This paper reports a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of lapatinib plus chemotherapy or endocrine therapy (CET) versus CET alone in human epidermal growth factor receptor 2-overexpressing (HER-2+) locally advanced or metastatic breast cancer.
Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were progression-free survival and overall survival. The side effects of each treatment were analyzed. The data extracted from the studies were combined by using the hazard ratio or risk ratio with their corresponding 95% confidence interval (CI).
A total of 113 references were identified and screened. The final analysis included four trials comprising 1,073 patients with HER-2+. The overall response rate was higher in patients who received the combination of CET plus lapatinib (risk ratio 0.78; 95% CI 0.71–0.85; P < 0.00001) but with significant heterogeneity (χ2 = 15.61, df = 3; P = 0.001; I2 = 81%). This result remained favorable to the use of lapatinib when a random-effects model analysis was performed (risk ratio 0.76; 95% CI 0.62–0.94; P = 0.01). Progression-free survival was also higher in patients who received CET plus lapatinib (hazard ratio 0.57; 95% CI 0.49–0.66; P < 0.00001) with no heterogeneity detected on this analysis (χ2 = 3.05; df = 3; P = 0.38; I2 = 1%). Overall survival was significantly longer in patients who received CET plus lapatinib (hazard ratio 0.80; 95% CI 0.69–0.92; P = 0.002) without heterogeneity on this analysis (χ2 = 1.26; df = 3; P = 0.74; I2 = 0%). Regarding adverse events and severe toxicities (grade ≥3), the group receiving CET plus lapatinib had higher rates of neutropenia (risk ratio 2.08; 95% CI 1.64–2.62; P < 0.00001), diarrhea (risk ratio 4.82; 95% CI 3.14–7.41; P < 0.00001), and rash (risk ratio 8.03; 95% CI 2.46–26.23; P = 0.0006).
The combination of CET plus lapatinib increased the overall response rate, progression-free survival, and overall survival in patients with HER-2+ locally advanced or metastatic breast cancer.
chemotherapy; lapatinib; breast cancer; meta-analysis
Sugammadex is the first clinical representative of a new class of drugs called selective relaxant binding agents. It has revolutionized the way anesthesiologists think about drug reversal. Sugammadex selectively binds rocuronium or vecuronium, thereby reversing their neuromuscular blocking action. Due to its 1:1 binding of rocuronium or vecuronium, it is able to reverse any depth of neuromuscular block. So far, it has been approved for use in adult patients and for pediatric patients over 2 years. Since its approval in Europe, Japan, and Australia, further insight on its use in special patient populations and specific diseases have become available. Due to its pharmacodynamic profile, sugammadex, in combination with rocuronium, may have the potential to displace succinylcholine as the “gold standard” muscle relaxant for rapid sequence induction. The use of rocuronium or vecuronium, with the potential of reverse of their action with sugammadex, seems to be safe in patients with impaired neuromuscular transmission, ie, neuromuscular diseases, including myasthenia gravis. Data from long-term use of sugammadex is not yet available. Evidence suggesting an economic advantage of using sugammadex and justifying its relatively high cost for an anesthesia-related drug, is missing.
reversal agent; cyclodextrin; PORC; SRBAs
Hyponatremia is the most common electrolyte abnormality seen in clinical practice. Most cases of euvolemic or hypervolemic hyponatremia involve arginine vasopressin (AVP). AVP leads to a concentrated urine and negative free water clearance. Given this primary role of AVP, antagonizing its effect through blockade of its receptor in the distal tubule is an attractive therapeutic target. Lixivaptan is a newer, non-peptide, vasopressin type 2 receptor antagonist. Recent studies have demonstrated efficacy. This review summarizes the clinical pharmacology and data for this new agent.
