Postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999–2002

ABSTRACT

Objective: The authors performed a postmarketing database analysis to evaluate the incidence of cardiovascular and other serious adverse events (SAEs) reported to the US Food and Drug Administration's Adverse Event Reporting System (AERS) involving the use of rofecoxib.

Research design and methods: The authors studied all adverse events involving rofecoxib reported to the AERS from inception of the drug until 2002. An emphasis was placed on cardiovascular and other SAEs of interest categorized using the high level group terms hemorrhage, edema, thrombosis, embolism, and death.

Results: There were 31,024 reports of SAEs associated with the use of rofecoxib, which was considered primary suspect in 97.8% of these reports. There were 3915, 3677, 1653, 1917, and 233 reports of hemorrhage, edema, death, thrombosis, and embolism, respectively. Relative to the overall population in this dataset, reports of hemorrhage, death, thrombosis, and embolism consisted of a greater proportion of males. The mean age for patients that reported hemorrhage, death, and thrombosis was older, whereas the mean age for embolism and edema was younger than the overall population in this dataset. Aspirin was the most commonly reported concomitant medication (7.4% of reports) followed by acetaminophen (5.4%). Reports containing concomitant use of anti-coagulants, Cox-1, and nonselective inhibitors (each p?<?0.001) but not Cox-2 inhibitors were associated with increased age while only anti-coagulants and Cox-1 inhibitors (each p?<?0.001) were associated with more males. Reports containing concomitant use of an anti-coagulant or an NSAID accounted for a disproportionate incidence of hemorrhage, edema, embolism, and death. Most notably, the odds of a hemorrhagic event for those reporting concomitant use of an anti-coagulant, Cox-1, non-selective, or Cox-2 inhibitor was 3.05 (p?<?0.001), 3.07 (p?<?0.001), 2.07 (p?<?0.001), and 1.18 (p?<?0.001), respectively. Some weaknesses of this type of analysis are the retrospective nature of such a study, the inability to find causality, and that the data can contains multiple reports from any one individual.

Conclusions: It can be postulated that in addition to the risk of heart attack and stroke, rofecoxib users were at increased risk of hemorrhage, in addition to other thrombotic and embolic adverse events, which was exacerbated in those taking blood thinners or NSAIDs.     

Assessment of potentially abuse-related events in two phase 3 studies of NKTR-181, a novel opioid analgesic,using the MADDERS® system (Misuse,Abuse, and Diversion Drug Event Reporting System)

Objective: To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®).

Methods: SUMMIT-07 was an enriched enrollment randomized withdrawal study that examined the safety and efficacy of NKTR-181 across 12?weeks in opioid-naïve subjects with chronic low back pain. SUMMIT-LTS was a 52 week open-label study in opioid-naïve and experienced subjects with chronic low back pain or noncancer pain rolled over from SUMMIT-07 or enrolled de novo. System evaluations were triggered by adverse events of interest and drug accountability discrepancies signaling potentially abuse-related events. Each event was assigned a primary classification and supplementary classification(s) by investigators and by a blinded, independent committee of substance abuse experts (adjudicators). At the final study visit, investigators administered a survey to subjects to identify overlooked events of interest.

Results: Seventy-nine (6.6%) of 1189 subjects were associated with 86 events in SUMMIT-07 and 51 (8.0%) of 638 subjects were associated with 59 events in SUMMIT-LTS. Most events were attributed to “Withdrawal” and, primarily in SUMMIT-07, “Therapeutic Error” (unintentional overuse) or “Misuse” (intentional overuse for a therapeutic purpose) of study medication. Adjudicators identified five possible “Abuse” events (three NKTR-181, two placebo) in SUMMIT-07 and four possible “Abuse” events (all NKTR-181) in SUMMIT-LTS.

Conclusions: The MADDERS® system discerns potentially abuse-related events and identified low rates of withdrawal and a low risk of abuse potential, diversion or addiction associated with NKTR-181 in phase 3 trials.     

Synthesis and antiproliferative activity evaluation of new thiazole–benzimidazole derivatives using real-time cell analysis (RTCA DP)

A series of new 2-[(5-substituted-1H-benzimidazol-2-yl)thio]-N-[4-[2-phenylthiazol-4-yl]phenyl]acetamide derivatives (4a–p) were synthesized according to the reported literature, and anticancer activity of the compounds was evaluated. Cytotoxic activity was confirmed by real-time cytotoxicity analysis system determining half maximal inhibitory concentrations (IC₅₀) of the title compounds based on the dose–response curves derived by xCELLigence measurements against NIH/3T3, A549 and Caco2 cell lines for 24, 48 and 72 h exposure. Compound 4c was found to be as the most efficient molecule that exhibited selective antiproliferative activity against both of the cancer cells.     

