What do we know and not know about mirabegron,a novel β3 agonist,in the treatment of overactive bladder?

Introduction and hypothesis

Mirabegron is a novel β3-adrenoceptor agonist recently approved by Japanese, American, and European authorities for overactive bladder (OAB) therapy. Here we review existing knowledge on this new class of medication, analyze existing literature on the topic, and make recommendations regarding its administration and necessary future studies.

Methods

We reviewed the current literature and analyzed mirabegron efficacy, safety, and suitability for treating OAB symptoms. We performed a systematic search of Medline/PubMed, and Embase. Studies exploring mechanisms involved in the effects of mirabegron were included. Searches were limited to the English language.

Results

Two phase II and two large-scale phase III multinational randomized controlled trials have supported mirabegron efficacy and tolerability with up to 12 weeks of therapy in OAB patients. The reported frequency and severity of treatment-emergent and serious adverse events were similar to antimuscarinics but with more than threefold lower incidence of dry mouth than with tolterodine. However, effects on the cardiovascular system, cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated.

Conclusion

Anticholinergic drugs should remain the first-line pharmacologic treatment for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy. However, it seems logical to use mirabegron as second-line treatment of OAB in patients who are poor responders or intolerant to anticholinergics.     

The reliability of clinical and biochemical assessment in symptomatic late‐onset hypogonadism: can a case be made for a 3‐month therapeutic trial?

OBJECTIVE: To assess whether testosterone (T) supplementation in men considered to have symptomatic late-onset hypogonadism (SLOH) can be evaluated clinically and biochemically. PATIENTS AND METHODS: To assess the relevance of the clinical and biochemical diagnosis of hypogonadism we investigated patients referred for the diagnosis and treatment of SLOH. Patients were assessed clinically and completed a screening questionnaire. The pituitary-adrenal-gonadal axis was comprehensively assessed biochemically. Those with a clinical diagnosis of hypogonadism and serum levels of T supporting such a diagnosis received exogenous T for >/= 3 months and were assessed for any clinical and biochemical response. Of an initial group of 45 men (mean age 59.2 years) 38 completed the study. RESULTS: Most men presented with symptoms of sexual dysfunction, lack of energy and/or depression. There were differences before and after treatment only in bioavailable T (BT), with none in the levels of total T (TT). There was a strong correlation before and after treatment in the levels of luteinizing hormone and follicle-stimulating hormone, and a weak negative correlation between gonadotrophins and BT. Neither TT nor BT had predictive value for the treatment response. There was a trend to a correlation between BT levels and treatment success. Changes in serum prostate specific antigen were insignificant during the limited period. CONCLUSION: The lack of accurate methods for diagnosing SLOH suggests that a therapeutic trial of T supplementation is warranted in men in whom there are no contraindications. The 3-month period largely circumvents the placebo effect and has minimal risks for serious adverse effects (mostly in relation to prostate safety). This controversial position needs further evaluation with a larger cohort and other biochemical measurements.     

The molecular biology of prostate cancer morbidity and mortality: Accelerated death from ejaculate poisoning?

The molecular biology of host-tumor interactions unique to human prostate cancer that cause patient morbidity are poorly understood despite the prevalence of this neoplasm. Little is known fundamentally about prostate-specific exocrine gene products secreted by metastatic prostate carcinoma cells at metastatic sites that cause diffuse bone pain, immunosuppression, anemia, cachexia, and other clinical signs of advanced prostate cancer. Growing evidence supports the presence of androgen-regulated exocrine gene products as independent mediators of prostate cancer morbidity. The experimental and clinical implications of a hypothesis that prostate-specific exocrine genes cause patient morbidity are discussed.     

‘Insignificant’ prostate cancer on prostatectomy and cystoprostatectomy: variation on a theme ‘low‐volume/ low‐grade’ prostate cancer?

Although ‘insignificant’ prostate cancer has been examined separately in radical prostatectomy (RP) and radical cystoprostatectomy (RCP) studies, it is not entirely clear whether cancers designated as ‘insignificant’ on RP and RCP represent the same, similar or different forms of prostate cancer. Insignificant prostate cancer has been traditionally defined based on the pathological findings in the whole prostate gland. In addition to the pathological determinants of ‘insignificant’ prostate cancer, it is also important to account for the biological and the clinical context of the disease, as well as patient age and health status to designate a prostate cancer ‘insignificant’. This review examines and compares prostate cancers described as ‘insignificant’ on RP and RCP. We conclude that in most cases these low‐volume/low‐grade prostate cancers represent an early stage and clinically ‘silent’ disease, which are only detected in different clinical settings.     