vasopressin; hyponatremia; heart failure; lixivaptan; therapy; outcomes
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as the B cell receptor and NFkB are implicated in the survival and proliferation of the CLL cells which are ultimately associated with persistence of the disease. The Bruton’s tyrosine kinase pathway regulates downstream activation of the B cell receptor and has emerged as an attractive target. Ibrutinib inhibits the Bruton’s tyrosine kinase pathway, and consequently induces apoptosis of B cells. Phase I and II studies have shown impressive response rates with an excellent safety profile in patients with refractory/relapsed CLL and elderly treatment-naïve CLL patients. This paper reviews the preclinical and clinical data for ibrutinib when used in the treatment of CLL. Recent studies showing the benefit of combination therapy using ibrutinib, monoclonal antibodies, and chemoimmunotherapy are also discussed.
ibrutinib; B-cell receptor; chronic lymphocytic leukemia; Bruton’s tyrosine kinase
Enzalutamide is an oral androgen receptor (AR) signaling inhibitor that was specifically engineered to overcome castration-resistant prostate cancer (CRPC) harboring AR amplification or overexpression. Enzalutamide has demonstrated significant activity in men with metastatic CRPC.
To update the evidence and provide an overview of the available data on enzalutamide.
Peer reviewed articles published and listed in Medline Search were reviewed. In addition, relevant ASCO and ESMO abstracts were searched. The activity of enzalutamide is mediated by potently antagonizing the full-length AR, impairing translocation of the AR from the cytoplasm into the nucleus, and inhibiting the transcriptional activity of the AR by modulating the interaction of the AR with androgen-response elements in gene promoter regions. Enzalutamide has a favorable safety profile and the most common adverse events include fatigue, hot flashes and headache; 1% of patients experienced seizure.
Place in Therapy
The AFFIRM phase III study evaluated the clinical utility of treatment with enzalutamide in men with docetaxel-refractory metastatic CRPC. Enzalutamide improved overall survival compared to placebo, with a median overall survival of 18.4 months versus 13.6 months respectively.
Enzalutamide has demonstrated impressive efficacy in men with metastatic CRPC, moving swiftly from a phase I/II study to two pivotal phase III trials testing this agent in both chemotherapy-pretreated as well as chemotherapy-naïve CRPC patients. Ongoing studies are aiming to explore the utility of enzalutamide in earlier stages of the disease, and to investigate the optimal sequencing and combination of enzalutamide with other standard and novel therapies for prostate cancer.
castration-resistant prostate cancer; enzalutamide; MDV3100; antiandrogen; androgen receptor
Obatoclax mesylate is an intravenously-administered drug under investigation in Phase I and II clinical trials as a novel anticancer therapeutic for hematological malignancies and solid tumors. Obatoclax was developed as a pan-inhibitor of antiapoptotic members of the B cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) family of proteins, which control the intrinsic or mitochondrial pathway of apoptosis. Resistance to apoptosis through dysregulation of BCL-2 family members is commonly observed in hematological malignancies, and can be linked to therapeutic resistance and poor clinical outcomes. By inhibiting pro-survival BCL-2 family proteins, including MCL-1, obatoclax is proposed to (1) trigger cell death as a single agent, and (2) potentiate the anticancer effects of other therapeutics. Preclinical investigations have supported these proposals and have provided evidence suggestive of a promising therapeutic index for this drug. Phase I trials of obatoclax mesylate in leukemia and lymphoma have defined well-tolerated regimens and have identified transient neurotoxicity as the most common adverse effect of this drug. In these studies, a limited number of objective responses were observed, along with hematological improvement in a larger proportion of treated patients. Published Phase II evaluations in lymphoma and myelofibrosis, however, have not reported robust single-agent activity. Emerging evidence from ongoing preclinical and clinical investigations suggests that the full potential of obatoclax mesylate as a novel anticancer agent may be realized (1) in rational combination treatments, and (2) when guided by molecular predictors of therapeutic response. By understanding the molecular underpinnings of obatoclax response, along with optimal therapeutic regimens and indications, the potential of obatoclax mesylate for the treatment of hematological malignancies may be further clarified.
obatoclax; leukemia; lymphoma; myelofibrosis; BCL-2; BH3 mimetic
The purpose of this work was to conduct a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy and side effect profile of hypofractionated versus conventional external-beam radiation therapy for prostate cancer.
