Pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma

Introduction: Liposarcomas (LPS) are a heterogeneous group of adipocytic soft tissue sarcomas with limited treatment options in the advanced/metastatic setting. Pazopanib is a multi-target tyrosine kinase inhibitor (TKI) with anti-angiogenic and antitumorigenic properties. Whilst targeted agents including TKIs have been extensively studied in other solid tumors and the sarcoma subtype gastrointestinal stromal tumor (GIST), we currently lack effective treatments for the liposarcoma subtype. Several phase II and III studies of oral TKIs in soft tissue sarcomas have excluded liposarcoma because of a reported lack of activity following the EORTC 62043 study.

Areas: We review the use of pazopanib in advanced intermediate and high-grade liposarcomas where complete surgical resection is not possible.

Expert opinion: The current clinical and pharmacological data demonstrate the efficacy of pazopanib in soft tissue sarcomas, but new data suggest that anti-angiogenic agents may have limited activity in liposarcoma. Anti-angiogenic TKIs are generally well tolerated and liposarcomas vary in their response to systemic chemotherapy; hence, there is a role for further exploration of the efficacy of this treatment amongst the histological subtypes of liposarcoma. This affords further understanding of biomarkers which may be associated with response to pazopanib and other anti-angiogenic TKI treatments.     

Clinical efficacy of eribulin mesylate for the treatment of metastatic soft tissue sarcoma

Introduction: Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12–18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma.

Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate’s mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas.

Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.     

Aldoxorubicin for the treatment of soft tissue sarcoma

Intoduction: Soft tissue sarcomas (STS) encompass a group of rare tumors arising from mesenchymal tissue. Traditionally, anthracycline-based chemotherapy, with doxorubicin, is the main treatment for advanced STS.

Areas covered: Aldoxorubicin is a doxorubicin derivative containing a carboxylic hydrazone and serves as a prodrug of doxorubicin. It covalently binds to albumin in the blood until reaching the acidic tumor environment, which dissolves the hydrazone linker, thus releasing doxorubicin into the tissue. In this review paper, we analyze the pharmacokinetics, current phase I, phase II, and phase III trials, as well as adverse effect profile of aldoxorubicin in patients with advanced STS.

Expert opinion: Aldoxorubicin represents a promising drug for treatment of sarcomas. The drug has minimal cardiac toxicity, which represents a significant advantage to doxorubicin. Preliminary phase 3 study results demonstrate PFS advantage in patients with leiomyosarcoma and liposarcoma. However, more studies are needed to establish the role of aldoxorubicin in sarcoma treatment.     

Targeted therapy and promising novel agents for the treatment of advanced soft tissue sarcomas

Introduction: Soft tissue sarcomas (STS) are a rare and difficult to treat malignancy. Efforts to utilize targeted therapy have been ongoing for the last decade and have resulted in the approval of pazopanib for treatment of advanced disease. Although several other agents have been investigated, the inability to predict responses remains a limiting factor to the incorporation of these agents into treatment.

Areas covered: The authors summarize recent clinical findings from studies focused on targeted agents in STS. The authors also discuss the potential approaches and ongoing clinical trials with novel agents.

Expert opinion: A major challenge in the treatment of advanced STS remains a lack of predictive biomarkers to guide therapy and the heterogeneity of response among different histologies of sarcoma. Incorporation of predictive biomarker analysis into clinical trials is warranted. Additionally, mechanisms of treatment resistance and parallel pathways of tumor growth pose challenges in how we treat these tumors. An active area of research in STS is the use of novel combinations of agents, such as chemotherapy combined with multi-targeted agents. The potential of immune check point inhibitors is being explored in advanced STS and is hoped to further expand our treatment armamentarium.     

Tetrahydroisoquinolines in therapeutics: a patent review (2010-2015)

Introduction: 1,2,3,4-Tetrahydroisoquinoline (THIQ) is one of the ‘privileged scaffolds’, commonly found in nature. Initially, this class of compounds was known for its neurotoxicity. Later on, 1-methyl-1,2,3,4-tetrahydroisoquinoline was proved as an endogeneous Parkinsonism-preventing agent in mammals. The fused THIQs have been studied for their role as anticancer antibiotics. The US FDA approval of the trabectedin for the treatment of soft tissue sarcomas, is a milestone in the anticancer drug discovery.

