Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study

AIMS

To examine the effect of β-adrenoceptor blocker treatment on cancer survival.

METHODS

In a UK primary care database, we compared patients with a new cancer diagnosis receiving β-adrenoceptor blockers regularly (n = 1406) with patients receiving other antihypertensive medication (n = 2056).

RESULTS

Compared with cancer patients receiving other antihypertensive medication, patients receiving β-adrenoceptor blocker therapy experienced slightly poorer survival (HR = 1.18, 95% CI 1.04, 1.33 for all β-adrenoceptor blockers; HR = 1.21, 95% CI 0.94, 1.55 for non-selective β-adrenoceptor blockers). This poorer overall survival was explained by patients with pancreatic and prostate cancer with no evidence of an effect on survival for patients with lung, breast or colorectal cancer. Analysis in a cancer-free matched parallel cohort did not suggest selection bias masked a beneficial effect.

CONCLUSION

Our study does not support the hypothesis that β-adrenoceptor blockers improve survival for common cancers.     

Sesquiterpenoids from myrrh inhibit androgen receptor expression and function in human prostate cancer cells

Aim:

To examine whether two naturally occurring sesquiterpenoids (ST1 and ST2) with anti-proliferative activity in prostate cancer cells inhibit androgen receptor (AR) signaling.

Methods:

Human prostate cancer cell lines LNCaP and PC3 were used. The expression of AR, AR translocation into the nucleus, and expression levels of AR coactivators ARA70 and steroid receptor coactivator-1 (SRC-1) in LNCaP cells were examined using real-time PCR and Western blot. Changes in prostate-specific antigen (PSA) protein levels, PSA promoter activity, and androgen response element (ARE)-mediated reporter gene activity were examined using enzyme-linked immunoabsorbent assay (ELISA) and transient transfection assays. Co-immunoprecipitation was performed to analyze the interaction between AR and the AR coactivators in ST1- and ST2-treated cells.

Results:

In LNCaP cells, ST1 and ST2 (40 μmol/L) led to a significant decrease in the expression of AR as well as a reduction of AR translocation into the nucleus, but had no effect on AR protein translation. ST1 and ST2 treatment also resulted in a significant decrease in the level of PSA protein secreted into the medium and was able to suppress PSA promoter-dependent and ARE-dependent luciferase activity. Furthermore, decreased expression of ARA70 and SRC-1 was observed when LNCaP cells were exposed to ST1 and ST2, which interfered with their ability to interact with AR.

Conclusion:

The observations suggest that suppression of AR transactivation by ST1 and ST2 may be mediated, in part, by inhibiting AR nuclear translocation and/or interfering with the interaction between AR and its coactivators ARA70 and SRC-1. Therefore, sesquiterpenoids could be developed as novel therapeutic agents for treating prostate cancer.     

Analysis of Antithrombotic Therapy After Cardioembolic Stroke Due to Atrial Fibrillation or Flutter

Background:

Guidelines recommend that all patients with atrial fibrillation and a history of ischemic stroke should receive an anticoagulant. Prior analyses show that warfarin is underutilized in most populations.

Objective:

To examine the use of antithrombotic and anticoagulant therapy in patients with atrial fibrillation or flutter during the index hospitalization for acute, ischemic stroke.

Methods:

Retrospective electronic medical record review of 200 patients treated at a tertiary care hospital with a primary ICD-9 code for ischemic stroke and a secondary ICD-9 code for atrial fibrillation or flutter. Exclusion criteria were active bleeding, pregnancy, age less than 18, pre-existing warfarin allergy, or dabigatran use.

Results:

Fifty-two percent of patients received at least one dose of warfarin during the index hospitalization. There was no relationship between CHADS₂ score and likelihood of receiving warfarin (P > .05). There was no significant difference in adverse event rate in patients receiving warfarin compared to those receiving aspirin (3.8% vs 9.1%; P = .14), but the rate of hemorrhagic transformation was lower in patients receiving warfarin (1% vs 7%; P = .03). The composite of hemorrhagic stroke or hemorrhagic transformation was significantly lower in patients receiving bridging therapy (0% vs 11%; P = .03). Sixteen patients were readmitted for stroke within 3 months of discharge. Ten were readmitted for ischemic stroke, 3 for hemorrhagic stroke or hemorrhagic transformation, and 3 for systemic bleeding. Ten patients (62.5%) were receiving warfarin at readmission, but only one of these patients had a therapeutic INR.