Several databases were searched, including Medline, EmBase, LiLACS, and Central. The endpoints were freedom from biochemical failure and side effects. We performed a meta-analysis of the published data. The results are expressed as the hazard ratio (HR) or risk ratio (RR), with the corresponding 95% confidence interval (CI).
The final analysis included nine trials comprising 2702 patients. Freedom from biochemical failure was reported in only three studies and was similar in patients who received hypofractionated or conventional radiotherapy (fixed effect, HR 1.03, 95% CI 0.88–1.20; P = 0.75), with heterogeneity [χ2 = 15.32, df = 2 (P = 0.0005); I2 = 87%]. The incidence of acute adverse gastrointestinal events was higher in the hypofractionated group (fixed effect, RR 2.02, 95% CI 1.45–2.81; P < 0.0001). We also found moderate heterogeneity on this analysis [χ2 = 7.47, df = 5 (P = 0.19); I2 = 33%]. Acute genitourinary toxicity was similar among the groups (fixed effect, RR 1.19, 95% CI 0.95–1.49; P = 0.13), with moderate heterogeneity [χ2 = 5.83, df = 4 (P = 0.21); I2 = 31%]. The incidence of all late adverse events was the same in both groups (fixed effect, gastrointestinal toxicity, RR 1.17, 95% CI 0.79–1.72, P = 0.44; and acute genitourinary toxicity, RR 1.16, 95% CI 0.80–1.68, P = 0.44).
Hypofractionated radiotherapy in localized prostate cancer was not superior to conventional radiotherapy and showed higher acute gastrointestinal toxicity in this meta-analysis. Because the number of published studies is still small, future assessments should be conducted to clarify better the true role of hypofractionated radiotherapy in patients with prostate cancer.
hypofractionated; radiotherapy; prostate cancer; systematic review; acute radiation effects
Methicillin-resistant Staphylococcus aureus (MRSA), including community-associated and hospital-associated strains, is a major cause of human morbidity and mortality. Treatment options have become limited due to the emergence of MRSA strains with decreased sensitivity to vancomycin, which has long been the first-line therapy for serious infections. This has prompted the search for novel antibiotics that are efficacious against MRSA. Linezolid, an oxazolidinone class of antibiotic, was approved by the Food and Drug Administration in 2000 for treatment of MRSA infections. Since then, there have been a multitude of clinical trials and research studies evaluating the effectiveness of linezolid against serious infections, including pneumonia (both community- and hospital-acquired), skin and soft-tissue infections such as diabetic foot ulcers, endocarditis, osteomyelitis, prosthetic devices, and others. The primary aim of this review is to provide an up-to-date evaluation of the clinical evidence for using linezolid to treat MRSA infections, with a focus on recently published studies, including those on nosocomial pneumonia. Other objectives are to analyze the cost-effectiveness of linezolid compared to other agents, and to review the pharmokinetics and pharmacodynamics of linezolid, emphasizing the most current concepts.