Cost–effectiveness analysis of sacral neuromodulation (SNM) with Interstim for fecal incontinence patients in Spain

ABSTRACT

Introduction: Fecal incontinence (FI) is a condition with a high impact on the psychological and social life of healthy people. Interstim, the sacral neuromodulation (SNM) therapy, has shown higher effectiveness and safety rates than surgical procedures like dynamic graciloplasty or artificial anal sphincter in patients with intact anal sphincter (IAS) and after sphincteroplasty in patients with structurally deficient anal sphincter (SDAS).

Objective: To assess the cost-effectiveness of FI management in two scenarios – with and without SNM – and to estimate the potential budget impact of its progressive introduction in the Spanish setting.

Methods: Two decision analytical models were developed (IAS and SDAS patients) representing the possible clinical paths for each of the scenarios (with and without SNM), as well as its clinical and economic consequences in the mid-to long term with a Markov model. Clinical and resource use data were retrieved from the literature and validated by a clinician expert panel. Effectiveness was measured with both QALYs and symptom-free years (SFY). A 3% discount rate was used for future costs and benefits (time horizon = 5 years). Prevalence figures were combined with Interstim sales forecasts to estimate the total number of patients to receive therapy over the next 5 years and the associated budget impact.

Results: The introduction of Interstim in the therapeutic management of FI has an associated cost-effectiveness of €16?181 (IAS patients) and €22?195 (SDAS patients) per QALY gained. The progressive introduction of Interstim in 75 to 100 patients/year will have an estimated budget impact of 0.1% of incremental costs in patients with FI.

Conclusions: Introducing Interstim in the management of FI in IAS and SDAS patients in the Spanish setting has shown to be an efficient measure with an incremental cost–effectiveness ratio below the accepted Spanish threshold (around €35?000/QALY), and with a relatively low additional cost for the Spanish NHS.     

Development of a docetaxel micellar formulation using poly(ethylene glycol)–polylactide–poly(ethylene glycol) (PEG–PLA–PEG) with successful reconstitution for tumor targeted drug delivery

Docetaxel (DTX)-loaded polymeric micelles (DTBM) were formulated using the triblock copolymer, poly(ethylene glycol)–polylactide–poly(ethylene glycol) (PEG–PLA–PEG), to comprehensively study their pharmaceutical application as anticancer nanomedicine. DTBM showed a stable formulation of anticancer nanomedicine that could be reconstituted after lyophilization (DTBM-R) in the presence of PEG 2000 and D-mannitol (Man) as surfactant and protectant, respectively. DTBM-R showed a particle size less than 150?nm and greater than 90% of DTX recovery after reconstitution. The robustly formed micelles might minimize systemic toxicity due to their sustained drug release and also maximize antitumor efficacy through increased accumulation and release of DTX from the micelles. From the pharmaceutical development point of view, DTBM-R showing successful reconstitution could be considered as a potent nanomedicine for tumor treatment.     

A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity

Rationale

The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional?Cmotivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional?Cmotivational reactivity is complex and bidirectional due to upcoming compensatory processes.

Objectives

Therefore, we further investigated the relationship of the FAAH polymorphism and emotional?Cmotivational reactivity in humans.

Methods

We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers.

Results

Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence.

Conclusions

Our findings emphasize the bidirectionality and thorough examination of the eCB system??s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.     

Quantitative analysis of a novel HIV fusion inhibitor (sifuvirtide) in HIV infected human plasma using high-performance liquid chromatography–electrospray ionization tandem mass spectrometry

A sensitive method for measuring sifuvirtide, a novel HIV fusion inhibitor peptide drug in HIV-1⁺ human plasma by liquid chromatography–tandem mass spectrometry (LC–MS/MS) was developed. The plasma samples were treated by solvent/detergent (S/D) method to inactivate viral activity before analysis. After protein precipitation sifuvirtide was determined by LC–MS/MS. A structure analog was used as internal standard (IS). The mass spectrometer was operated in positive ion and multiple reaction monitoring mode with transitions m/z 946.3 → 159.0 for sifuvirtide and 951.7 → 159.2 for IS. The intra-day precision ranged from 2.74% to 7.57% with accuracy from 91.63% to 102.53%. The inter-day precision ranged from 2.65% to 3.58% and the accuracy from 95.53% to 105.28%. Stability studies showed that sifuvirtide was stable both during the assay procedure and long-term storage. The lower limit of quantitation (LLOQ) was 9.75 ng ml⁻¹. The method was used for analyzing samples from phase IIa clinical study of sifuvirtide in China.     

Bladder/lung cancer mortality in Blackfoot-disease (BFD)-endemic area villages with low (<150 μg/L) well water arsenic levels – An exploration of the dose–response Poisson analysis

ObjectiveTo examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data.MethodPoisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150 μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data.ResultsUse of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors.ConclusionThe cancer rates are higher among the low-dose (<150 μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.