Conclusions:

Warfarin was underutilized as secondary stroke prophylaxis in these high-risk patients. Bridging therapy appeared to be safe and was not associated with an increase in adverse events.     

Comparison of the Efficacy and Safety of Two Different Insulin Infusion Protocols in the Medical Intensive Care Unit

Background:

New guidelines recommend using less intensive glycemic goals in critically ill patients receiving insulin infusions.

Objective:

To compare the efficacy and safety of a modified insulin infusion protocol (MIIP) with less stringent blood glucose (BG) goals to an intensive insulin infusion protocol (IIIP) in patients in a medical intensive care unit (MICU)

Methods:

Retrospective review of patients receiving an insulin infusion for at least 24 hours. Patients treated for hyperglycemic emergencies were excluded. The primary endpoint of the study was mean area under the BG curve (BG-AUC) at 24 and 48 hours. Other endpoints included mean BG, hours until BG at goal, rate of BG above goal, frequency of BG measurements, and rate of hypoglycemia.

Results:

BG-AUC at 24 hours was similar between the groups (MIIP = 5177.7 ± 1221.3 mg/dL x h vs IIIP = 4850.3 ± 1301.7 mg/dL x h; P = .20). The mean BG level at 24 hours was 225.1 ± 91.1 mg/dL in the MIIP group and 205.7 ± 89.7 mg/dL in the IIIP group (P = .06). In the MIIP group, 61.7% of the BG levels were above goal as compared to 87.5% in the IIIP group (P < .0001). Patients were able to achieve BG goals faster with the MIIP (12.58 ± 10.5 hours vs 29.37 ± 16.8 hours; P < .001). The rate of severe hypoglycemia was lower at 24 hours in the patients following the MIIP (0% vs 0.3%; P = .01).

Conclusion:

The study showed that by having less intensive glycemic goals, goal BG levels can achieved faster and the rate of severe hypoglycemia can decrease.     

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation

Aim:

To determine the efficacy and toxicities of sorafenib in the treatment of patients with multiple recurrences of hepatocellular carcinoma (HCC) after liver transplantation in a Chinese population.

Methods:

Twenty patients with multiple recurrences of HCC after liver transplantation were retrospectively studied. They received either transarterial chemoembolization (TACE) or TACE combined with sorafenib.

Results:

The median survival times (MST) after multiple recurrences was 14 months (TACE+sorafenib group) and 6 months (TACE only group). The difference was significant in MST between the two groups (P=0.005). The TACE + sorafenib group had more stable disease (SD) patients than the TACE group. The most frequent adverse events of sorafenib were hand–foot skin reaction and diarrhea. In the univariate analysis, preoperative bilirubin and CHILD grade are found to be significantly associated with tumor-free survival time, the survival time after multiple recurrences and overall survival time. TACE+sorafenib group showed a better outcome than single TACE treatment group. In the multivariate COX regression modeling, the preoperative high CHILD grade was found to be a risk factor of tumor-free survival time. In addition, the preoperative high bilirubin grade was also found to be a risk factor of survival time after recurrence and overall survival time. Furthermore, survival time after recurrence and overall survival time were also associated with therapeutic schedule, which was indicated by the GROUP.

Conclusion:

Treatment with TACE and sorafenib is worthy of further study and may have more extensive application prospects.     

Effectiveness of three times daily lansoprazole/amoxicillin dual therapy for Helicobacter pylori infection in Korea

AIM

We compared three times daily dual therapy with standard triple therapy for effectiveness and safety in H. pylori infection.

METHODS

Two hundred and four H. pylori positive patients with peptic ulcer were randomly assigned to one of two regimens: (i) triple therapy with amoxicillin, clarithromycin and lansoprazole twice daily for 2 weeks or (ii) dual therapy with amoxicillin and lansoprazole three times daily for 2 weeks. The success of eradication was evaluated 4 to 5 weeks after completing treatment.