linezolid; MRSA; clinical trials; pneumonia; skin infections
The Polifeprosan 20 with carmustine (BCNU, bis-chloroethylnitrosourea, Gliadel®) polymer implant wafer is a biodegradable compound containing 3.85% carmustine which slowly degrades to release carmustine and protects it from exposure to water with resultant hydrolysis until the time of release. The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events. Based on these trials and other supporting data, US and European regulatory authorities granted approval for its use in recurrent and newly diagnosed malignant glioma, and it remains the only approved local treatment. The preclinical and clinical data suggest that it is optimally utilized primarily in the proportion of patients who may have total or near total removal of gross tumor. The aim of this work was to review the evidence for the use of carmustine implants in the management of malignant astrocytoma (World Health Organization grades III and IV), including newly diagnosed and recurrent disease, especially in the setting of a standard of care that has changed since the randomized trials were completed. Therapy has evolved such that patients now generally receive temozolomide chemotherapy during and after radiotherapy treatment. For patients undergoing repeat resection for malignant glioma, a randomized, blinded, placebo-controlled trial demonstrated a median survival for 110 patients who received carmustine polymers of 31 weeks compared with 23 weeks for 122 patients who only received placebo polymers. The benefit achieved statistical significance only on analysis adjusting for prognostic factors rather than for the randomized groups as a whole (hazard ratio = 0.67, P = 0.006). A blinded, placebo-controlled trial has also been performed for carmustine implant placement in newly diagnosed patients prior to standard radiotherapy. Median survival was improved from 11.6 to 13.9 months (P = 0.03), with a 29% reduction in the risk of death. When patients with glioblastoma multiforme alone were analyzed, the median survival improved from 11.4 to 13.5 months, but this improvement was not statistically significant. When a Cox’s proportional hazard model was utilized to account for other potential prognostic factors, there was a significant 31% reduction in the risk of death (P = 0.04) in this subgroup. Data from other small reports support these results and confirm that the incidence of adverse events does not appear to be increased meaningfully. Given the poor prognosis without possibility of cure, these benefits from a treatment with a favorable safety profile were considered meaningful. There is randomized evidence to support the use of carmustine wafers placed during resection of recurrent disease. Therefore, although there is limited specific evidence, this treatment is likely to be efficacious in an environment when nearly all patients receive temozolomide as part of initial management. Given that half of the patients in the randomized trial assessing the value of carmustine implants in recurrent disease had received prior chemotherapy, it is likely that this remains a valuable treatment at the time of repeat resection, even after temozolomide. There are data from multiple reports to support safety. Although there is randomized evidence to support the use of this therapy in newly diagnosed patients who will receive radiotherapy alone, it is now standard to administer both adjuvant temozolomide and radiotherapy. There are survival outcome reports for small cohorts of patients receiving temozolomide with radiotherapy, but this information is not sufficient to support firm recommendations. Based on the rationale and evidence of safety, this approach appears to be a reasonable option as more information is acquired. Available data support the safety of using carmustine wafers in this circumstance, although special attention to surgical guidelines for implanting the wafers is warranted.
carmustine; Polifeprosan 20; malignant glioma
Icatibant, a first-in-class B2 bradykinin receptor antagonist, appears to have a favorable efficacy and safety profile for the treatment of acute attacks of hereditary angioedema in adults.
To update the evidence and provide an overview of the available data on icatibant.
Peer reviewed articles published and listed in Medline Search and published updated guidelines for the treatment of acute attacks in hereditary angioedema type I and II in adults were reviewed. The validity and quality of evidence were evaluated.
Place in therapy
Clinical evidence for the treatment of acute hereditary angioedema attacks with icatibant is strong. Approximately 10% of the patients require a second dose. No serious adverse reactions have been reported. The only significant side effects consistently registered by 90% of patients are transient local pain, swelling, and erythema at the local injection site.
Subcutaneously administered 30 mg icatibant has been shown to be a safe and efficacious treatment in clinical trials. It is the only specific treatment authorized for self-administration by the subcutaneous route offering increased patient independence.
icatibant; hereditary angioedema; self-administration; acute attacks
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is universally fatal. Despite surgical resection, radiotherapy, and systemic chemotherapy, the median overall survival is less than 15 months. As current therapies are not tumor-specific, treatment commonly results in toxicity. The epidermal growth factor receptor variant III (EGFRvIII) is a naturally occurring mutant of EGFR and is expressed on approximately 20% to 30% of GBMs. As it is not expressed on normal cells, it is an ideal therapeutic target. Rindopepimut is a peptide vaccine which elicits EGFRvIII-specific humoral and cellular immune responses. Phase I and II clinical trials have demonstrated significantly higher progression-free and overall survival times in vaccinated patients with EGFRvIII-expressing GBM tumors. Side effects are minimal and mainly consist of hypersensitivity reactions. Due to the efficacy and safety of rindopepimut, it is a promising therapy for patients with GBM. Currently, rindopepimut is undergoing clinical testing in an international Phase III trial for newly diagnosed GBM and a Phase II trial for relapsed GBM.
