usage.

A data accounting system for clinical investigators.

Clinical investigators often preprocess, process, and analyze their data without benefit of formally organized research centers to oversee data management. This article outlines a practical three-file structure to help guide these investigators track and document their data through processing and analyses. The proposed process can be implemented without additional training or specialized software. Thus, it is particularly well suited for research projects with small budgets or limited access to viable research/data coordinating centers.

A Pharmacovigilance Signaling System Based on FDA Regulatory Action and Post-Marketing Adverse Event Reports.

INTRODUCTION: Many serious drug adverse events (AEs) only manifest well after regulatory approval. Therefore, the development of signaling methods to use with post-approval AE databases appears vital to comprehensively assess real-world drug safety. However, with millions of potential drug-AE pairs to analyze, the issue of focus is daunting. OBJECTIVE: Our objective was to develop a signaling platform that focuses on AEs with historically demonstrated regulatory interest and to analyze such AEs with a disproportional reporting method that offers broad signal detection and acceptable false-positive rates. METHODS: We analyzed over 1500 US FDA regulatory actions (safety communications and drug label changes) from 2008 to 2015 to construct a list of eligible signal AEs. The FDA Adverse Event Reporting System (FAERS) was used to evaluate disproportional reporting rates, constrained by minimum case counts and confidence interval limits, of these selected AEs for 109 training drugs. This step led to 45 AEs that appeared to have a low likelihood of being added to a label by FDA, so they were removed from the signal eligible list. We measured disproportional reporting for the final group of eligible AEs on a test group of 29 drugs that were not used in either the eligible list construction or the training steps. RESULTS: In a group of 29 test drugs, our model reduced the number of potential drug-AE signals from 41,834 to 97 and predicted 73 % of individual drug label changes. The model also predicted at least one AE-drug pair label change in 66 % of all the label changes for the test drugs. CONCLUSIONS: By concentrating on AE types with already demonstrated interest to FDA, we constructed a signaling system that provided focus regarding drug-AE pairs and suitable accuracy with regard to the issuance of FDA labeling changes. We suggest that focus on historical regulatory actions may increase the utility of pharmacovigilance signaling systems.

A Drug Safety Rating System Based on Postmarketing Costs Associated with Adverse Events and Patient Outcomes.

BACKGROUND: Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. OBJECTIVE: To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. METHODS: All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. RESULTS: The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However, other EPCs with median scores of 75 and above included hepatitis C virus NS3/4A protease inhibitor, recombinant human interferon beta, vascular endothelial growth factor-directed antibody, and tumor necrosis factor blocker. When Anatomical Therapeutic Chemical classifications were analyzed, antineoplastic drugs were outliers with approximately 80% of their individual scores 60 and above, while approximately 20%-30% of blood and anti-infective drugs had scores of 60 and above. Within-drug class results served to differentiate similar drugs. For example, 6 serotonin reuptake inhibitors had a score range of 35 to 53. CONCLUSIONS: This scoring system is based on estimated direct medical costs associated with postmarketing AEs and poor patient outcomes and thereby helps fill a large information gap regarding drug safety in real-world patient populations.

Stimulated reporting: the impact of US food and drug administration-issued alerts on the adverse event reporting system (FAERS).

BACKGROUND: The US Food and Drug Administration (FDA) uses the Adverse Event Reporting System (FAERS) to support post-marketing safety surveillance programs. Currently, almost one million case reports are submitted to FAERS each year, making it a vast repository of drug safety information. Sometimes cited as a limitation of FAERS, however, is the assumption that "stimulated reporting" of adverse events (AEs) occurs in response to warnings, alerts, and label changes that are issued by the FDA. OBJECTIVE: To determine the extent of "stimulated reporting" in the modern-day FAERS database. METHODS: One hundred drugs approved by the FDA between 2001 and 2010 were included in this analysis. FDA alerts were obtained by a comprehensive search of the FDA's MedWatch and main websites. Publicly available FAERS data were used to assess the "primary suspect" AE reporting pattern for up to four quarters before, and after, the issuance of an FDA alert. RESULTS: A few drugs did demonstrate "stimulated reporting" trends. A majority of the drugs, however, showed little evidence for significant reporting changes associated with the issuance of alerts. When we compared the percentage changes in reporting after an FDA alert with those after a sham "control alert", the overall reporting trends appeared to be quite similar. Of 100 drugs analyzed for short-term reporting trends, 21 real alerts and 25 sham alerts demonstrated an increase (greater than or equal to 1 %) in reporting. The long-term analysis of 91 drugs showed that 24 real alerts and 28 sham alerts demonstrated a greater than or equal to 1 % increase. CONCLUSIONS: Our results suggest that most of modern day FAERS reporting is not significantly affected by the issuance of FDA alerts.

The Weber effect and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS): analysis of sixty-two drugs approved from 2006 to 2010.

