Cardiogenic shock in a 28-year-old woman associated with sibutramine use.

A 28-year-old woman collapsed in her home, and her companion rushed to call emergency services. Upon arrival, a physician performed CPR and endotracheal intubation, successfully restoring her voluntary heart rhythm. However, while en route to the hospital, ventricular fibrillation recurred. Despite the restoration of her voluntary rhythm through electrical defibrillation, she remained in a comatose state, which eventually led to multiple organ failures. Family members revealed that she had a 2-month history of taking diet pills. Histological examination revealed cardiomyocyte necrosis, contraction band necrosis, interstitial hemorrhage, collagen deposition, interstitial fiber proliferation, and myofiber remodeling. Analysis of blood and urine using GC-MS and LC-MS detected sibutramine and its primary metabolites, M1 and M2, which were consistent with the composition of the medication she was taking. The deceased was in good health with no underlying heart disease. The above information confirmed that the cause of her death was sibutramine.

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Therapeutic approach with squaric acid dibutylester for steroid resistant-alopecia areata incognita: A pilot study of a single center.

Topical immunotherapy is widely used in the treatment of alopecia areata (AA). Alopecia areata incognita (AAI) is a relatively common disorder, predominantly affecting females, characterized by widespread hair thinning in the absence of typical alopecic patches. AAI can have a chronic relapsing course and in some cases can be resistant to current standard treatments. Topical immunotherapy has been used in the management of AA with encouraging results, but to date there are no literature studies reporting the efficacy of topical immunotherapy with squaric acid dibutylester (SADBE) in AAI. The aim of our study is to evaluate the efficacy and tolerance of topical immunotherapy with SADBE in AAI not responding to conventional steroid therapy. A total of 12 patients were enrolled in our Hair Disease Outpatient Service, with a proved histological diagnosis of AAI, and resistant to classical steroid therapy. Each patient underwent global photography, pull test, and trichoscopy at beginning and during the follow-ups. The efficacy of topical immunotherapy with SADBE was assessed by evaluating the changes of clinical and trichoscopic signs. Complete regrowth was achieved in 66.7% of cases (8/12), three patients remained unchanged on clinical evaluation but showed subclinical improvement on trichoscopy, whereas one patient progressed and worsened both on clinical and trichoscopic examination. All patients reported scalp diffuse mild erythema and itching the day after the application of SADBE, which were well tolerated. Three patients developed reactive cervical lymphoadenomegaly. No other side effects were observed. Topical immunotherapy with SADBE is widely used in the management of patchy AA and can be considered an effective alternative in resistant AAI, providing visible clinical and trichoscopic improvement in the majority of cases. Further studies are warranted to confirm and validate our findings.

[Efficacy of lobaplatin plus S-1 and the predictive value of circulating tumor cell in patients with advanced gastric cancer].

Objective: To investigate the efficacy and safety of lobaplatin (LBP) plus S-1 for advanced gastric cancer (AGC) and determine the potential role of circulating tumor cells (CTC) for predicting the therapeutic response and prognosis. Methods: From January 2014 to February 2015, 64 consecutive patients with AGC received lobaplatin plus S-1 chemotherapy in Liaocheng People's Hospital. The clinical features, clinical response, adverse effects, prognosis and CTC pre- and post-treatment were retrospectively analyzed. The correlation between CTC and patients' disease control rate (DCR), objective response rate (ORR), progression free survival (PFS) as well as overall survival (OS) were investigated. Results: All 64 patients completed 2 cycles of chemotherapy.The number of patients who achieved complete regression, partial regression, stable and progression were 0, 24 (37.5%), 18 (28.1%) and 22 (34.4%), respectively. ORR was 37.5% and DCR was 65.6%. The median PFS was 10.8 months(95%CI 7.1-12.0) and the median OS was 16.1 months(95%CI 12.4-18.8). The ORR and PFS were not significantly different between patients with baseline CTC≥2 and CTC<2 (25.0% vs 53.6%, P=0.150; 6.2 months vs 7.5 months, P=0.780), while the DCR and OS were significantly different (45.9% vs 90.0%, P=0.008; 10.5 months vs 17.2 months, P<0.001). After 2 cycles of chemotherapy, the ORR and DCR in patients with CTC≥2 were 16.7% and 45.9%, respectively, which were significantly lower than those observed in patients with CTC<2 (50.0% and 90.0%, respectively). The former also had shorter median PFS and OS (6.6 months vs 8.9 months, 8.4 months vs 15.0 months, respectively). Patients with persistently CTC<2 or those exhibiting an conversion to CTC<2 following chemotherapy had an improved PFS and OS, while patients with persistently CTC≥2 or those exhibiting an conversion to CTC≥2 following therapy had shorter PFS and OS.The most frequent adverse effects were grade 1 or 2 gastrointestinal discomfort and myelosuppression. No patients discontinued chemotherapy because of adverse events. Conclusions: Lobaplatin plus S-1 had manageable safety profile and promising antitumor activity in patients with AGC. CTC could be used as a biomarker in evaluating therapeutic response and predicting their prognosis.