Areas covered: This review covers the patents on various therapeutic activities of the THIQ derivatives in the years between 2010 and 2015. Patents were collected using a thorough search of Espacenet and WIPO databases. The therapeutic areas covered include cancer, malaria, central nervous system (CNS), cardiovascular, metabolic disorders, and so on. This also includes several patents on specific THIQs of clinical importance.

Expert opinion: A large number of the THIQ derivatives have been synthesised for various therapeutic activities, with noticeable success in the area of drug discovery for cancer and CNS. They may also prove to be promising candidates for various infectious diseases, such as malaria, tuberculosis, HIV-infection, HSV-infection, leishmaniasis, etc. They can also be developed as novel class of drugs for various therapeutic activities with unique mechanism of action.     

Dental implants modified with drug releasing titania nanotubes: therapeutic potential and developmental challenges

Introduction: The transmucosal nature of dental implants presents a unique therapeutic challenge, requiring not only rapid establishment and subsequent maintenance of osseointegration, but also the formation of resilient soft tissue integration. Key challenges in achieving long-term success are sub-optimal bone integration in compromised bone conditions and impaired trans-mucosal tissue integration in the presence of a persistent oral microbial biofilm. These challenges can be targeted by employing a drug-releasing implant modification such as TiO₂ nanotubes (TNTs), engineered on titanium surfaces via electrochemical anodization.

Areas covered: This review focuses on applications of TNT-based dental implants towards achieving optimal therapeutic efficacy. Firstly, the functions of TNT implants will be explored in terms of their influence on osseointegration, soft tissue integration and immunomodulation. Secondly, the developmental challenges associated with such implants are reviewed including sterilization, stability and toxicity.

Expert opinion: The potential of TNTs is yet to be fully explored in the context of the complex oral environment, including appropriate modulation of alveolar bone healing, immune-inflammatory processes, and soft tissue responses. Besides long-term in vivo assessment under masticatory loading conditions, investigating drug-release profiles in vivo and addressing various technical challenges are required to bridge the gap between research and clinical dentistry.     

Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome

Introduction: Irritable bowel syndrome diarrhea predominant (IBS-D) is a highly prevalent GI disease, affecting nearly a third of all patients diagnosed with irritable bowel syndrome. Current treatment options are limited.

Areas covered: This review discusses the pharmacotherapeutic options for IBS-D including currently used medications, the two newly FDA approved medications, as well as emerging therapies with potential benefit in IBS-D. Particular emphasis is placed on rifaximin and eluxadoline and their possible use in IBS-D.

Expert Opinion: Current pharmacological treatment of IBS-D includes loperamide, bile acid sequestrants, antispasmodics, tricyclic antidepressants, alosetron, eluxadoline and rifaximin. The latter two treatments have significantly added to the pharmacotherapeutic options for patients suffering from IBS-D.     

First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis

Objectives: To conduct a systematic review and network meta-analysis (NMA) to assess effectiveness of first-line treatments for advanced renal cell carcinoma (RCC).

Methods: Database searches were conducted to identify randomized controlled trials (RCTs) reporting results for eligible treatments. A fixed-effect Bayesian NMA was conducted to assess the relative effectiveness of treatments, with progression-free survival (PFS) reported as hazard ratios (HRs) and 95% credible intervals (CrIs).

Results: Eleven unique RCTs were suitable for inclusion in the NMA. In the base case, in terms of PFS, sunitinib was superior compared with bevacizumab + IFN-α (HR = 0.79, 95% CrI: 0.64 – 0.96), everolimus (HR = 0.70, 95% CrI: 0.56 – 0.87), sorafenib (HR = 0.56, 95% CrI: 0.40 – 0.77) and temsirolimus + bevacizumab (HR = 0.74, 95% CrI: 0.56 – 0.96). Although, the point values for the mean and median HRs were < 1.0, there was no significant difference in PFS between sunitinib and axitinib, pazopanib or tivozanib. Although sensitivity analyses impacted the results of the NMA, no treatment was significantly more efficacious than sunitinib.