BACKGROUND: The United States Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) consists of adverse event (AE) reports linked to approved drugs. The database is widely used to support post-marketing safety surveillance programs. Sometimes cited as a limitation to the usefulness of FAERS, however, is the 'Weber effect,' which is often summarized by stating that AE reporting peaks at the end of the second year after a regulatory authority approves a drug. Weber described this effect in 1984 based upon a single class of medications prescribed in the United Kingdom. Since that time, the FDA has made a concerted effort to improve both reporting and the database itself. Both volume and quality of AE reporting has dramatically improved since Weber's report, with an estimated 800,000 yearly reports now being logged into FAERS. OBJECTIVE: The aim of this study was to determine if current FAERS reporting follows the trend described by Weber. METHODS: Sixty-two drugs approved by the FDA between 2006 and 2010 were included in this analysis. Publicly available FAERS data were used to assess the 'primary suspect' AE reporting pattern for up to a 4-year period following each drug's approval date. RESULTS: A total of 334,984 AE reports were logged into FAERS for the 62 drugs analyzed here. While a few of the drugs demonstrated what could be considered 'Weber effect' curves, a majority of the drugs showed little evidence for the effect. In fact, the general AE reporting pattern observed in this study appears to consist simply of increasing case counts over the first three quarters after approval followed by relatively constant counts thereafter. CONCLUSIONS: Our results suggest that most of the modern adverse event reporting into FAERS does not follow the pattern described by Weber. Factors that may have contributed to this finding include large increases in the volume of AE reports since the Weber effect was described, as well as a concerted effort by the FDA to increase awareness regarding the utility of post-marketing AE reporting.

Comparison of the quantification of acetaminophen in plasma, cerebrospinal fluid and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

Acetaminophen (paracetamol, N-(4-hydroxyphenyl) acetamide) is one of the most commonly prescribed drugs for the management of pain in children. Quantification of acetaminophen in pre-term and term neonates and small children requires the availability of highly sensitive assays in small volume blood samples. We developed and validated an LC-MS/MS assay for the quantification of acetaminophen in human plasma, cerebro-spinal fluid (CSF) and dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the deuterated internal standard were the only manual steps. Extracted samples were analyzed on a Kinetex 2.6 µm PFP column using an acetonitrile/formic acid gradient. The analytes were detected in the positive multiple reaction mode. Alternatively, DBS were automatically processed using direct desorption in a sample card and preparation (SCAP) robotic autosampler in combination with online extraction. The range of reliable response in plasma and CSF was 3.05-20,000 ng/ml (r(2)>0.99) and 27.4-20,000 ng/ml (r(2)>0.99) for DBS (manual extraction and automated direct desorption). Inter-day accuracy was always within 85-115% and inter-day precision for plasma, CSF and manually extracted DBS were less than 15%. Deming regression analysis comparing 167 matching pairs of plasma and DBS samples showed a correlation coefficient of 0.98. Bland Altman analysis indicated a 26.6% positive bias in DBS, most likely reflecting the blood: plasma distribution ratio of acetaminophen. DBS are a valid matrix for acetaminophen pharmacokinetic studies.

Quantification of the 5-lipoxygenase inhibitor zileuton in human plasma using high performance liquid chromatography-tandem mass spectrometry.

Zileuton is an orally active, selective inhibitor of 5-lipoxygenase, which catalyzes the first step in the conversion of arachadonic acid into leukotrienes. Given the important role of leukotrienes in inflammation and cell signaling, multiple studies have investigated the efficacy of zileuton in the treatment of human disease. Examples of disease targets include asthma, ulcerative colitis, rheumatoid arthritis, and more recently, acne, ischemic/reperfusion injury, inflammatory pain, and sickle cell anemia. Zileuton is currently approved for the prophylaxis and chronic treatment of asthma. We report the development and validation of a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of zileuton in human EDTA plasma. The range of reliable response was 3.05-20,000ng/mL in human plasma. The calibration curves had a correlation coefficient of r(2)>0.99. The intra-day precision was 3.4-5.3%. The inter-day precision ranged from 4.5% to 7.3% and inter-day accuracy from 100% to 107%. No matrix interferences, ion suppression/enhancement, or carry-over was observed. The assay met all predefined acceptance criteria and was subsequently employed to measure plasma zileuton concentrations in a clinical trial.

A survey of the FDA's AERS database regarding muscle and tendon adverse events linked to the statin drug class.

BACKGROUND: Cholesterol management drugs known as statins are widely used and often well tolerated; however, a variety of muscle-related side effects can arise. These adverse events (AEs) can have serious impact, and form a significant barrier to therapy adherence. Surveillance of post-marketing AEs is of vital importance to understand real-world AEs and reporting differences between individual statin drugs. We conducted a review of post-approval muscle and tendon AE reports in association with statin use, to assess differences within the drug class. METHODS: We analyzed all case reports from the FDA AE Reporting System (AERS) database linking muscle-related AEs to statin use (07/01/2005-03/31/2011). Drugs examined were: atorvastatin, simvastatin, lovastatin, pravastatin, rosuvastatin, and fluvastatin. RESULTS: Relative risk rates for rosuvastatin were consistently higher than other statins. Atorvastatin and simvastatin showed intermediate risks, while pravastatin and lovastatin appeared to have the lowest risk rates. Relative risk of muscle-related AEs, therefore, approximately tracked with per milligram LDL-lowering potency, with fluvastatin an apparent exception. Incorporating all muscle categories, rates for atorvastatin, simvastatin, pravastatin, and lovastatin were, respectively, 55%, 26%, 17%, and 7.5% as high, as rosuvastatin, approximately tracking per milligram potency (Rosuvastatin>Atorvastatin>Simvastatin>Pravastatin ≈ Lovastatin) and comporting with findings of other studies. Relative potency, therefore, appears to be a fundamental predictor of muscle-related AE risk, with fluvastatin, the least potent statin, an apparent exception (risk 74% vs rosuvastatin). INTERPRETATION: AE reporting rates differed strikingly for drugs within the statin class, with relative reporting aligning substantially with potency. The data presented in this report offer important reference points for the selection of statins for cholesterol management in general and, especially, for the rechallenge of patients who have experienced muscle-related AEs (for whom agents of lower expected potency should be preferred).

