Safety and tolerability of extended-release niacin with laropiprant

Introduction: Niacin is one of the oldest drugs used in the treatment of dyslipidemia. Previously its use has been limited because of excessive flushing. Now an agent laropiprant (LRP) has been developed, which blocks the flushing pathway. Therefore, it is time to collate available information to assess the safety and tolerability of combining niacin with LRP.

Areas covered: The authors searched PubMed and MEDLINE for literature published between January 2006 and July 2011, for safety and tolerability reports of extended-release niacin (ERN) with LRP.

Expert opinion: The addition of LRP to ERN, by reducing the side effect ‘flushing’, may enable lipidologists and physicians to use niacin more widely as part of lipid modification therapy, especially since the combination can be safely added to statins. However, it has to be accepted that the addition of LRP does not completely abolish flushing. The favorable safety profile supports the use of LRP to achieve higher therapeutic dosing of niacin.     

Radium-223 dichloride for the treatment of metastatic prostate cancer

Introduction: Bone metastases are a frequent complication of many malignancies and are particularly common in metastatic prostate cancer, where they are associated with a high degree of morbidity. Until recently, treatments relied on palliative bone targeting measures with no proven survival-prolonging action or on systemic agents with general anti-prostate cancer activity but significant toxicities. Radium-223 dichloride is a bone-seeking, α-emitting, radionuclide that has recently been licensed in the US and Europe for the treatment of men with castration-resistant prostate cancer, bone metastases and no known visceral metastases. Radium-223 is the first bone-seeking radionuclide therapy proven to result in increased overall survival versus placebo.

Areas covered: The existing market of bone-targeted agents is reviewed before considering what radium-223 adds by examining its pharmacology, pharmacokinetics and clinical efficacy and safety data. Initial relevant papers were identified by searching PubMed using combinations of the terms, ‘Radium’, ‘Prostatic neoplasms’, ‘Bone’, ‘Neoplasm metastasis’.

Expert opinion: Consideration is given to further preclinical work needed into the mechanism of action of radium-223 and future clinical directions of the drug including combinations with other agents.     

Silodosin: a new subtype selective alpha-1 antagonist for the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia

Introduction: Silodosin is a new uroselective alpha-blocker with high pharmacological selectivity for the _1A adrenoceptor. It is an effective and well-tolerated treatment in men with lower urinary tract symptoms (LUTS), due to presumed bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The efficacy of silodosin is at least equivalent to existing selective alpha-1 antagonists such as tamsulosin. A beneficial consequence of its high selectivity is improved cardiovascular safety and failure to interact with other therapies such as anti-hypertensives and phosphodiesterase type-5 inhibitors.

Areas covered: This paper discusses the mechanism of action, uroselectivity and clinical efficacy/tolerability of Silodosin. Additionally, drug interactions and urodynamic effects are reviewed with a focus on ejaculatory dysfunction.

Expert opinion: Silodosin is a rapidly efficacious and safe agent in the treatment of LUTS/BPH in men. A lack of clinically important cardiovascular side effects makes it of potential use in the elderly. There is a higher risk of ejaculatory dysfunction, which may lead to discontinuation in younger men. The availability of generic counterparts may make this compound less marketable in countries with social healthcare systems.     

Vandetanib for the treatment of lung cancer

Introduction: VEGF and EGFR are validated pathways for targeted therapy in non-small cell lung cancer (NSCLC). Once considered to be separate targets, VEGF and EGFR are now shown to have interconnected downstream pathways, potentiating the effectiveness of their dual signaling inhibition in cancer therapy. Molecules such as vandetanib that inhibit VEGFR and EGFR have also been reported to inhibit other receptors, including RET and additional kinases, and may be beneficial in treating patients with solid tumors.

Areas covered: This review covers the significance of targeting VEGF and EGFR in the treatment of NSCLC and the rationale behind their dual inhibition. Clinical trials that evaluate the use of vandetanib in the setting of refractory NSCLC are also explored.

