Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?

PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD-12-281 (aka GSK 842470), CDP840, CI-1018, D-4418, IC485, L-826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub-therapeutic or at the very bottom of the efficacy dose-response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many 'new(er)' PDE4 inhibitors in development are reported to have an improved therapeutic window including tetomilast, oglemilast, apremilast, ONO 6126, IPL-512602 and IPL-455903 (aka HT-0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti-inflammatory activity of PDE inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 inhibitors to suppress inflammation still remains a viable concept.     

To give or not to give? Towards the indication of CSE inhibitors ("statins")

The indication for HMG-CoA-reductase-inhibitors (CSE inhibitors, "statins") for primary prevention of atherosclerosis requires a careful risk/benefit calculation. For this, the PROCAM and SCORE risk scores offer validated, hands on decision support tools. In patients with manifest atherosclerosis and diabetes mellitus statins are indicated regardless of the serum cholesterol level.     

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.     

PDE4 in the human heart – major player or little helper?

PDEs restrict the positive inotropic effects of β-adrenoceptor stimulation by degrading cAMP. Hence, PDE inhibitors sensitize the heart to catecholamines and are therefore used as positive inotropes. On the downside, this is accompanied by exaggerated energy expenditure, cell death and arrhythmias. For many years, PDE3 was considered to be the major isoform responsible for the control of cardiac force and rhythm. However, recent work in gene-targeted mice and rodent cells has indicated that PDE4 is also involved. Furthermore, selective PDE4 inhibitors augment catecholamine-stimulated cAMP levels and induce arrhythmias in human atrial preparations, which suggests that PDE4 has a more prominent role in the human heart than anticipated, and that PDE4 inhibitors such as roflumilast may carry an arrhythmogenic risk. In this issue of the journal, a team of researchers from three laboratories report on the effect of PDE3 and PDE4 inhibitors on ventricular trabeculae from explanted human hearts. The key result is that the PDE4 inhibitor rolipram does not affect the positive inotropic effects of β₁- or β₂-adrenoceptor stimulation. Given that the ventricle rather than the atria is the critical region in terms of arrhythmogenic consequences, this is an important and reassuring finding.

Linked Article

This article is a commentary on the research paper by Molenaar et al., pp. 528–538 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12167     

Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium

Acting through a low-affinity site of the β₁-adrenoceptor (β_1LAR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 μM) on the (−)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 ± 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (−)-CGP12177 (−logEC₅₀M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 ± 9% of the effect of 200 μM (−)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (−)-CGP12177 (−logEC₅₀M = 7.4) but concurrent rolipram + cilostamide caused potentiation (−logEC₅₀M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the β_1LAR-induced cAMP compartment through which (−)-CGP12177 causes tachycardia. In contrast to the (−)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (−)-CGP12177-evoked increases of left atrial contractility through β_1LAR.     

Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit?

Phosphodiesterase-4 (PDE4) belongs to an important family of proteins that regulates the intracellular level of cyclic adenosine monophosphate (cAMP). Several lines of evidence indicate that targeting PDE4 with selective inhibitors may offer novel strategies in the treatment of age-related memory impairment and Alzheimer's disease. The rationale for such an approach stems from preclinical studies indicating that PDE4 inhibitors can counteract deficits in long-term memory caused by pharmacological agents, aging or overexpression of mutant forms of human amyloid precursor proteins. In addition to their pro-cognitive and pro-synaptic plasticity properties, PDE4 inhibitors are potent neuroprotective, neuroregenerative and anti-inflammatory agents. Based on the fact that Alzheimer's disease is a progressive neurodegenerative disorder that is characterised by cognitive impairment, and that neuroinflammation is now recognised as a prominent feature in Alzheimer's pathology, we have concluded that targeting PDE4 with selective inhibitors may offer a novel therapy aimed at slowing progression, prevention and, eventually, therapy of Alzheimer's disease.     

GIP or not GIP? That is the question

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that is released during a meal and facilitates the disposal of both glucose and fat. Because of the insulinotropic action of GIP, this hormone has been considered as a potential therapy of type 2 diabetes, where insulin secretion is inadequate. However, a recent study using GIP receptor knockout mice suggests that inhibition of GIP signalling might be a new target for anti-obesity drugs.     

PDE4 inhibitors: a review of current developments (2005 – 2009)

Background: Despite the sound preclinical database and some promising data from clinical trials, development of PDE4 inhibitors for the treatment of inflammatory or neurological diseases has been hampered by dose-limiting class-related side effects. Objective: In the past years, companies opted for different approaches to improve the therapeutic window of their compounds including topical administration of PDE4 inhibitors with the goal of minimizing systemic exposure. This change in strategy is reflected by the disclosure of novel and chemically diverse molecules that demonstrate the continued interest of pharmaceutical industry in developing PDE4 inhibitors. Conclusion: This review summarizes the clinical development of PDE4 inhibitors since 2005 and the associated patent literature with a focus on strategies applied to minimize systemic adverse effects. In sum, although a significant number of new drugs designed for improved tolerability entered clinical trials, so far none of them fulfilled expectations and best progress has been achieved recently with the oral, non-isoform selective PDE4 inhibitor roflumilast.     