Clinical and pathological features of screen vs non‐screen‐detected prostate cancers: is there a difference?

OBJECTIVE

To evaluate the clinical and pathological characteristics of screen vs non‐screen‐detected prostate cancers, to determine if there is a difference in the same prostate‐specific antigen (PSA) range.

PATIENTS AND METHODS

In all, 997 patients who had had a radical prostatectomy were evaluated; 806 were Tyrolean screening volunteers, and 191 were from outside Tyrol, representing the ‘referred prostate cancer’ group. PSA level, age, prostate volume and pathological characteristics were assessed, as was the amount of over‐ and under‐diagnosis.

RESULTS

There were no statistically significant differences in patient age or PSA levels in the two groups. Even in the same PSA range there were statistically significantly more extraprostatic cancers in the referral group, at 31.7% and 17.4%, respectively. In the referred and screening groups there was over‐diagnosis in 7.9% and 16.8%, and under‐diagnosis in 40.8% and 27.8%, respectively.

CONCLUSION

This study suggests that screening volunteers have a statistically significantly higher rate of organ‐confined prostate cancers, and a statistically significantly lower rate of extracapsular extension and positive surgical margins than their counterparts in the referral group even in the same PSA range. As the pathological stage and surgical margin status are significant predictors of recurrence, these findings support the concept of PSA screening.     

Anti‐PSMA immunotoxin as novel treatment for prostate cancer? High and specific antitumor activity on human prostate xenograft tumors in SCID mice

BACKGROUND: Expression of the prostate specific membrane antigen (PSMA) is highly restricted to prostate epithelial cells. Therefore, toxin-based immunotherapy against this antigen may represent an alternative therapeutic option for prostate cancer. For these purposes, the effects of the recombinant anti-PSMA immunotoxin A5-PE40 on prostate tumor growth were investigated in vitro and in vivo. METHODS: The in vitro binding and cytotoxicity of A5-PE40 were tested on the PSMA-expressing prostate cancer cell line C4-2 and on the PSMA-negative cell line DU145 by flow cytometry and WST assays. The binding of the immunotoxin to SCID mouse xenografts and to various mouse organs was examined by Western blot analysis. In vivo, the antitumor activity of the immunotoxin was tested by injecting A5-PE40 in mice bearing C4-2 or DU145 xenografts. RESULTS: In vitro, a specific binding of A5-PE40 to C4-2 cells could be shown with a concentration-dependent cytotoxicity (IC(50) value=220 pM). In the next step, a specific binding of the immunotoxin to C4-2 xenografts could be demonstrated. In contrast, no binding on mouse organs expressing high homologous mouse PSMA was found. The treatment of mice with C4-2 tumors caused a significant inhibition of tumor growth in vivo, whereas DU145 xenografts remained totally unaffected. CONCLUSIONS: A5-PE40 represents a recombinant anti-PSMA immunotoxin with potent antitumor activity in mice bearing human prostate cancer xenograft tumors. Therefore, A5-PE40 could be a promising candidate for therapeutic applications in patients with prostate cancer.     

Remifentanil tolerance and hyperalgesia: short‐term gain,long‐term pain?

The unique pharmacology of remifentanil makes it a popular intra‐operative analgesic. Short‐acting opioids like remifentanil have been associated with acute opioid tolerance and/or opioid‐induced hyperalgesia, two phenomena which have different mechanisms and are pharmacologically distinct. Clinical studies show heterogeneity of remifentanil infusion regimens, durations of infusion, maintenance of anaesthesia, cumulative dose of remifentanil and pain measures, which makes it difficult to draw conclusions about the incidence of acute tolerance or hyperalgesia. However, it appears that intra‐operative remifentanil infusion rates of above 0.25 μg.kg^?1.min^?1 are associated with higher postoperative opioid consumption, suggesting tolerance. Infusion rates greater than 0.2 μg.kg^?1.min^?1 are characterised by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia. The use of concurrent multimodal analgesia, especially N‐methyl‐D‐aspartate receptor antagonists, may be an effective preventive strategy. The clinical significance and long‐term consequences of these entities is still uncertain.     