A PET/MRI study towards finding the optimal [18F]Fluciclovine PET protocol for detection and characterisation of primary prostate cancer.

PURPOSE: [18F]Fluciclovine PET imaging shows promise for the assessment of prostate cancer. The purpose of this PET/MRI study is to optimise the PET imaging protocol for detection and characterisation of primary prostate cancer, by quantitative evaluation of the dynamic uptake of [18F]Fluciclovine in cancerous and benign tissue. METHODS: Patients diagnosed with high-risk primary prostate cancer underwent an integrated [18F]Fluciclovine PET/MRI exam before robot-assisted radical prostatectomy with extended pelvic lymph node dissection. Volumes-of-interest (VOIs) of selected organs (prostate, bladder, blood pool) and sub-glandular prostate structures (tumour, benign prostatic hyperplasia (BPH), inflammation, healthy tissue) were delineated on T2-weighted MR images, using whole-mount histology samples as a reference. Three candidate windows for optimal PET imaging were identified based on the dynamic curves of the mean and maximum standardised uptake value (SUVmean and SUVmax, respectively). The statistical significance of differences in SUV between VOIs were analysed using Wilcoxon rank sum tests (p<0.05, adjusted for multiple testing). RESULTS: Twenty-eight (28) patients [median (range) age: 66 (55-72) years] were included. An early (W1: 5-10 minutes post-injection) and two late candidate windows (W2: 18-23; W3: 33-38 minutes post-injection) were selected. Late compared with early imaging was better able to distinguish between malignant and benign tissue [W3, SUVmean: tumour vs. BPH 2.5 vs. 2.0 (p<0.001), tumour vs. inflammation 2.5 vs. 1.7 (p<0.001), tumour vs. healthy tissue 2.5 vs. 2.0 (p<0.001); W1, SUVmean: tumour vs. BPH 3.1 vs. 3.1 (p=0.771), tumour vs inflammation 3.1 vs. 2.2 (p=0.021), tumour vs. healthy tissue 3.1 vs. 2.5 (p<0.001)] as well as between high-grade and low/intermediate-grade tumours (W3, SUVmean: 2.6 vs. 2.1 (p=0.040); W1, SUVmean: 3.1 vs. 2.8 (p=0.173)). These differences were relevant to the peripheral zone, but not the central gland. CONCLUSION: Late-window [18F]Fluciclovine PET imaging shows promise for distinguishing between prostate tumours and benign tissue and for assessment of tumour aggressiveness.

Childhood epidermolysis bullosa acquisita during squaric acid dibutyl ester immunotherapy for alopecia areata.

Epidermolysis bullosa acquisita (EBA) is a rare acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. Although EBA manifests more frequently in adults, it can occur in childhood. We describe a 6-year-old boy who developed the inflammatory variant of EBA shortly after initiation of immunotherapy with squaric acid dibutyl ester (SADBE) for scalp alopecia areata. The disease rapidly regressed following SADBE discontinuation and starting combined steroid and dapsone therapy, and never recurred after treatment tapering and withdrawal. The association of EBA with other autoimmune diseases is common, but EBA occurring during alopecia areata has not been described previously. The development of EBA during SADBE treatment is also notable: the clinical history and therapeutic response in our patient point to a possible role of SADBE in EBA onset.

Angioedema After Squaric Acid Treatment in a 6-Year-Old Girl.

Alopecia areata (AA) involves the immune-related destruction of hair follicles, resulting in patches of complete hair loss, most often on the scalp. The topical sensitizer squaric acid dibutylester (SADBE) is a popular treatment option given its low side-effect profile, hair regrowth potential, and lack of cross-reactivity with other chemicals. We describe a unique case of a 6-year-old girl who developed angioedema after SADBE treatment for AA.

An open-label, single-arm phase II clinical study of docetaxel plus lobaplatin for Chinese patients with pulmonary and hepatic metastasis of nasopharyngeal carcinoma.