RESULTS

The eradication rate was 82.8% in the triple therapy group and 78.4% in the dual therapy group by per protocol analysis. This difference was not significant (P= 0.573). Adverse events were more frequent in the triple therapy group than in the dual therapy group (P= 0.002).

CONCLUSIONS

Because dual therapy had fewer side effects than triple therapy and a similar eradication rate, dual therapy may provide an acceptable alternative first line therapy for H. pylori eradication in Korea.     

Retrospective Analysis of Levetiracetam Compared to Phenytoin for Seizure Prophylaxis in Adults with Traumatic Brain Injury

Background:

Phenytoin is standard of care for seizure prophylaxis following traumatic brain injury (TBI). Levetiracetam, an alternative antiepileptic drug, is utilized for seizure prophylaxis despite limited data supporting its use.

Objective:

Our primary outcome was post-TBI seizure activity measured by electroencephalogram (EEG) for levetiracetam versus phenytoin. Secondary outcomes were length of intensive care unit (ICU) stay, requirement for additional antiepileptic drugs (AED), and drug and monitoring costs.

Methods:

A retrospective review was performed of patients admitted to neurosurgical or surgical trauma ICU. Adult patients with at least 1 day of EEG monitoring were included. Patients were excluded if they had history of epilepsy, prior TBI, less than 48 hours of AED therapy, or additional AED prior to EEG monitoring.

Results:

A total 90 patients met inclusion criteria, with 18 receiving levetiracetam and 72 receiving phenytoin. Prevalence of EEG-confirmed seizure activity was similar between the levetiracetam and phenytoin groups (28% vs 29%; P = .99). ICU length of stay (13 vs 18 days; P = .28), time to EEG-confirmed seizure activity (4 vs 6 days; P = .24), and duration of seizure prophylaxis (9 vs 14 days; P = .18) were also similar. The median daily cost of levetiracetam therapy was $43 compared to $55 for phenytoin therapy and monitoring (P = .08). When all anticonvulsant therapy and monitoring were included, costs were lower for the levetiracetam group ($45 vs $83; P = .02).

Conclusion:

Levetiracetam may provide an alternative treatment option for seizure prevention in TBI patients in the ICU. Total antiepileptic drug and monitoring costs were lower for levetiracetam patients.     

Survey and Systematic Literature Review of Probiotics Stocked in Academic Medical Centers within the United States

Background:

Probiotics have a wide variation in their effectiveness in preventing or treating conditions due to the varying beneficial effects of specific probiotic strains. In other words, there is no “generic equivalency” between different probiotic species. However, it is has been noted that many practitioners consider probiotics in generic terms and may not realize the impact of these differences between probiotics.

Objective:

The aims of this study were to identify probiotics used in US academic medical centers and to determine whether those probiotics were supported by a reliable evidence base.

Methods:

A phone survey of 126 inpatient pharmacies in US academic medical centers was conducted to determine which probiotics were stocked. A systematic search was conducted to identify relevant studies that were then critically evaluated to determine whether the identified probiotics are supported by a reliable evidence base.

Results:

There was a 90.5% (114/126) response rate of academic medical centers that were contacted through the phone survey. Ten probiotic products were identified through the phone survey. The probiotic most often stocked in academic medical centers was Culturelle (27.2%) followed by Lactinex (25.4%). The systematic search identified evidence that evaluated Culturelle, Florastor, Lactinex, and VSL #3. Of those 4 probiotics, none were supported by a strong evidence base. However, the results suggested that both Culturelle and Florastor appear to be supported by more evidence compared to other probiotics.

Conclusion:

A majority of academic medical centers did not stock a probiotic that was supported by a reliable evidence base.     

A variation in NOS1AP gene is associated with repaglinide efficacy on insulin resistance in type 2 diabetes of Chinese

Aim:

To investigate a potential association between SNP rs10494366 in the neural nitric oxide synthase adaptor protein (NOS1AP) and efficacy of repaglinide (an insulin secretagogue) in newly diagnosed Shanghai Chinese type 2 diabetes patients.