Influence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatin.

The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 through 18. Pharmacokinetic studies were conducted on day 4 (pravastatin alone) and day 18 (pravastatin + darunavir/ritonavir). Pravastatin area under the plasma concentration-time curve (AUC(tau)) was 21% higher during administration with darunavir/ritonavir compared with pravastatin alone; however, this difference was not statistically significant (P = .11). Group 3 variants had 96% higher pravastatin AUC(tau) on day 4 and 113% higher pravastatin AUC(tau) on day 18 compared with group 1. The relative change in pravastatin pharmacokinetics was largest in group 3 but did not differ significantly between diplotype groups. In sum, the influence of SLCO1B1*15 and *17 haplotypes on pravastatin pharmacokinetics was maintained in the presence of darunavir/ritonavir. Because OATP1B1 inhibition would be expected to be greater in carriers of normal or high-functioning SLCO1B1 haplotypes, these findings suggest that darunavir/ritonavir is not a potent inhibitor of OATP1B1-mediated pravastatin transport in vivo.

Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns.

SAR-943 (32-deoxo rapamycin) is a proliferation signal inhibitor via interaction with the mammalian target of rapamycin (mTOR). Most importantly, SAR-943 has improved chemical stability compared to rapamycin (sirolimus) and is currently under investigation as a drug coated on coronary stents. It was the goal of this study to identify the SAR-943 metabolites generated after incubation with human liver microsomes using high-resolution mass spectrometry (MS) and MS/iontrap (MS(n)) and comparison of fragmentation patterns of the metabolites with those of SAR-943 and other known rapamycin derivatives. Our study showed that SAR-943 is mainly hydroxylated and/or demethylated by human liver microsomes. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O-desmethyl, 16-O-desmethyl and 27-O-desmethyl SAR-943; hydroxylated metabolites: hydroxy piperidine SAR-943, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 46-hydroxy and 49-hydroxy SAR-943; didemethylated metabolites: 16,39-O-didesmethyl and 27,39-O-didesmethyl SAR-943; demethylated-hydroxylated metabolites: 39-O-desmethyl, 23- or 24-hydroxy and 39-O-desmethyl, hydroxy piperidine SAR-943 and dihydroxylated metabolites: 12-,23- or 24-dihydroxy SAR-943. In addition, several other demethylated-hydroxylated and dihydroxylated metabolites were detected. However, their exact structures could not be identified.

Continuous administration of a selective alpha7 nicotinic partial agonist, DMXBA, improves sensory inhibition without causing tachyphylaxis or receptor upregulation in DBA/2 mice.

Stimulation of nicotinic receptors, specifically the alpha7 subtype, improves sensory inhibition and cognitive function in receptor deficient humans and rodents. However, stimulation with a full agonist, such as nicotine, produces rapid tachyphylaxis of the P20N40-measured sensory inhibition process. 3-(2,4-dimethoxybenzylidine) anabaseine (DMXBA, also GTS-21) selectively activates the alpha7 nicotinic receptor, and in acute administration studies, has been shown to improve deficient sensory inhibition in both humans and rodents with repeated dosing. Unlike nicotine, this partial agonist acted without inducing tachyphylaxis. Here, we assessed the ability of DMXBA to improve sensory inhibition in DBA/2 mice after 7 days of continuous administration via a subcutaneously implanted osmotic minipump. When assessed on day 8, mice receiving saline showed the characteristic deficient sensory inhibition seen with untreated DBA/2 mice. The 25- and 50-mg/ml infusion concentrations of DMXBA, but not the 100-mg/ml, produced significantly improved sensory inhibition in the mice, exclusively through a decrease in test amplitude. No concentration significantly upregulated hippocampal alpha7 receptor levels. DMXBA levels in the brain were higher than plasma at 2 of the 3 concentrations infused. These data suggest that continuous exposure to DMXBA does not significantly affect the underlying responsiveness of the sensory inhibition pathway to this partial agonist, nor cause receptor upregulation, at these relatively low brain concentrations. The ability of DMXBA to maintain its effectiveness during constant administration conditions may be due to an ability to activate alpha7 receptors at low concentrations, and consequently low fractional occupancy of the five possible binding sites on this homomeric receptor.