CDX-110; EGFRvIII; glioblastoma; immunotherapy; PEPvIII
Pancreatic exocrine insufficiency (PEI) is often observed in patients with pancreatic diseases, including chronic pancreatitis, cystic fibrosis, and tumors, or after surgical resection. PEI often results in malnutrition, weight loss and steatorrhea, which together increase the risk of morbidity and mortality. Therefore, nutritional interventions, such as low-fat diets and pancreatic enzyme replacement therapy (PERT), are needed to improve the clinical symptoms, and to address the pathophysiology of pancreatic exocrine insufficiency. PERT with delayed-release pancrelipase is now becoming a standard therapy for pancreatic exocrine insufficiency because it significantly improves the coefficients of fat and nitrogen absorption as well as clinical symptoms, without serious treatment-emergent adverse events. The major adverse events were tolerable gastrointestinal tract symptoms, such as stomach pain, nausea, and bloating. Fibrosing colonopathy, a serious complication, is associated with high doses of enzymes. Several pancrelipase products have been approved by the US Food and Drug Administration in recent years. Although many double-blind, placebo-controlled trials of pancrelipase products have been conducted in recent years, these studies have enrolled relatively few patients and have often been less than a few weeks in duration. Moreover, few studies have addressed the issue of pancreatic diabetes, a type of diabetes that is characterized by frequent hypoglycemia, which is difficult to manage. In addition, it is unclear whether PERT improves morbidity and mortality in such settings. Therefore, large, long-term prospective studies are needed to identify the optimal treatment for pancreatic exocrine insufficiency. The studies should also examine the extent to which PERT using pancrelipase improves mortality and morbidity. The etiology and severity of pancreatic exocrine insufficiency often differ among patients with gastrointestinal diseases or diabetes (type 1 and type 2), and among elderly subjects. Finally, although there is currently limited clinical evidence, numerous extrapancreatic diseases and conditions that are highly prevalent in the general population may also be considered potential targets for PERT and related treatments.
pancreatic exocrine insufficiency; chronic pancreatitis; pancreatic diabetes; steatorrhea; pancreatic enzyme replacement therapy; extrapancreatic diseases
Colesevelam hydrochloride is a molecularly engineered, second-generation bile acid sequestrant demonstrating enhanced specificity for bile acids which has been approved for use as adjunctive therapy to diet and exercise as monotherapy or in combination with a β-hydroxymethylglutaryl-coenzyme A reductase inhibitor for the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. It is also the only lipid-lowering agent currently available in the United States which has been approved for use as adjunctive therapy in patients with type 2 diabetes mellitus whose glycemia remains inadequately controlled on therapy with metformin, sulfonylurea, or insulin. With the recent emphasis upon drug safety by the Food and Drug Administration and various consumer agencies, it is fitting that the role of nonsystemic lipid-lowering therapies such as bile acid sequestrants – with nearly 90 years of in-class, clinically safe experience – should be reexamined. This paper presents information on the major pharmacologic effects of colesevelam, including a discussion of recent data derived from both in vitro and in vivo rodent and human studies, which shed light on the putative mechanisms involved.
colesevelam; bile acid sequestrants; cholesterol; low-density lipoprotein
Atrial fibrillation (AF) is a common cardiac arrhythmia, especially in the elderly population. It is associated with cardioembolic complications, particularly strokes, resulting in severe functional deficit or death. AF patients are first stratified into low, intermediate, and high risk for thromboembolic events using the CHADS2 and CHA2DS2-VASc score systems. Depending on their risks, patients are treated with either therapeutic anticoagulation with warfarin or acetylsalicylic acid for stroke prevention. Although warfarin is the recommended therapy, it is underutilized clinically due to concern for narrow therapeutic window, drug-to-drug and drug-to-food interactions, and hemorrhagic complications. Newer anticoagulant agents such as dabigatran (a direct thrombin inhibitor) and rivaroxaban (a direct factor Xa inhibitor) have already been approved by US Food and Drug Administration for stroke prevention in patients with nonvalvular atrial fibrillation. Apixaban is the newest oral direct factor Xa inhibitor and it has been extensively studied in the AVERROES and ARISTOTLE trials. Apixaban demonstrated reduced incidence of primary outcome of stroke and bleeding events when compared with warfarin. Apixaban is currently being reviewed by the Food and Drug Administration as a stroke prophylactic agent. In addition, there are several other indirect factor Xa inhibitors and vitamin K antagonists under study presently. Results from these studies will provide us with information about possible alternatives to warfarin.
