Ticagrelor.

Coronary artery disease (CAD) is the single leading cause of death in the U.S. Therapies for CAD have been developed to inhibit platelet aggregation underlying atherogenesis. Clinical benefit has been shown with antagonists of the P2Y(12) receptor, such as clopidogrel. However, concerns over patient resistance to treatment and relatively slow onset and offset of action have indicated the need for further pharmacotherapeutic development. Ticagrelor (formally AZD-6140) is a novel, reversible oral P2Y(12) antagonist developed by AstraZeneca. In vitro and in vivo studies have confirmed that ticagrelor provides rapid, enhanced and maintained antiplatelet effects. These findings have translated to clinical trial investigations with further evidence for a significantly reduced mortality rate associated with cardiovascular events, myocardial infarction (MI) or stroke, and a favourable safety profile. Key clinical trials to date include the DISPERSE, DISPERSE2, PLATO, ONSET/OFFSET and RESPOND. Ticagrelor has been put forward for approval to the European Medical Agency (EMEA) and the Food and Drug Administration (FDA) as an investigational oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndrome.

Dexlansoprazole for the treatment of esophagitis and GERD.

Occasional acid reflux occurs frequently in the general population but gastroesophageal reflux disease (GERD), a chronic disease that affects millions of adults and children, is diagnosed if persistent reflux occurs more than twice a week. The development of proton pump inhibitors (PPIs) dramatically improved the treatment of GERD; however, the treatment of patients with refractory GERD remains a challenge. Dexlansoprazole (TAK-390MR, Kapidex), a pure enantiomer of lansoprazole, is a PPI that, with a novel dual delayed release formulation, provides prolonged inhibition of gastric acid secretion resulting in marked improvements in symptoms of GERD with high maintenance rates and good tolerability. Dexlansoprazole recently received Food and Drug Administration approval for the once-daily oral treatment of heartburn associated with symptomatic nonerosive GERD, the healing of erosive esophagitis (EE) and the maintenance of healed EE.

Chronicles in drug discovery.

Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight agents that target and deplete immunosuppressive regulatory T cells, which are produced by tumor cells to hinder innate immunity against, or chemotherapies targeting, tumor-associated antigens. Antiviral treatments for respiratory syncytial virus, a severe and prevalent infection in children, are limited due to their side effect profiles and cost. New strategies currently under clinical development include monoclonal antibodies, siRNAs, vaccines and oral small molecule inhibitors. Recent therapeutic lines for Huntington's disease include gene therapies that target the mutated human huntingtin gene or deliver neuroprotective growth factors and cellular transplantation in apoptotic regions of the brain. Finally, we highlight the antiinflammatory and antinociceptive properties of new compounds targeting the somatostatin receptor subtype sst4, which warrant further study for their potential application as clinical analgesics.

The effect of inflammation on Fos expression in the ferret trigeminal nucleus.

We have previously carried out detailed characterization and identification of Fos expression within the trigeminal nucleus after tooth pulp stimulation in ferrets. The aim of this study was to determine the effect of pulpal inflammation on the excitability of central trigeminal neurons following tooth pulp stimulation. Adult ferrets were prepared under anesthesia to allow tooth pulp stimulation, recording from the digastric muscle, and intravenous injections at a subsequent experiment. In some animals, pulpal inflammation was induced by introducing human caries into a deep buccal cavity. After 5 d, animals were re-anaethetized, and the teeth were stimulated at 10 times the threshold of the jaw-opening reflex. Stimulation of all tooth pulps induced ipsilateral Fos in the trigeminal subnuclei caudalis and oralis. All non-stimulated animals showed negligible Fos labeling, with no differences recorded between inflamed and non-inflamed groups. Following tooth pulp stimulation, Fos expression was greater in animals with inflamed teeth than in animals with non-inflamed teeth, with the greatest effect seen in the subnucleus caudalis. These results suggest that inflammation increases the number of trigeminal brainstem neurons activated by tooth pulp stimulation; this may be mediated by peripheral or central mechanisms.

