Proton pump inhibitors: the beginning of the end or the end of the beginning?

Despite the dramatic success of pharmacological acid suppression in healing peptic ulcers (PUs) and managing patients with gastro-esophageal reflux disease (GERD) a number of challenges remain in the management of acid-related disorders. Several new drugs are currently being investigated to provide a significant advance over current treatments. These include new drug formulations, novel proton pump inhibitors (PPIs) as well as potassium-competitive acid blockers (P-CABs), which have already reached clinical testing. Some others (like NO-releasing antisecretory compounds) are still in preclinical development and require proof of concept in humans. While H(2)-receptor antagonists (especially soluble or OTC formulations) will become the 'antacids of the third millennium' and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. Since an increasing proportion of patients fail to respond to the best PPI treatment, more potent and long-acting drugs and more effective regimens are needed.     

Hydrogen sulfide: from the smell of the past to the mediator of the future?

Gases such as nitric oxide and carbon monoxide play important roles both in normal physiology and in disease. In recent years, interest has been directed towards other naturally occurring gases, notably hydrogen sulfide (H₂S), which is both a potent vasodilator and a mediator of long-term potentiation in the brain. This article focuses on recent work that suggests a role for H₂S, and perhaps other gases, in the CNS and cardiovascular system.     

Ketolides: the future of the macrolides?

The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.     

Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm?

Pre-eclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause pre-eclampsia. This review provides an alternative to the ‘two-stage model’ of pre-eclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (sFlt-1 also known as sVEGFR) and very low placenta growth factor (PlGF) are unique to pre-eclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking, pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the ‘accelerator’. The ‘braking system’ includes the protective pathways of haem oxygenase 1 (also referred as Hmox1 or HO-1) and cystathionine-γ-lyase (also known as CSE or Cth), which generate carbon monoxide (CO) and hydrogen sulphide (H₂S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, pre-eclampsia is an accelerator–brake defect disorder. CO and H₂S hold great promise because of their unique ability to suppress the anti-angiogenic factors sFlt-1 and soluble endoglin as well as to promote PlGF and endothelial NOS activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

Secondary patents in the pharmaceutical industry: missing the wood for the trees?

Introduction: The critics of the Innovator pharmaceutical industry allege that secondary patents are trivial modifications over the primary patent, which extend its term and delay the entry of the generics in the market place. The protagonists regard secondary patents a result of continuous research and development (R&D), which help them introduce and protect new, differentiated products.

Areas covered: The areas covered are Product life cycle management (PLCM), Drug approval process, Orange book (OB) listed patents, US patent data.

Expert opinion: Our analysis of the patents and products of four innovators viz., AstraZeneca, Takeda, Eisai and Wyeth in the field of proton pump inhibitors (PPI’s) and Merck and Pfizer in the field of Statins shows that secondary patents help innovators sustain competition against other innovators in the specific product segment. The number of secondary patents listed in OB per NCE depends on the innovators interest in exploiting the NCE, the success of R & D effort and product lifecycle management strategy in the wake of market competition. Market entry decisions of innovators are strategic rather than a mere fallout of the secondary patents granted. Entry of another innovator is more unpredictable and hurts the first entrant more vis a vis the entry of generics who can enter the market when the patents protecting a product are no more enforceable, and hence more predictable. Generic entry in the field of PPI’s shows that the term of the primary patent is not extended by the secondary patents.     

Does the brain noradrenaline network mediate the effects of the CO2 challenge?

The inhalation of carbon dioxide (CO2) is commonly used in patients and volunteers as a means of producing anxiety or panic. It is generally believed that patients with panic disorder are more vulnerable to the effects of CO2 than patients with other anxiety disorders or healthy volunteers and there is speculation and debate as to the mechanism for this apparent sensitivity. Recent work from our group has shown that a single inhalation of 35% CO2 activates the hypothalamic-pituitary-adrenocortical (HPA) axis, increases blood pressure (BP) and increases subjective fear responses in healthy volunteers. Correlation analyses reveal a relationship between the changes in BP and the cortisol increase. These findings led us to postulate that a common mechanism may mediate these and the subjective responses to inhalation of CO2. We propose that the noradrenergic system, particularly the locus coeruleus (LC), but including the A1 and A2 cell groups, may be a key mediator of these responses. This article examines the evidence and discusses the results of studies from our laboratory in relation to a neuroanatomical model centring on the LC.     