atrial fibrillation; stroke prevention; apixaban
Both irritable bowel syndrome (IBS), characterized by chronic and recurrent abdominal pain and altered bowel habits, and functional constipation are highly prevalent gastrointestinal problems for which many patients seek medical advice. A diverse number of treatment approaches are currently recommended to treat persons with chronic constipation as well as patients with IBS in which constipation is the main gastrointestinal symptom (IBS-C). These approaches have had somewhat limited success, and many patients remain dissatisfied with available therapy. Recently, linaclotide, a novel intestinal secretagogue, which works by activating the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium, has been demonstrated to be efficacious in patients with both chronic functional constipation and with IBS-C in a series of randomized, placebo-controlled studies in these populations. Evidence for this assertion is provided in this systematic review of the pharmacologic properties of this novel agent and the published pivotal studies which support the efficacy of this agent in targeted populations.
linaclotide; constipation; irritable bowel syndrome; safety; efficacy
Dapagliflozin is a sodium-glucose co-transporter-2 inhibitor that lowers plasma glucose by decreasing its renal reabsorption. The resulting excretion of glucose in the urine (glucosuria) has transformed what was once solely regarded as an adverse facet of diabetes into a potential novel therapeutic strategy. Glucosuria leads to weight loss, due to a reduction in calories, which is thought to rehabilitate insulin sensitivity, at least partially. By acting independently of insulin action or secretion, dapagliflozin appears to avert or minimize two key barriers to optimal glycemic control: hypoglycemia and weight gain. From the clinical studies conducted thus far in patients with type 2 diabetes, dapagliflozin significantly decreases HbA1c (by ~0.5%–1%, from a baseline of 8%–9%), as well as body weight (~2–3 kg), without increased risk of hypoglycemia. Dapagliflozin thus represents a paradigm shift in the treatment of diabetes. While long-term data on safety and efficacy are forthcoming, the results published to date suggest that this agent has the potential to be another option in the treatment of diabetes treatments. This article examines the evidence currently available on the efficacy and safety of dapagliflozin.
dapagliflozin; SGLT2 inhibitors; type 2 diabetes mellitus; kidney
Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous) to one in 1,000,000 (homozygous). Mutations of the low-density lipoprotein (LDL) receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH) or in adulthood (heterozygous FH). Current treatment modalities include lifestyle modification, combination drug therapy (statin-based), and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%–47%, lipoprotein(a) levels by 20%–40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%–100%), flu-like symptoms (29%–46%), and elevated transaminases associated with an increased liver fat content (6%–15%). Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated.
antisense oligonucleotide; statin intolerance; apolipoprotein B
Gaucher disease is an inherited lysosomal storage disorder, characterized by deficient activity of glucocerebrosidase leading to storage of glucocerebroside in tissue macrophages. Type I disease, the most prevalent form, lacks central nervous system involvement but presents primarily with variable degrees of hepatosplenomegaly, cytopenia, and bone disease. Intravenous enzyme replacement therapy can reverse these manifestations. In addition to the two enzymes currently authorized for use, the newest enzyme, taliglucerase alfa, is at the late stages of clinical development. Taliglucerase alfa is a unique product, as it is the first plant cell–based recombinant enzyme therapy. This review considers the existing evidence for therapeutic efficacy of taliglucerase alfa in the treatment of the non-neuronopathic manifestations of Gaucher disease. Clinical studies encompass one phase I trial in healthy volunteers, one phase III trial, and preliminary results from both an extension study and a switch study. In the 9-month, randomized, double-blind phase III trial, treatment-naïve patients with type I Gaucher disease were treated with either 30 or 60 U/kg every 2 weeks. Dose-dependent improvements were achieved after 6 and 9 months of therapy, with reductions in spleen and liver volumes and improvements in hemoglobin levels. Platelet counts improved initially only in the higher-dose group, but preliminary results from the extension study also show significant increases in the lower-dose group. Bone marrow involvement, as assessed by magnetic resonance imaging, improved in almost all patients. Taliglucerase alfa has shown a good safety profile, with few patients experiencing hypersensitivity reactions and developing antibodies. An additional enzyme replacement therapy for Gaucher disease would enable the treatment of more patients and would provide backup for unexpected production problems. Furthermore, it is expected that this new treatment would reduce the costs of therapy. Taliglucerase alfa is a valuable new treatment modality for the non-neuronopathic manifestations of Gaucher disease.