Conclusion: Results from this analysis suggest that there is no treatment superior to the current benchmark treatment, sunitinib, in the management of advanced RCC in the first-line setting.     

Can binimetinib,encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?

Introduction: Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations.

Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT.

Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.     

Treating pulmonary hypertension in pediatrics

Introduction: Pulmonary hypertension is a hemodynamic condition occurring rarely in pediatrics. Nevertheless, it is associated with significant morbidity and mortality. When characterized by progressive pulmonary vascular structural changes, the disease is called pulmonary arterial hypertension (PAH). It results in increased pulmonary vascular resistance and eventual right ventricular failure. In the vast majority of cases, pediatric PAH is idiopathic or associated with congenital heart disease, and, contrary to adult PAH, is rarely associated with connective tissue, portal hypertension, HIV infection or thromboembolic disease.

Areas covered: This article reviews the current drug therapies available for the management of pediatric PAH. These treatments target the recognized pathophysiological pathways of PAH with endothelin-1 receptor antagonists, prostacyclin analogs and PDE type 5 inhibitors. New treatments and explored pathways are briefly discussed.

Expert opinion: Although there is still no cure for PAH, quality of life and survival have been improved significantly with specific drug therapies. Nevertheless, management of pediatric PAH remains challenging, and depends mainly on results from adult clinical trials and pediatric experts. Further research on PAH-specific treatments in the pediatric population and data from international registries are needed to identify optimal therapeutic strategies and treatment goals in the pediatric population.     

Hyaluronic acid modified daunorubicin plus honokiol cationic liposomes for the treatment of breast cancer along with the elimination vasculogenic mimicry channels

Background: Breast cancer is an alarming global public health problem and a main cause of cancer-related death in women. Systemic chemotherapy is the most widely used treatment for breast cancer. However, current chemotherapy treatments are far from desirable due to poor targeting specificity, severe side effects and vasculogenic mimicry (VM).

Purpose: Hyaluronic acid (HA)-modified daunorubicin plus honokiol (HNK) cationic liposomes were prepared and characterised for treatment of breast cancer by eliminating VM.

Methods: HA-modified daunorubicin plus HNK cationic liposomes were prepared by a thin-film hydration method. Evaluations were performed on MCF-7 cells and MDA-MB-435S cells, which are human breast cancer cells, and xenografts of MDA-MB-435S cells.

Results: In vitro results revealed that the HA-modified daunorubicin plus HNK cationic liposomes enhanced the cellular uptake and destroyed VM channels. In vivo results demonstrated that the liposomes prolonged the circulation time in the blood, obviously accumulated in the tumour region, and enhanced the overall anticancer effects. Action mechanisms were related to down-regulation of VM protein indicators including FAK, EphA2, MMP-2 and MMP-9.

Conclusions: The prepared HA-modified daunorubicin plus HNK cationic liposomes may serve as a promising therapeutic strategy for the treatment of breast cancer.     

Clinical efficacy of piperacillin/tazobactam in the treatment of complicated skin and soft tissue infections

Introduction: Complicated skin and soft tissue infections (cSSTIs) are skin and soft tissue infections (SSTIs) that involve deep soft tissue. cSSTIs often require surgical intervention and/or hospitalization. cSSTIs are associated with significant mortality and morbidity, and carry a significant burden on health care systems. Piperacillin/tazobactam has been regarded as a standard treatment for cSSTIs because of its antibiotic spectrum, safety and clinical efficacy. Several antibiotics, as compared to piperacillin/tazobactam, have been evaluated in the treatment of cSSTIs.

Areas covered: This review summarizes randomized controlled trials (RCTs) evaluating the clinical efficacy of piperacillin/tazobactam for the treatment of cSSTIs.

Expert opinion: Piperacillin/tazobactam, which covers most causative organisms in cSSTIs, is the drug of choice for the treatment of cSSTIs. Other options such as ertapenem and moxifloxacin may be reasonable where multiple daily dosing or intravenous administration is inappropriate. But in general, they should be avoided as an empirical treatment because of their highly association with resistant bacteria, which are becoming a global threat. Therefore, piperacilin/tazobactam is appropriate as an empirical therapy for the treatment of SSTIs and should be de-escalated as soon as causative organisms are identified, their drug-sensitivity results are available, and clinical condition becomes stable.     