Changes in sodium channel expression following trigeminal nerve injury.

We have investigated the expression of TTX-sensitive (TTXs) and TTX-resistant (TTXr) sodium channel subtypes following injury to the inferior alveolar nerve (IAN), in order to determine their potential role in the development of trigeminal neuropathic pain. In seven anaesthetised ferrets, fluorogold (2%) was injected into the left IAN to identify cell bodies with axons in this nerve. In four animals, the nerve was sectioned distal to the injection site and the remaining three served as controls. After 3 days, the animals were perfused with 4% paraformaldehyde. The left and right IANs and trigeminal ganglia were processed using indirect immunofluorescence with specific primary antibodies to TTXs subtypes Na(v)1.3 and Na(v)1.7 and TTXr subtypes Na(v)1.8 and Na(v)1.9. Image analysis was used to quantify the percentage area of staining (PAS) in the nerves. In the ganglia, counts were made of positively labelled cells in the fluorogold population. PAS for Na(v)1.8 and Na(v)1.9 was significantly greater in injured nerves than in either contralateral or control nerves. After injury, significantly fewer cells in the ganglia expressed Na(v)1.3 (controls 36.9%; injured 13.1%), Na(v)1.7 (controls 17.0%; injured 8.1%) and Na(v)1.9 (controls 60.3%; injured 29.0%) (p<0.05, unpaired t test). These changes are different from those previously reported in the dorsal root ganglion following damage to peripheral nerves of spinal origin. As they occur at a time of known high abnormal neural discharge, it seems likely that changes in sodium channel expression may play a role in nerve injury-induced trigeminal pain.

Chronicles in drug discovery.

Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight new options to prevent oral mucositis, a treatment-limiting adverse effect of chemotherapy. Studies are currently focusing on mechanism-based therapies to prevent or repair DNA damage to epithelial and submucosal cells and the cascade or events that follow to cause tissue damage or analgesics to ease the associated oral cavity pain. Therapeutic limitations also exist for the use of the highly effective antibiotic gentamicin, as it evokes acute renal failure. Mechanistic investigations have shed some light on potential targets: the kallikreins, peroxynitrite-related pathways, superoxide production and the accumulation of aminoglycosides. New antibiotic strategies for trachoma, the leading cause of preventable blindness, are also explored along with studies to aid the development of vaccine candidates. Finally, we discuss the utility of allosteric-potentiating ligands to modulate nicotinic acetylcholine receptors, mimicking the reward/addictive effects of nicotine, as potential strategies for smoking cessation.

Spotlight on tNOX: a tumor-selective target for cancer therapies.

Tumor-associated NOX (tNOX) is a novel cell surface ECTO-NOX protein that represents a promising target for selective antitumor therapy. Studies have confirmed the unique presence of tNOX on the cell surface of invasive human cancers and in the sera of cancer patients. Furthermore, as there is a resolute difference between tNOX and the drug-resistant constitutive NOX isoform constitutive NOX, it represents an attractive target for drug, vaccine and diagnostic strategies for cancer. Interestingly, several products currently utilized or under development for cancer display tNOX inhibition as one of their underlying mechanisms, these include non- steroidal antiinflammatory drugs, (-)-epigallocatechin gallate, phenoxodiol and doxorubicin hydrochloride (Adria- mycin). This spotlight article will also highlight tNOX inhibitors under preclinical development and new lines of research to target tNOX for cancer therapeutics.

Spotlight on: clinical development of mycophenolate mofetil in multiple sclerosis.

This month's Spotlight on... focuses on the clinical development of the immunomodulatory agent mycophenolate mofetil as an adjunctive therapy for multiple sclerosis. Mycophenolate mofetil (MMF) is postulated to target several mechanisms underlying the progression of this autoimmune disease, and clinical studies to date have provided evidence for treatment-associated clinical improvements or a halt in disease progression. Ongoing phase II/III clinical trials are investigating the efficacy and safety of MMF as both a monotherapy or in combination with interferon beta-1a.

Rising to the pain challenge.