lysosomal storage disorder; glucocerebrosidase deficiency; enzyme replacement therapy; plant-derived recombinant human glucocerebrosidase
Premature ejaculation (PE) is a major issue in male sexual health. The global prevalence of PE is estimated to be between 20% and 40%, making it the most common sexual dysfunction in men. PE causes distress and reduced quality of life for patients and has a negative impact on interpersonal relationships. Historically, it has been treated with cognitive therapy, behavioral methods, and off-label use of selective serotonin reuptake inhibitors usually used to treat depression and other psychological disorders. Dapoxetine is a selective serotonin reuptake inhibitor specifically designed to treat PE. This paper reviews the current evidence for use of dapoxetine in the treatment of PE in adult men. There is substantial evidence that dapoxetine 30 mg or 60 mg taken “on-demand” results in a significant increase in intravaginal ejaculatory latency time when compared with placebo. Patient-reported outcomes are clearly improved relative to placebo following dapoxetine therapy, indicating greater control over ejaculation, more satisfaction with intercourse, less ejaculation-related distress, and, importantly, significantly reduced interpersonal difficulty. These data were supported by consistent reports of improvement in Clinical Global Impression of change in PE following treatment with dapoxetine. Further studies are needed to evaluate long-term efficacy and health economics. The unique pharmacology of dapoxetine makes it ideal for on-demand dosing, and the clinical evidence shows dapoxetine to be an efficacious and tolerable treatment for lifelong and acquired PE.
dapoxetine; intravaginal ejaculatory latency time; patient-reported outcomes; premature ejaculation
Lixisenatide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist mimicking several favorable actions of endogenous GLP-1 that result in improved glycemic control with little or no hypoglycemia and weight loss. Phase II trials have shown that lixisenatide 20 μg once daily restores first-phase insulin release in patients with type 2 diabetes and improves the second-phase insulin response. Administered once or twice daily for 4 weeks, it significantly reduced postprandial and fasting blood glucose levels, and glycosylated hemoglobin (HbA1c). The efficacy and safety of lixisenatide once daily is being assessed in the GETGOAL Phase III clinical trial program. Results have shown beneficial effects on HbA1c compared with placebo in combination with commonly used antidiabetes agents, with no increased risk of hypoglycemia and with beneficial weight reduction. Adverse effects were similar to those observed for available GLP-1 receptor agonists, the most frequent being gastrointestinal. Both GLP-1 receptor agonists and long-acting insulin analogs have demonstrated protective effects on beta cells in preclinical studies. This, along with the pronounced effect of lixisenatide on postprandial plasma glucose, provides a rationale for combining it with long-acting basal insulin analogs, in the hope that the additive effects on glycemic control combined with a potential benefit on islet cells may lead to a new treatment approach to control blood glucose better and prevent long-term complications in patients with type 2 diabetes.