Methods:

A total of 104 newly diagnosed type 2 diabetes patients (69 men, 35 women) were recruited and treated with repaglinide for 24 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 24-week treatment. Genotyping was performed by sequencing.

Results:

The baseline value of BMI, HOMA-IR, HOMA-B, and fasting insulin level were significantly different between GG, GT, and TT genotypes (P=0.024, 0.030, 0.005, and 0.007, respectively). Carriers of TT genotype were in significant insulin resistance at baseline. After 24-week repaglinide monotherapy, the Δ value of fasting insulin (P=0.019) and HOMA-IR (P=0.011) were significantly different. TT carriers had the least insulin resistance after treatment. The mixed model analysis showed that the variation had an interaction effect with repaglinide treatment only on HOMA-IR (P=0.013).

Conclusion:

A common variant in rs10494366 is associated with repaglinide monotherapy efficacy on insulin resistance in newly diagnosed Shanghai Chinese type 2 diabetes patients.     

Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure

AIMS

To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure.

METHODS

The concentration of rosiglitazone at 3 h and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects.

RESULTS

Rosiglitazone concentration was significantly correlated with paclitaxel exposure (P = 0.018) while ERMBT had no predictive value (P = 0.47).

CONCLUSIONS

The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity.     

Amoxicillin/clavulanic acid-warfarin drug interaction: a randomized controlled trial

AIMS

To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy.

METHODS

In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo.

RESULTS

The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P= 0.94). The day 7–day 1 factor II, R(–) and S(–) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P= 0.81, P= 0.45, P= 0.75, respectively).

CONCLUSION

Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.     

Taking an Antibiotic Time-out: Utilization and Usability of a Self-Stewardship Time-out Program for Renewal of Vancomycin and Piperacillin-Tazobactam

Background:

Antibiotic time-outs can promote critical thinking and greater attention to reviewing indications for continuation.

Objective:

We pilot tested an antibiotic time-out program at a tertiary care teaching hospital where vancomycin and piperacillin-tazobactam continuation past day 3 had previously required infectious diseases service approval.

Methods:

The time-out program consisted of 3 components: (1) an electronic antimicrobial dashboard that aggregated infection-relevant clinical data; (2) a templated note in the electronic medical record that included a structured review of antibiotic indications and that provided automatic approval of continuation of therapy when indicated; and (3) an educational and social marketing campaign.

Results:

In the first 6 months of program implementation, vancomycin was discontinued by day 5 in 93/145 (64%) courses where a time-out was performed on day 4 versus in 96/199 (48%) 1 year prior (P = .04). Seven vancomycin continuations via template (5% of time-outs) were guideline-discordant by retrospective chart review versus none 1 year prior (P = .002). Piperacillin-tazobactam was discontinued by day 5 in 70/105 (67%) courses versus 58/93 (62%) 1 year prior (P = .55); 9 continuations (9% of time-outs) were guideline-discordant versus two 1 year prior (P = .06). A usability survey completed by 32 physicians demonstrated modest satisfaction with the overall program, antimicrobial dashboard, and renewal templates.

Conclusions:

By providing practitioners with clinical informatics support and guidance, the intervention increased provider confidence in making decisions to de-escalate antimicrobial therapy in ambiguous circumstances wherein they previously sought authorization for continuation from an antimicrobial steward.     

髂内动脉超选择性栓塞化疗术治疗晚期前列腺癌

目的 研究髂内动脉栓塞术在晚期前列腺癌治疗中的作用.方法 60例晚期前列腺癌患者随机分为两组,介入组28例,行双侧髂内动脉超选择性栓塞化疗并行双侧睾丸切除术加内分泌治疗;对照组32例,行双侧睾丸切除术加内分泌治疗.对两组治疗后的前列腺体积变化情况、尿流率及前列腺特异性抗原（PSA）等进行比较.结果 治疗后2周介入组前列腺体积较对照组有明显的缩小（P＜0.05）,尿流率改善显著（P＜0.05）,PSA降低更明显（P＜0.05）.介入组与对照组3年生存率分别为70.59%、66.67%（P＞0.05）.结论 前列腺癌的髂内动脉超选择性栓塞化疗术是治疗晚期前列腺癌有效的方法之一,尤其是对雄激素非依赖性的前列腺癌具有更大的意义.     