To evaluate the efficacy and safety of the chemotherapy program of docetaxel combined with lobaplatin for Chinese patients with pulmonary and hepatic metastasis of nasopharyngeal carcinoma (NPC). This study included 37 NPC patients with pulmonary and hepatic metastasis. The chemotherapy program included docetaxel (75 mg/m, day 1) plus lobaplatin (30 mg/m, day 1). Cycle repetition was every 21 days. Patients were monitored for 7-41 months, with a median follow-up duration of 18 months. The total efficiency of this group was 67.6% and the disease control rate was 81.1%. The median progression-free survival was 9.4 months (95% confidence interval, 6.8-14.3 months), the median overall survival was 18.3 months (95% confidence interval, 13.7-22.8 months), and the 2-year survival rate was 37.8%. The main hematological toxicities were leukopenia (91.9%), anemia (81.1%), and thrombocytopenia (70.3%); other adverse reactions were mild. Changes in Epstein-Barr-DNA levels can basically reflect the dynamic changes in the efficacy of chemotherapy. Docetaxel combined with lobaplatin has a favorable outcome for the treatment of pulmonary and hepatic metastatic NPC. It has been a convenient regimen with tolerable toxicity.

The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects.

BACKGROUND: Neutrophils are effector cells recruited to airways in patients with asthma. Migration of neutrophils occurs predominantly through activation of the CXCR1 and CXCR2 receptors by CXC chemokines, including IL-8 and Gro-α. The dual CXCR1/CXCR2 antagonist SCH 527123 has been developed to target neutrophil migration to alleviate airway neutrophilia. This study investigated the effects of SCH 527123 on neutrophil levels within the bone marrow, peripheral blood and airways, and on isolated bone marrow and peripheral blood neutrophil migration from mild allergic asthmatics. METHODS: Thirteen subjects with mild allergic asthma completed a double blind, placebo-controlled, multi-center crossover study and were randomized to daily dosing of 30 mg SCH 527123 and placebo for 8 days. Subjects provided bone marrow, peripheral blood and sputum samples pre-dosing and on the last day of dosing. Neutrophil numbers were quantified in all samples and chemotaxis assays were performed on neutrophils purified from bone marrow and peripheral blood. RESULTS: Neutrophil numbers fell significantly in the peripheral blood and sputum following treatment with SCH 527123 compared to placebo treatment. No change in neutrophil numbers was observed in bone marrow. SCH 527123 reduced IL-8-induced migration of purified peripheral blood neutrophils (p < 0.05), but had limited effects on migration of neutrophils purified from bone marrow. CONCLUSIONS: The results from this study demonstrate that oral administration of the dual CXCR1/CXCR2 antagonist SCH 527123 reduces neutrophil levels in the circulation and airways through inhibition of migration. There were no toxic effects of SCH 527123 on granulocytic progenitor cells in the bone marrow.

Diagnostic performance and safety of NMK36 (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid)-PET/CT in primary prostate cancer: multicenter Phase IIb clinical trial.

OBJECTIVE: We performed a multicenter Phase IIb clinical trial of NMK36, a novel amino acid analog for positron emission tomography containing trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid, to evaluate its safety and diagnostic performance for primary prostate cancer. METHODS: Sixty-eight subjects with primary prostate cancer scheduled for radical prostatectomy or hormone therapy underwent whole-body positron emission tomography/computed tomography after injection of NMK36. The diagnostic performances of NMK36-positron emission tomography/computed tomography were evaluated for (i) regional lymph node metastasis: comparison with contrast-enhanced computed tomography under setting reference standard (histopathology or 6-month follow-up), (ii) bone metastasis: concordance rate with conventional imaging (combination of bone scintigraphy and contrast-enhanced computed tomography) and (iii) primary lesion: comparison with histopathological findings. RESULTS: The accuracy of NMK36-positron emission tomography/computed tomography and contrast-enhanced computed tomography for regional lymph node metastasis were 85.5 and 87.3%, respectively. NMK36-positron emission tomography/computed tomography showed positive findings for regional lymph nodes with short-axis diameters of 5-9 mm at 23 regions in 13 patients of hormone therapy cohort, but they were not confirmed with reference standard in this study. The concordance rate of NMK36-positron emission tomography/computed tomography with conventional imaging for bone metastases was 83.3%, and seven patients had positive findings only by NMK36-positron emission tomography/computed tomography. The sensitivity and specificity of NMK36-positron emission tomography/computed tomography for primary lesion in six-segment analysis was 92.5 and 90.1%, respectively. Seven of non-serious adverse events were observed in six patients. CONCLUSIONS: This study showed the comparable diagnostic performance of NMK36-positron emission tomography/computed tomography compared with conventional imaging. Some lesions of lymph node and bone were positive solely by NMK36-positron emission tomography/computed tomography, which needs to be confirmed with reference standard in future study to evaluate the usefulness of NMK36-positron emission tomography/computed tomography in staging prostate cancer.