The 5th Congress of the European Federation of the Association for the Study of Pain (IASP) Chapters 2006 took place in Istanbul, Turkey, from September 13 to 16, 2006. This meeting brought together international members from different disciplines, all interested in improving the understanding of pain mechanisms, and the management of acute and chronic pain. This report will focus on some of the highlights from this meeting.

Characterization of a model of cutaneous inflammatory pain produced by an ultraviolet irradiation-evoked sterile injury in the rat.

Neuroimmune interactions are of known importance in the genesis and maintenance of inflammatory pain states. However, the immune response to tissue damage is likely to differ depending on whether or not the injury is accompanied by infection. Many clinically important inflammatory pain states involve a sterile tissue injury. However, existing animal models of cutaneous inflammatory pain use injuries that are likely to involve those components of the immune system that are specialized for combating pathogens (e.g., injections of Complete Freund's Adjuvant, carrageenan, or zymosan). We describe here a model of cutaneous inflammatory pain in the rat produced by a sterile injury evoked by a single exposure to ultraviolet irradiation. The animals develop heat-hyperalgesia, mechano-hyperalgesia, mechano-allodynia, and cold-allodynia that last for several days. Cold-allodynia appears within 6 h or less, but the other symptoms are not clearly evident until 12-36 h after exposure. This model offers several advantages for the experimental analysis of the causes of inflammatory allodynia and hyperalgesia.

nNOS expression following inferior alveolar nerve injury in the ferret.

Damage to the inferior alveolar nerve (IAN) may result in permanent painful dysaesthesia, and there is compelling evidence to suggest that ectopic activity from the injury site plays a crucial role in the initiation of this disorder. The aim of this study was to determine whether neuronal nitric oxide synthase (nNOS), a regulator of neuronal excitability, could be involved in the development of the abnormal activity. In seven ferrets, the left IAN was exposed and a retrograde tracer, fluorogold, was applied to the nerve for the identification of cell bodies in the trigeminal ganglion with axons in the IAN. In four animals, the nerve was sectioned distal to the injection site, and three served as controls. After 3 days, the animals were perfused with fixative, and the left and right IANs and trigeminal ganglia were processed using indirect immunofluorescence for nNOS. Image analysis was used to quantify the percentage area of staining (PAS) at the injury site. In the ganglia, counts were made of positively labelled cells in the fluorogold population. At the injury site, PAS was significantly greater in injured nerves than in either contralateral or control nerves, and contralateral PAS was elevated compared to control. In the ganglia, the proportion of nNOS-labelled cells was significantly reduced following injury. These results indicate a possible translocation of the nNOS protein from the cell body to the site of nerve injury, where it accumulates. Thus, nNOS could play a role in the development of ectopic activity at a site of trigeminal nerve injury.

Peripheral mechanisms for the initiation of pain following trigeminal nerve injury.

Injury to a branch of the trigeminal nerve may lead to the development of chronic pain in the affected area. The etiology of this condition is not clear, but there is strong evidence to suggest that spontaneous and mechanically induced neural discharge from the injury site plays a crucial role. In laboratory studies, we have characterized this discharge following injury to the inferior alveolar or lingual nerves and have shown a temporal association with the accumulation of neuropeptides in the damaged axons. Substance P, calcitonin gene-related peptide, and vasoactive intestinal polypeptide were all found to be capable of increasing the discharge when applied systemically, and enkephalin caused a decrease. There were also changes in the expression of specific sodium channels and nitric oxide synthase, both at the injury site and in the trigeminal ganglion. Studies on lingual nerve neuromas taken from patients undergoing nerve repair also revealed accumulation of peptides, as well as inflammatory and structural changes, but the presence of these features did not correlate directly with the reported symptoms. The application of corticosteroids to an experimental injury site decreased the mechanically induced discharge, and the anticonvulsant carbamazepine reduced the spontaneous discharge in some axons. Some of the responses that result from damage to a branch of the trigeminal nerve appear to differ from those that follow damage to other peripheral nerves. These differences will need to be taken into account when developing new therapeutic approaches for the management of injury-induced trigeminal pain.