Expert opinion: Vandetanib is currently not approved in the setting of NSCLC. However, its approval for medullary thyroid cancer makes it promising for identifying markers and potentially a NSCLC patient population who will benefit from the treatment.     

A review of iniparib in ovarian cancer

Introduction: Patients with metastatic ovarian cancer continue to experience high recurrence rates and significant morbidity from standard treatments. There is a great need for efficacious tumor-specific agents in ovarian cancer. Iniparib (BSI-201) is a targeted drug currently under investigation.

Areas covered: The authors identified the mechanistic and clinical data available on the role of iniparib in ovarian cancer. Iniparib was initially thought to act via the poly-ADP ribose polymerase 1 (PARP-1) pathway, but recent studies have shown only nonspecific interactions between the drug and PARP proteins. Although iniparib is only active in cancer cells, the exact mechanism of action remains unclear. Iniparib was well tolerated at all dose levels in Phase I studies of solid organ malignancies. Preliminary data from Phase II studies of iniparib for the treatment of platinum-sensitive and platinum-resistant recurrent ovarian cancer show improvement in survival compared to historic controls. There are currently no Phase III studies.

Expert opinion: Iniparib shows promise in early clinical trials; however, understanding the pathways of cytotoxicity will be crucial as cancer therapy becomes increasingly individualized.     

A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection

Introduction: More than a million people acquire HIV infection annually. Pre-exposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone preclinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection.

Areas covered: The tenofovir drug development pathway from compound discovery, preclinical animal model testing and human testing were reviewed for safety, tolerability and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favored prevention option for women compared with the tablets, which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood.

Expert opinion: Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials.     

A drug safety evaluation of everolimus in kidney transplantation

Introduction: Calcineurin inhibitors (CNI) have greatly reduced the rate of acute rejection and improved short-term graft survival after organ transplantation, however, long-term survival has hardly changed since their introduction. CNIs are believed to contribute to graft fibrosis, have side effects that adversely affect cardiovascular risk, and are associated with an increased rate of post-transplant malignancies. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is not associated with graft fibrosis, has a superior cardiovascular risk profile to CNI therapy and has shown potential for the prevention and treatment of diverse forms of cancer.

Areas covered: This review summarizes key aspects of everolimus, including its mechanism of action, pharmacokinetics, pharmacodynamics, drug–drug interactions and pivotal clinical studies with a focus on safety and efficacy.

Expert opinion: Everolimus is effective in improving graft function in selected kidney transplant patients. Most adverse events are present for a short time after the introduction of everolimus, and are manageable. Everolimus has the potential to become an important agent in de novo and maintenance immunotherapy in kidney transplant recipients.     

Tolterodine for the treatment of urge urinary incontinence

Introduction: Overactive bladder (OAB) and its resultant urge urinary incontinence (UUI) are significant problems that medically, psychologically and financially affect people. The constellation of symptoms comprising OAB affects ～ 16% of the adult population and its prevalence increases with aging. The typical class of medications used to treat OAB is antimuscarinics.

Areas covered: OAB medications, with a focus on tolterodine for the treatment of UUI are reviewed. A thorough review of English language literature using EMBASE/Medline and PubMed has been performed.

Expert opinion: Tolterodine provides a reasonable starting point when treating patients with OAB and UUI. Efficacy and tolerability are generally comparable between tolterodine and other newer antimuscarinics. Tolterodine is a good option as part of the algorithm in the treatment of OAB and UUI.     

Dabigatran etexilate for venous thromboembolism: a safety evaluation

Introduction: Recently, new oral anticoagulants (NOACs) have become available to treat thromboembolic disorders. The efficacy and safety of these agents have been thoroughly tested in various clinical trials. In this article, we discuss the evidence for the safety and efficacy of dabigatran in the prevention and treatment of venous thromboembolism (VTE).

Areas covered: We discuss the pharmacology of dabigatran and compare it to that of warfarin and two of the other popular NOACs, rivaroxaban and apixaban. The indications for and evidence behind dabigatran in the prevention of VTE are presented, as well as the trials examining its potential use for the treatment and extended treatment of VTE. We conclude by considering the safety aspects of the drug.