How we use pazopanib in treating soft-tissue sarcoma: experience at our multidisciplinary sarcoma centers

Objective: Soft-tissue sarcomas (STSs) are rare malignant tumors arising from tissues of mesenchymal origin throughout the body with poor prognosis in advanced disease. This commentary describes the current treatment landscape for patients with advanced STS undergoing chemotherapy as well as how pazopanib, a newer multitargeted tyrosine kinase inhibitor, has been incorporated into treatment for different subtypes of STS in our clinical practice.

Methods: PubMed was searched (2010–2015) for articles involving the treatment and management of advanced STS. Key search terms included “soft tissue sarcoma”, “pazopanib”, “chemotherapy”, “doxorubicin”, “ifosfamide”, “trabectedin” and “gemcitabine”. Additionally, ClinicalTrials.gov was searched to identify ongoing studies evaluating pazopanib in STS. Reference citations within relevant articles revealed further sources of value.

Results: Standard treatment for advanced STS is single agent or combination systemic chemotherapy. The efficacy of these treatments varies widely, likely because of tumor heterogeneity and cellular mechanisms of chemoresistance, and adverse effects may be a limiting factor for combination therapy. Pazopanib, approved for the treatment of advanced STS in patients who received prior chemotherapy, has demonstrated clinical benefit in a variety of histologic types of advanced STS where the prognosis is often poor. While pazopanib has a favorable safety profile compared with commonly prescribed chemotherapies, it has several safety concerns and dose-limiting adverse effects. We share our best practice for managing adverse events to ensure patient tolerability.

Conclusions: Use of pazopanib increases the treatment options available to control advanced STS, with management of adverse events through close monitoring, patient education and treatment as necessary.     

Choosing drugs for the treatment of diabetic neuropathy

Introduction: Diabetic sensorimotor polyneuropathy (DSP) affects 50% of diabetes patients and is painful in about 26%. Although disease-modifying therapies are not available for DSP, symptomatic treatments for painful diabetic neuropathy (PDN) are effective.

Areas covered: We performed a MEDLINE search on PubMed using the search terms: treatment diabetic neuropathy and treatment PDN. This review outlines the problem posed by DSP, the clinical presentation and the characterization of PDN. A discussion of disease-modifying interventions, including the benefits of strict glycemic control, is followed by a focus on interventions for PDN including antidepressants, anticonvulsants and other treatments.

Expert opinion: Disease modification in DSP remains an unmet need in clinical medicine affecting a large percentage of the population with concomitant healthcare costs. Strict glycemic control and attention to potential risk factors such as hypertension, hyperlipidemia and obesity may minimize DSP. Many patients benefit from treatment of their painful symptoms with anticonvulsants or antidepressants, but all are associated with significant side effects that limit their usefulness. There is a need for treatments of PDN with fewer side effects and more effective pain relief.     

Vasovagal syncope: an update on the latest pharmacological therapies

Introduction: Syncope is an abrupt loss of consciousness in response to reduced perfusion to the brain. Neurocardiogenic or vasovagal syncope results from a complex neurologic reflex, and treatments to prevent recurrence attempt to modulate aspects of that reflex.

Areas covered: Pharmacologic treatments for vasovagal syncope address the syncope reflex in multiple ways. Fludrocortisone and sodium chloride increase systemic fluid volume. Midodrine, β blockers and norepinephrine transport inhibitors modulate the sympathetic nervous system. Other treatments for syncope modulate other neurotransmitters or affect heart rate. The most recent trials evaluating established and novel therapies are reviewed.

Expert opinion: To reduce recurrence of vasovagal syncope, conservative measures are first line. If these fail to prevent recurrence, the most promising medical therapy includes midodrine. Randomized placebo-controlled data evaluating fludrocortisone, midodrine and β blockers in older patients are awaited. Because of the significance of the placebo effect in this condition, any treatment must be evaluated in a randomized double-blind placebo-controlled trial before being accepted as effective.     