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk.

Areas covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence.

Expert opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.     

COX-2 expression in atherosclerosis: the good, the bad or the ugly?

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.     

Comparative analysis for the institutions of the adulterated 

假劣药品是我国乃至全世界所共同面临的重大社会问题,它严重影响了用药安全,破坏了社会安定和谐。现通过对中美假劣药品现状和监管制度的比较分析,包括假劣药品的界定、规制措施以及受害者的救济制度等方面的比较分析,着重指出了我国假劣药品监管制度的不足,并借鉴美国先进监管经验,就完善我国假劣药品监管制度给出了若干建议,以保障用药安全。     

Creatine: are the benefits worth the risk?

Creatine monohydrate is a popular sports supplement used to maintain levels of high-energy phosphates during exercise. As a supplement, varying amounts are consumed per person corresponding to parameters such as body mass and level of training (i.e. maintenance versus loading doses). Numerous studies have reported beneficial effects including increased muscle mass during training and neural protection. However, negative reports have also been made of possible side effects, such as muscle cramping during exercise, and potential impurities. The present paper introduces the positive and negative aspects of creatine supplementation and focuses on the toxicological data of creatine, its metabolites and associated mutagenicity or carcinogenicity, genomeceutical effect(s), and any potential 'contaminants.' Additionally, the novel applications of creatine to the areas of neurology, cardiology, and diabetes are presented and discussed along with the representative data for sports nutrition.     

Lipoic acid - the drug of the future?

Numerous experimental and clinical studies proved efficiency of treatment with lipoic acid-containing drugs in diseases, in which pro- and antioxidant balance is disrupted (diabetes, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), tumors, etc.). Efficiency of lipoate has been attributed to unique antioxidant properties of lipoate/dihydrolipoate system, its reactive oxygen species (ROS) scavenging ability and significant effect on the tissue concentrations of reduced forms of other antioxidants, including one of the most powerful, glutathione (thus lipoate is called an antioxidant of antioxidants). Moreover, analysis of literature data suggests participation of lipoic acid in processes of cell growth and differentiation. This fact can be crucial to clinical practice, however, this problem requires further studies.     

Update on the effects of the sodium pump α1 subunit on human glioblastoma: from the laboratory to the clinic

Introduction: Glioblastoma is a debilitating disease that is associated with poor prognosis and a very limited response to therapies; thus, molecularly targeted therapeutics and personalized therapy are urgently needed. The Na⁺/K⁺-ATPase sodium pump is a transmembrane protein complex that has recently been recognized as an important transducer and integrator of various signals. The sodium pump α1 subunit, which is highly expressed in most glioblastomas compared with that in normal brain tissues, is an emerging cancer target that merits further investigation.

Area covered: The purpose of this narrative review is to explore the important roles of the sodium pump α1 subunit in glioblastoma and analyze its potential therapeutic applications.

Expert opinion: Expression of the sodium pump α1 subunit in glioblastoma tissues is generally higher than that in normal tissues. Sodium pump α1 subunit-mediated pivotal antiglioblastoma signaling pathways have been reviewed, and their impact on the sensitivity of glioblastoma cells to anticancer drugs has recently been clarified. In addition, various pharmacologically optimized sodium pump inhibitors have recently reached early clinical trials, and explorations of sodium pump α1 subunit inhibitors may hold promise for the development of stratification strategies in which patients are treated based on their isoform expression status.     

Gene medicines: the end of the beginning?

First-generation gene medicines and genetic vaccines represent a promising new class of therapeutics that have the potential to prevent, correct, or modulate genetic or acquired diseases. The rational design of synthetic gene delivery and expression systems continues to be essential to enable the precise temporal and spatial control of transgene expression in vivo. With the tantalizing efficacy results and outstanding safety profile observed with nonviral, plasmid-based product candidates in early clinical trials, a multidisciplinary approach remains critical to further improve the effectiveness, reduce the manufacturing costs, and maintain the safety of gene therapeutics and vaccines for their successful development. This commentary provides an historical perspective on somatic gene therapy and briefly addresses the rate-limiting steps in effective gene transfer and expression. The importance of understanding plasmid pharmacokinetics after administration by conventional routes in animal models and in humans is emphasized. Pharmaceutical scientists have a pivotal role to play in deciphering the key biological parameters to effective gene transfer and designing gene delivery systems that will enable plasmid-based products to become an integral part of the future medical armamentarium.