Expert opinion: For most patients the overall net clinical benefit would seem to be in favour of dabigatran. Both efficacy and safety have been proven in the setting of robust randomised controlled trials. ‘Real world’ registry data as well as long-term trial follow-up will add further critical information. Long-term experience might be one of the few advantages warfarin still has over dabigatran in patients who are eligible for both.     

Everolimus in the treatment of hormone receptor-positive breast cancer

Introduction: The phosphoinositide triphosphate kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is a central regulatory pathway involved in cell proliferation, growth, differentiation, metabolism and survival. Deregulation of this pathway is well described in breast cancer and is associated to the development of endocrine resistance among hormone receptor (HR)-positive tumors. Everolimus, an mTOR-inhibitor has clinical activity against breast cancer and has shown to restore sensitivity to endocrine therapy.

Areas covered: We review the clinical data and the results of the recently published clinical trials evaluating the use of everolimus in HR-positive breast cancer patients in combination with endocrine therapy. We discuss the data regarding efficacy but also describe in detail the side effect profile of this drug.

Expert opinion: Everolimus represents a new therapeutic alternative for the treatment of HR-positive metastatic breast cancer. Everolimus is in general a well-tolerated drug, however, stomatitis, fatigue and hematological abnormalities are common. It is still unclear if there are specific subgroups of patients that receive greater benefit from everolimus and whether there is a relationship between the presence of PIK3CA mutations and efficacy. The results of biomarker studies will hopefully provide information that will help us determine which patients are most likely to benefit from this treatment.     

Rifaximin for the treatment of irritable bowel syndrome

Introduction: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS.

Areas covered: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed.

Expert opinion: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.     

Targeting thymidylate synthase in colorectal cancer: critical re-evaluation and emerging therapeutic role of raltitrexed

Introduction: 5-fluorouracil continues to be the cornerstone of treatment for colorectal cancer. Although fluoropyrimidines are generally considered as well-tolerated drugs, severe toxicities can be a major clinical problem, and the recommended prolonged infusion of 5-fluorouracil provokes discomfort in patients. Raltitrexed (Tomudex), a quinazoline analogue of folinic acid, is a selective and direct thymidylate synthase (TS) inhibitor with a convenient 3-weekly schedule of administration.

Areas covered: In this review, through critical insight into the mechanism of action and main clinical experiences, the authors suggest the necessity to reconsider raltitrexed as a valuable anticancer drug and as a suitable option for colorectal cancer. The authors highlight its emerging therapeutic role in clinical practice for patients with fluoropyrimidine-induced cardiotoxicity or a significant history of cardiac disease.

Expert opinion: This review discusses if TS could still be a relevant target for colorectal cancer in the era of molecular therapy and if raltitrexed should still be considered a drug with a life-threatening toxicity. Furthermore, this review discusses the principal combination clinical experiences of raltitrexed and its emerging therapeutic role in clinical practice as a suitable option for colorectal cancer patients with fluoropyrimidine-induced cardiotoxicity or a significant history of cardiac disease.     

Injectable testosterone undecanoate for the treatment of hypogonadism

Introduction: Injectable testosterone undecanoate (TU) is a long-acting testosterone (T) formulation available for the treatment of male hypogonadism (HG) since 2003.

Areas covered: The efficacy and safety of injectable TU are assessed, as obtained by meta-analyzing available evidence. An extensive Medline, Embase and Cochrane search was performed. All uncontrolled and placebo-controlled randomized clinical trials (RCTs), evaluating the effect of injectable TU on different outcomes, were included. Of the 98 retrieved articles, 33 were included in the study. Among those, 11 were placebo-controlled RCTs. Injectable TU was significantly associated with a reduction of fat mass and HbA1c in both controlled and uncontrolled trials, in particular when hypogonadal subjects were enrolled. Similar results were observed for the improvement of erectile function. In addition, TU ameliorated several other outcomes, including blood pressure, lipid profile, waist circumference and body mass index in uncontrolled studies, but these data were not confirmed in placebo-controlled trials. The treatment was well tolerated and no risk of prostate cancer or cardiovascular disease was observed.