Inflammation in Heart Failure: known knowns and unknown unknowns

Introduction: The review deals with inflammation in heart failure (HF). Many data show that systemic inflammation is frequent in HF and implicate that inflammation contributes to damage and dysfunction of the cardiovascular system.

Areas Covered: Experimental data have been mainly obtained in acute laboratory animal models. It is questionable whether animals’ data can be translated into clinical settings with patients with chronic HF who have concomitant pathologies.

The idea of a common inflammatory pathway that characterizes all different forms of clinical HF is unrealistic. It seems realistic that inflammation differs in non-cardiac and cardiac diseases.

Research therapeutic options address the use of inhibitors of cytokines, of agents antagonizing oxidative stress, of MMP and of PI3K signaling pathways.

Expert Opinion: Considering the many unknowns in our knowledge it is not surprising that early trials aimed to antagonize inflammation in HF have been disappointing. We are far away from having solid therapeutic schedules to use immunomodulation in all subtypes of HF. However, modern trials on HF due to virus infections have proven that immunomodulation is therapeutically effective.

We should wisely use the known facts and accept that we have many unknowns. By appropriate selection of the subtypes of HF we may be able to find the appropriate therapy against inflammation in HF.     

Treatments options for alopecia

Introduction: Hair disorders have a very high social and psychological impact. Treatment is often frustrating and time-consuming both for the patients and the clinicians and requires special skills and expertise.

Areas covered: This paper aims to provide an overview of available treatments for the most common forms of alopecia in adults (androgenetic alopecia [AGA], alopecia areata and cicatricial alopecias) after reviewing the literature in PubMed, Google Scholar and ClinicalTrial.gov.

Expert opinion: Before starting treatment, it is very important to confirm diagnosis and discuss patient’s expectations. Treatment of hair disorders requires time and first results are usually visible a few months after beginning of therapy. Treatment of most hair disorders is mostly not evidenced-based as randomized controlled trials are available only for AGA.     

Investigational agents for treatment of traumatic brain injury

Introduction: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no pharmacologic agents proven to improve outcomes from TBI because all the Phase III clinical trials in TBI have failed. Thus, there is a compelling need to develop treatments for TBI.

Areas covered: The following article provides an overview of select cell-based and pharmacological therapies under early development for the treatment of TBI. These therapies seek to enhance cognitive and neurological functional recovery through neuroprotective and neurorestorative strategies.

Expert opinion: TBI elicits both complex degenerative and regenerative tissue responses in the brain. TBI can lead to cognitive, behavioral, and motor deficits. Although numerous promising neuroprotective treatment options have emerged from preclinical studies that mainly target the lesion, translation of preclinical effective neuroprotective drugs to clinical trials has proven challenging. Accumulating evidence indicates that the mammalian brain has a significant, albeit limited, capacity for both structural and functional plasticity, as well as regeneration essential for spontaneous functional recovery after injury. A new therapeutic approach is to stimulate neurovascular remodeling by enhancing angiogenesis, neurogenesis, oligodendrogenesis, and axonal sprouting, which in concert, may improve neurological functional recovery after TBI.     

Current advances in treatment of gastroparesis

Introduction: Gastroparesis is a syndrome defined by delayed gastric emptying in the absence of mechanical obstruction. Gastroparesis has significant symptomatology and negative impacts on the patient’s quality of life.

Areas covered: This article reviews current treatment options for gastroparesis, recent advances in treatment and future directions that treatment may head. Current options are broadly divided into prokinetics and symptom modulators. Within each group, current modalities as well as recent advances are discussed according to agent mechanism of action. Lastly, findings regarding the cellular pathophysiology involved in gastroparesis will be briefly reviewed along with their implications for future treatments.

Expert opinion: The numerous motor functions and neural inputs that control gastric motility are complex and not fully understood. Our lack of understanding of its pathophysiology has led to treatment options which are empirical, palliative and often ineffective. Newly intensified interest in the cellular pathophysiology behind gastroparesis provides promise for a new era of treatments. Identification of common cellular changes in gastroparesis has provided targets for treatment that may allow us to one day better treat the symptoms of gastroparesis related to its underlying pathophysiology. This is the future of gastroparesis therapy.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.