Can social media data lead to earlier detection of drug-related adverse events?

PURPOSE: To compare the patient characteristics and the inter-temporal reporting patterns of adverse events (AEs) for atorvastatin (Lipitor® ) and sibutramine (Meridia® ) in social media (AskaPatient.com) versus the FDA Adverse Event Reporting System (FAERS). METHODS: We identified clinically important AEs associated with atorvastatin (muscle pain) and sibutramine (cardiovascular AEs), compared their patterns in social media postings versus FAERS and used Granger causality tests to assess whether social media postings were useful in forecasting FAERS reports. RESULTS: We analyzed 998 and 270 social media postings between 2001 and 2014, 69 003 and 7383 FAERS reports between 1997 and 2014 for atorvastatin and sibutramine, respectively. Social media reporters were younger (atorvastatin: 53.9 vs. 64.0 years, p < 0.001; sibutramine: 36.8 vs. 43.8 years, p < 0.001). Social media reviews contained fewer serious AEs (atorvastatin, pain: 2.5% vs. 38.2%; sibutramine, cardiovascular issues: 7.9% vs. 63.0%; p < 0.001 for both) and concentrated on fewer types of AEs (proportion comprising the top 20 AEs: atorvastatin, 88.7% vs. 55.4%; sibutramine, 86.3% vs. 65.4%) compared with FAERS. While social media sibutramine reviews mentioning cardiac issues helped predict those in FAERS 11 months later (p < 0.001), social media atorvastatin reviews did not help predict FAERS reports. CONCLUSIONS: Social media AE reporters were younger and focused on less-serious and fewer types of AEs than FAERS reporters. The potential for social media to provide earlier indications of AEs compared with FAERS is uncertain. Our findings highlight some of the promises and limitations of online social media versus conventional pharmacovigilance sources and the need for careful interpretation of the results. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

Long-term effects of weight-reducing drugs in people with hypertension.

BACKGROUND: All major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect. PRIMARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). SECONDARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. SEARCH METHODS: We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015). SELECTION CRITERIA: Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long-term pharmacologic interventions for weight loss with placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity. MAIN RESULTS: After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by -1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative.

The effect of sibutramine prescribing in routine clinical practice on cardiovascular outcomes: a cohort study in the United Kingdom.

BACKGROUND/OBJECTIVES: The marketing authorization for the weight loss drug sibutramine was suspended in 2010 following a major trial that showed increased rates of non-fatal myocardial infarction and cerebrovascular events in patients with pre-existing cardiovascular disease. In routine clinical practice, sibutramine was already contraindicated in patients with cardiovascular disease and so the relevance of these influential clinical trial findings to the 'real World' population of patients receiving or eligible for the drug is questionable. We assessed rates of myocardial infarction and cerebrovascular events in a cohort of patients prescribed sibutramine or orlistat in the United Kingdom. SUBJECTS/METHODS: A cohort of patients prescribed weight loss medication was identified within the Clinical Practice Research Datalink. Rates of myocardial infarction or cerebrovascular event, and all-cause mortality were compared between patients prescribed sibutramine and similar patients prescribed orlistat, using both a multivariable Cox proportional hazard model, and propensity score-adjusted model. Possible effect modification by pre-existing cardiovascular disease and cardiovascular risk factors was assessed. RESULTS: Patients prescribed sibutramine (N=23,927) appeared to have an elevated rate of myocardial infarction or cerebrovascular events compared with those taking orlistat (N=77,047; hazard ratio 1.69, 95% confidence interval 1.12-2.56). However, subgroup analysis showed the elevated rate was larger in those with pre-existing cardiovascular disease (hazard ratio 4.37, 95% confidence interval 2.21-8.64), compared with those with no cardiovascular disease (hazard ratio 1.52, 95% confidence interval 0.92-2.48, P-interaction=0.0076). All-cause mortality was not increased in those prescribed sibutramine (hazard ratio 0.67, 95% confidence interval 0.34-1.32). CONCLUSIONS: Sibutramine was associated with increased rates of acute cardiovascular events in people with pre-existing cardiovascular disease, but there was a low absolute risk in those without. Sibutramine's marketing authorization may have, therefore, been inappropriately withdrawn for people without cardiovascular disease.

The effects of the CXCR2 antagonist, MK-7123, on bone marrow functions in healthy subjects.