Src inhibitors: drugs for the treatment of osteoporosis, cancer or both?

Src was one of the first proto-oncogenes to be identified and is a prototype of non-receptor type tyrosine kinases. The role of Src in bone metabolism first became apparent in Src-deficient mice and has been confirmed using low-molecular-weight Src inhibitors in animal models of osteoporosis. At the cellular level, it is well established that Src plays an important role in proliferation, and adhesion and motility. In addition, recent data indicate an involvement of Src in cell survival and intracellular trafficking in various specialized cell types. These new findings suggest that Src inhibitors might have therapeutic value in the suppression of tumor growth, tumor angiogenesis and bone resorption.     

Beta-amyloid aggregation inhibitors for the treatment of Alzheimer's disease: dream or reality?

Amyloid (Abeta) deposition remains a hallmark in the pathology of Alzheimer's disease (AD). Important drug discovery efforts dedicated to the inhibition of the polymerization process leading to amyloid neurotoxicity are pursued by academic groups and the pharmaceutical industry as a potential preventive treatment for AD. The aim of this review is to up-date current knowledge on the amyloid aggregation process and the various available peptidic and non-peptidic Abeta aggregation inhibitors.     

To legalize or not to legalize? Economic approaches to the decriminalization of drugs

Drug legalization is gaining ever-widening support in most Western societies. A liberalization of current drug laws will most probably lead to a fall in drug prices. The present article focuses on recent economic studies examining the effects of a fall in prices on quantities consumed and recruitment. Estimates of price elasticities indicate that a substantial increase in consumption by current drug users should be expected if prices decrease, whereas estimates of participation elasticities suggest an increase in the number of users. Tests of the so-called gateway theory (i.e., whether the use of a less harmful drug increases the risk of future use of more harmful drugs) offers less unambiguous results.     

Urine monitoring of diazepam abuse- new intake or not?

Testing for drugs-of-abuse in urine is requested for multiple reasons, including legal and workplace policies. Two cases were studied in which there was a suspicion that the patients continued to abuse diazepam, because of repeatedly positive urine samples. In these cases, diazepam metabolites were measured in urine samples by gas or liquid chromatography coupled to mass spectrometry. The concentrations of diazepam metabolites were subsequently creatinine correlated. Very long elimination times were found in the described cases. None of them had in fact ingested diazepam again during the study period. By the use of pharmacogenetic typing, one of the subjects was found to have a slow metabolism for CYP2C9 as well as for CYP2C19. In the second case, there was a possible drug interaction between diazepam and zolpidem.     

PDE inhibitors: a new approach to treat metabolic syndrome?

About one third of people in the world suffer from metabolic syndrome (MetS), with symptoms such as hypertension and elevated blood cholesterol, and with increased risk of developing additional diseases such as diabetes mellitus and heart disease. The progression of this multifactorial pathology, which targets various tissues and organs, might necessitate a renewal in therapeutic approaches. Since cyclic nucleotide phosphodiesterases (PDEs), enzymes which hydrolyze cyclic AMP and cyclic GMP, play a crucial role in regulating endocrine and cardiovascular functions, inflammation, oxidative stress, and cell proliferation, all of which contribute to MetS, we wonder whether PDE inhibitors might represent new therapeutic approaches for preventing and treating MetS.     

Adenosine in the treatment of stroke: yes, maybe, or absolutely not?

Agonist stimulation of adenosine A(1) receptors has been consistently shown to result in reduction of brain damage following experimentally induced global and focal brain ischaemia in animals. Unsurprisingly, the use of adenosine A(1) receptors as targets for the development of clinical therapeutics suitable for treatment of ischaemic brain disorders has been suggested by many authors. The latest studies of adenosine and its receptors indicate that adenosine-mediated actions might be far more complex than originally anticipated, casting some doubt about the rapid development of stroke treatment based on adenosine. This review discusses the possible role of adenosine receptor subtypes (A(1), A(2) and A(3)) in the context of their potential as therapeutics in stroke.     

Adenosine in the treatment of stroke: yes,maybe, or absolutely not?

Agonist stimulation of adenosine A₁ receptors has been consistently shown to result in reduction of brain damage following experimentally induced global and focal brain ischaemia in animals. Unsurprisingly, the use of adenosine A₁ receptors as targets for the development of clinical therapeutics suitable for treatment of ischaemic brain disorders has been suggested by many authors. The latest studies of adenosine and its receptors indicate that adenosine-mediated actions might be far more complex than originally anticipated, casting some doubt about the rapid development of stroke treatment based on adenosine. This review discusses the possible role of adenosine receptor subtypes (A₁, A₂ and A₃) in the context of their potential as therapeutics in stroke.