GLP-1 receptor agonist; combination therapy; GETGOAL program; insulin; lixisenatide; postprandial plasma glucose; type 2 diabetes
Cystic fibrosis (CF) is a genetic disease caused by abnormal chloride transport across cellular membranes. In the respiratory tract, this molecular defect causes obstruction of the airways by mucus and chronic endobronchial infection. The majority of patients suffer early death from chronic respiratory disease. Pseudomonas aeruginosa is the predominant chronic airway pathogen in older children and adults with CF and is associated with worse outcomes. However, overall survival in CF has been greatly improved in recent decades due in large part to the aggressive treatment of chronic infections such as P. aeruginosa. While intravenous and oral antibiotics are commonly used in the management of CF respiratory infections, inhaled anti-infective therapies offer the benefit of delivering the drug directly to the site of infection and avoiding potential toxicities associated with systemic absorption. Aztreonam lysine (AZLI) has recently been developed as an inhaled antibiotic for chronic use in CF patients with endobronchial P. aeruginosa infection. This paper reviews background data and the clinical studies which contributed to AZLI’s formal FDA approval and growing role in the management of CF pulmonary disease.
cystic fibrosis; aztreonam lysine; Pseudomonas aeruginosa; inhaled antibiotics
Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are refractory to bortezomib and immunomodulatory agents. This review focuses on the pharmacology, safety, and efficacy of carfilzomib for the treatment of multiple myeloma in bortezomib-naïve and bortezomib-exposed populations.
carfilzomib; multiple myeloma; pharmacology; safety; efficacy
Ticagrelor, the first direct-acting, reversibly binding oral P2Y12 receptor antagonist, appears to have a favorable efficacy and safety profile.
To update the evidence and provide an overview of the available data on ticagrelor.
Peer reviewed articles published and listed under Medline Search, and published updated guidelines for pharmacotherapies in acute coronary syndromes were reviewed.
Place in therapy:
Clinical evidence is increasing to support the use of new thienopyridines and the direct-acting P2Y12 receptor in the setting of acute coronary syndromes.
The options for drugs to inhibit the platelet P2Y12 receptor for adenosine diphosphate are rapidly expanding. Ticagrelor has shown benefits in clinical trials. Its rapid onset of platelet inhibition and short half-life make it an attractive alternative to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required.
platelet; acute coronary syndromes; antiplatelet; coronary artery disease; percutaneous coronary intervention; stent
High-dose chemotherapy and autologous transplantation of hematopoietic cells is a crucial treatment option for hematologic malignancy patients. Current mobilization regimes often do not provide adequate numbers of CD34+ cells. The chemokine receptor CXCR4 and ligand SDF-1 are integrally involved in homing and mobilization of hematopoietic progenitor cells. Disruption of the CXCR4/SDF-1 axis by the CXCR4 antagonist, plerixafor, has been demonstrated in Phase II and Phase III trials to improve mobilization when used in conjunction with granulocyte colony-stimulating factor (G-CSF). This approach is safe with few adverse events and produces significantly greater numbers of CD34+ cells when compared to G-CSF alone. New plerixafor initiatives include use in volunteer donors for allogeneic hematopoietic cell transplant and in other disease targets.
plerixafor; autologous hematopoietic cell transplant; CD34; lymphoma; myeloma; granulocyte colony-stimulating factor (G-CSF)
Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system and represents one of the most common causes of chronic neurologic disability in young adults. All the current disease-modifying drugs are administered parenterally, and can be associated with varying degrees of injection site or infusion-related reactions. Together with other side effects, the parenteral route of administration is one of the key factors affecting adherence to therapy in multiple sclerosis. Fingolimod (FTY720) is an immunomodulator that acts on sphingosine 1-phosphate (S1P) receptors and is the first oral drug approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis. Downmodulation of S1P receptor type 1 (S1P1) slows the egress of lymphocytes from lymph nodes and recirculation to the central nervous system, reduces astrogliosis, and inhibits angiogenesis during chronic neuroinflammation. Fingolimod also regulates the migration of B cells and dendritic cells, and enhances endothelial barrier function. Results from Phase II and III clinical trials provide robust evidence of the efficacy of fingolimod in relapsing-remitting multiple sclerosis. While some caution should be exercised in terms of safety issues, the introduction of fingolimod represents a great advance in the treatment of relapsing-remitting multiple sclerosis. The pharmacologic data on fingolimod and its efficacy and safety in multiple sclerosis are reviewed in this paper.
FTY720; fingolimod; S1P receptors; oral treatment; multiple sclerosis