The CXCR2 antagonist MK-7123 causes dose-dependent reductions in absolute neutrophil counts (ANC) and decreases neutrophil tissue responses, but its effects on bone marrow functions are not yet known. We conducted a double-blind, randomized study in 18 healthy subjects comparing the effects of either MK-7123 (30mg, po, daily for 28days) or placebo on peripheral blood counts and bone marrow myeloid cell populations. MK-7123 caused a reversible decrease (approximately 50%) in the ANC as demonstrated on days 1 and 28, the first and last days of the treatment period. Bone marrow aspirate smears and biopsy imprints did not differ in the proportion of mature neutrophils in pretreatment, day 28, day 56 or placebo samples. There were no treatment effects on biopsy or aspirate clot cellularity, myeloid to erythroid or myeloid post-mitotic to mitotic ratios; flow-cytometric analyses of aspirate cells; or bone marrow fat to cell balance as assessed by MRI. MK-7123 was generally well tolerated with neutropenia being the most common adverse event; however, there were no clinical symptoms associated with decreased ANCs. These findings indicate that the CXCR2 antagonist MK-7123 causes rapidly reversible decrease in the ANC without measurable myelosuppressive effects. The results support the development of CXCR2 antagonists as potentially useful anti-inflammatory agents, primarily interrupting neutrophil trafficking.

Assessment of potential cardiovascular risks of methylphenidate in comparison with sibutramine: do we need a SCOUT (trial)?

With the recent approval of methylphenidate (MPH) for treating attention-deficit/hyperactivity disorder (ADHD) in adults, the number of patients exposed will increase tremendously. The ongoing debate on the cardiovascular safety of MPH has triggered two large retrospective cohort studies in children and adolescents as well as in young to middle-aged adults. These studies looked into serious cardiovascular events (sudden cardiac death, acute myocardial infarction and stroke) as primary endpoints and concluded that MPH was safe after a mean duration of 2.1 years of follow-up in children and adolescents and mean duration of 0.33 years of current use in adults. The results are encouraging with respect to the short- and medium-term use of MPH. Without the inherent limitations of retrospective cohort studies, a prospective randomized, double-blind, placebo-controlled, multicenter trial in individuals stratified for cardiovascular risk factors would allow for an optimized risk assessment. With many millions of patients treated per year and drawing parallels to the lately discovered risks of sibutramine, another sympathomimetic with an overlapping mode of action and similar side effects on heart rate and blood pressure, we hypothesize that such a trial might be a dedicated risk mitigation strategy for public health. A critical assessment of cardiovascular side effects of MPH appears particularly warranted, because ADHD is associated with obesity, smoking and poor health in general. We summarize recent findings with the focus on cardiovascular risks of MPH in humans; we additionally analyze the limited number of rodent studies that have addressed cardiovascular risks of MPH.

Comparison of efficacy and toxicity profiles between paclitaxel/lobapoatin- and cisplatin/5-fluorouracil-based concurrent chemoradiotherapy of advanced inoperable oesophageal cancer.

BACKGROUND AND AIM: Current chemoradiotherapy doesn't usually effectively control oesophageal cancer progression. This study assessed the efficacy and toxicity profiles of paclitaxel/lobaplatin (TL)- and cisplatin/5-fluorouracil (PF)-based concurrent chemoradiotherapy (CCRT) in patients with advanced inoperable oesophageal cancer. METHODS: A total of such 68 patients was recruited and randomised to receive TL or PF-based CCRT. Radiotherapy was given at a total dose of 60-70 Gy over 6 weeks. In the TL group of patients, paclitaxel 60 mg/m(2) was administered intravenously on day 1, 8 and 15 and lobaplatin 30 mg/m(2) was administered on day 2 in two cycles at 3-week intervals. In the PF group, cisplatin 75 mg/m(2) was administered intravenously on day 1, and 5-fluorouracil 500 mg/m(2) and leucovorin 200 mg/m(2) were administered intravenously daily for 5 days in two cycles at 3-week intervals. Adverse events, treatment response and follow-up data were collected. RESULTS: The treatment response rates were 73.53% and 50.00% in the TL and PF groups respectively (P = 0.040). The median tumour progression-free survival (PFS) was 13.0 and 6.5 months in the TL and PF groups respectively (P = 0.034). Compared with PF group, the TL group demonstrated decreased grade 3/4 nausea and vomiting (5.88% vs 35.29%, P = 0.003), decreased granulocytopenia (11.76% vs 32.35%, P = 0.041) and platelet count reduction (32.5% vs 8.8%, P = 0.016). CONCLUSIONS: The TL treatment regimen demonstrated higher efficacy with less overall toxicity in patients with advanced inoperable oesophageal cancer compared with the PF regimen. Further study is warranted to validate our current observations.