Descriptive Analysis of Patient Readmissions Within 60 Days Due to Medication-Related Events

Background:

Hospital readmissions have become a marker for quality health care. Readmissions secondary to failures of the medication use process are poorly documented and underrecognized.

Objective:

To identify the incidence of readmissions related to the medication use process and identify associated patient- and therapy-related risk factors.

Methods:

A prospective observational cohort study including patients discharged from an acute care medicine unit and readmitted within 60 days. The primary outcome was percentage of readmissions related to drug-related problems (DRPs) as defined by Pharmaceutical Care Network Europe (PCNE). Secondary outcomes included classification of problems using PCNE criteria, type and extent of pharmacist involvement in patient care, and identification of variables associated with a readmission related to a DRP.

Results:

One hundred patients provided informed consent and were included for analysis. A DRP associated with readmission was identified in 64 patients. Sixty-one percent were classified as a potential problem with effect or lack of effect of pharmacotherapy. Patients who had a pharmacy consult were less likely to have a DRP (27% vs 47%; P = .04), and patients who missed follow-up appointments were more than 3 times as likely to have a DRP (20% vs 4%; P = .03). Presence of a pharmacy consult (odds ratio [OR], 0.38; 95% CI, 0.15-0.99; P = .05) and missed follow-up appointments (OR, 5.63; 95% CI, 1.52-20.86; P = .01) remained significant in a multivariate regression model.

Conclusion:

DRPs were frequent in patients who were readmitted within 60 days. Clinical pharmacist involvement in care and support for appropriate patient follow-up may reduce unnecessary admissions.     

Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

AIM

The aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients.

METHODS

Forty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6–21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (f_u) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with ¹⁴C-tamsulosin.

RESULTS

C_max in plasma at 4.4 h for total tamsulosin was 15.2 ng ml⁻¹ and AUC(0,24 h) was 282 ng ml⁻¹ h, while for prostate C_max at 11.4 h post-dose was 5.4 ng ml⁻¹ and AUC(0,24 h) was 120 ng ml⁻¹ h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). f_u was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma C_max concentrations.

CONCLUSIONS

These data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma.     

Sildenafil improves renal function in patients with pulmonary arterial hypertension

Aim

Elevated serum creatinine (sCr) and low estimated glomerular filtration rate (eGFR) are associated with poor outcomes in patients with pulmonary arterial hypertension (PAH) whereas sildenafil treatment improves PAH outcomes. This post hoc analysis assessed the effect of sildenafil on kidney function and links with clinical outcomes including 6-min walk distance, functional class, time to clinical worsening and survival.

Methods

Patients with PAH received placebo or sildenafil 20, 40 or 80 mg three times daily in the SUPER-1 study and open-label sildenafil titrated to 80 mg three times daily (as tolerated) in the extension study.

Results

Baseline characteristics were similar among groups (n = 277). PAH was mostly idiopathic (63%) and functional class II (39%) or III (58%). From baseline to week 12, kidney function improved (increased eGFR, decreased sCr) with sildenafil and worsened with placebo. In univariate logistic regression, improved kidney function was associated with significantly improved exercise and functional class (odds ratios 1.17 [95% CI 1.01, 1.36] and 1.21 [95% CI 1.03, 1.41], respectively, for sCr and 0.97 [95% CI 0.94, 0.99] and 0.97 [95% CI 0.94, 0.99] for eGFR, all P < 0.05). In patients who maintained or improved kidney function, time to worsening was significantly delayed (P < 0.02 for both kidney parameters). Observed trends towards improved survival were not significant. Patients with eGFR <60 (vs. ≥60) ml min^–1 1.73 m^–2 appeared to have worse survival.

Conclusions

Sildenafil treatment was associated with improved kidney function in patients with PAH, which was in turn associated with improved exercise capacity and functional class, a reduced risk of clinical worsening, and a trend towards reduced mortality.