Expert opinion: Injectable TU is a safe and effective treatment for male HG. The possibility of a therapeutic intervention just four to five times per year frees the patient, at least partially, from having a chronic condition, thus maintaining a positive, active role in self-caring.     

Asenapine review,part II: clinical efficacy,safety and tolerability

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

Areas covered: The purpose of this review is to describe the clinical profile of asenapine.

Expert opinion: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 – 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.     

Resiquimod,a topical drug for viral skin lesions and skin cancer

Introduction: Resiquimod is an immune response modifier which stimulates cells through a toll-like receptors (TLR) 7 and 8 dependent pathway resulting in activation of immune responses that are effective against viral and tumor lesions.

Areas covered: Studies on genital herpes, hepatitis C and actinic keratosis (AK) as well as papers of molecular activities of resiquimod were identified by a PubMed search. Although effective against genital HSV-2 in animal models, development of topical resiquimod for the treatment of recurrent genital herpes in humans was stopped due to inconsistent results in clinical trials. Reduction of HCV viral load was achieved by oral application but was associated with unacceptable side effects. Topical treatment of AK was well tolerated and effective with clearance rates higher compared to imiquimod. The molecular mode of action underlying the clinical efficacy primarily depends on cytokine induction in TLR7/8 expressing dendritic cells in the skin.

Expert opinion: Topical resiquimod was shown to be a safe and effective treatment option for AK and appears to have potential as a treatment modality for patients with extended skin areas affected with AK (field cancerization). Resiquimod may also have potential for the therapy or prevention of epithelial viral infections.     

Sorafenib in liver cancer

Introduction: With growing knowledge of the molecular pathway of carcinogenesis, targeted therapies have become the ‘blue ocean' of cancer treatment. sorafenib is an oral multikinase inhibitor that targets Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) and several tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-β) that has shown efficacy in hepatocellular carcinoma (HCC).

Areas covered: An updated summary of the preclinical and clinical experience with sorafenib in HCC is presented in this paper. Data are based on abstracts from international conferences and journal articles found in a PubMed search of literature published up to December 2011.

Expert opinion: Based on favorable data from preclinical and clinical trials, sorafenib has been approved as a standard therapy in advanced HCC. However, further efforts to understand the additional roles of sorafenib in the treatment of HCC are still necessary. Data for sorafenib will guide the development of new drugs for the treatment of HCC.     

Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence

Introduction: Both alcohol and benzodiazepine dependence (AD, BD) are severe and chronic conditions with devastating physical and mental health effects. The relative scarcity and controversial evidential status of available pharmacological interventions for the treatment of patients' acute withdrawal syndrome and/or relapse prevention call for the clinical investigation of novel safe and efficacious agents.

Areas covered: We review published studies of pregabalin as monotherapy in the treatment of AD and BD in more than 450 patients. Available evidence includes four RCTs, two in AD with active comparator drugs (naltrexone, tiapride, and lorazepam) and one placebo-controlled, and one placebo-controlled in BD. We also review other available studies on pregabalin's potential to reduce benzodiazepine consumption, its side effects, especially cognitive, as well as extant reports on its liability for abuse.

Expert opinion: Available evidence suggests that monotherapy with pregabalin, within the dosage range of 150 – 600 mg/d, is a promising “novel” option for the safe and efficacious relapse prevention of both AD and BD. However, its efficacy as monotherapy in the acute treatment of AD withdrawal syndrome is still controversial. Clinicians should be cautious in prescribing pregabalin to patients with a history of multiple substance recreational use, and monitor its effects on cognition at dosages above 450 mg/d. Further, well-designed clinical research is still needed for the eventual consolidation of pregabalin's place in the treatment of AD and BD.