The good, the bad, and the ugly: should we completely banish human albumin from our intensive care units?

Implications: Human albumin is still widely used in critically ill patients for volume replacement therapy or for correcting hypoproteinemia. Most meta-analyses on the value of albumin administration are over 15 yr old and raise more questions than they answer. With the help of a MEDLINE analysis, we examined more recent studies in humans using albumin. Most of these studies have recommended a very cautious use of albumin in critically ill patients.     

Prevalence and characteristics of screen‐detected prostate carcinomas at low prostate‐specific antigen levels: aggressive or insignificant?

Screening for prostate cancer at low prostate-specific antigen (PSA) levels (相似文献   

Donor organ intervention before kidney transplantation: Head‐to‐head comparison of therapeutic hypothermia,machine perfusion,and donor dopamine pretreatment. What is the evidence?

Therapeutic hypothermia, hypothermic pulsatile machine perfusion (MP), and renal‐dose dopamine administered to stable brain‐dead donors have shown efficacy to reduce the dialysis requirement after kidney transplantation. In a head‐to‐head comparison of the three major randomized controlled trials in this field, we estimated the number‐needed‐to‐treat for each method, evaluated costs and inquired into special features regarding long‐term outcomes. The MP and hypothermia trials used any dialysis requirement during the first postoperative week, whereas the dopamine trial assessed >1 dialysis session as primary endpoint. Compared to controls, the respective rates declined by 5.7% with MP, 10.9% with hypothermia, and 10.7% with dopamine. Costs to prevent one endpoint in one recipient amount to approximately $17 000 with MP but are negligible with the donor interventions. MP resulted in a borderline significant difference of 4% in 3‐year graft survival, but a point of interest is that the preservation method was switched in 25 donors (4.6%) for technical reasons. Graft survival was not improved with dopamine on intention‐to‐treat but suggested an exposure–response relationship with infusion time. MP was less efficacious and cost‐effective to prevent posttransplant dialysis. Whether the benefit on early graft dysfunction achieved with any method will improve long‐term graft survival remains to be established.     

The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free‐to‐total prostate‐specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies?

Study Type – Diagnosis (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To determine the performance characteristics of the prostate cancer gene 3 (PCA3) score on the outcome of biopsy relative to different ranges of free‐to‐total prostate‐specific antigen (PSA) ratio (f/tPSA) in men with a previous negative biopsy and a PSA level of 2.5–10 ng/mL, as urine tests like PCA3 are currently under investigation in order to improve prostate cancer diagnosis and to decrease the rate of unnecessary rebiopsies.

PATIENTS AND METHODS

Data from the previous prospective European multicentre study were reviewed. Only patients with a PSA level of 2.5–10 ng/mL were included in the present study. In all, 301 patients had complete data. The diagnostic accuracy of the PCA3 score for predicting a positive biopsy outcome was studied using sensitivity, specificity, negative and positive predictive values. The PCA3 performance was evaluated relative to three different subgroups of f/tPSA, as follows: >20% (group 1), 10–20% (group 2) and <10% (group 3).

RESULTS

The prostate cancer detection rates were 18.8%, 23.9% and 34.8% in groups 1, 2 and 3, respectively. The area under the receiver operating characteristic curve of the PCA3 score, total PSA and f/tPSA was 0.688, 0.553 and 0.571, respectively. The percentage of men with positive biopsies was 30.6%, 37.0% and 44.4% in those with a PCA3 score of >30, vs 10.3%, 15.5% and 28.6% when the PCA3 score was <30, in groups 1, 2 and 3, respectively. The difference was significant only in groups 1 and 2. In men with a f/tPSA of ≤10% the difference in detection rates relative to the PCA3 score was not statistically significant regardless of which PCA3 threshold was used. A high PCA3 score was significantly associated with age, clinical T2 stage and positive biopsy (P < 0.001, 0.013 and <0.001, respectively). In bivariate analysis accounting for the PCA3 score and the f/tPSA, a PCA3 score of >30 was a significant independent predictor of positive biopsies (odds ratio 3.01; 95% confidence interval 1.74–5.23; P < 0.001).

CONCLUSIONS

PCA3 remained a better predictor of prostate cancer than f/tPSA. In men with a f/tPSA of >10%, the use of the PCA3 score was highly correlated with the risk of having cancer on re‐biopsy, and could prevent unnecessary prostate biopsies if the value is low.