Histamine H₄ receptor: a novel target for inflammation therapy

Histamine, a low molecular weight amine has been extensively studied for its various pharmacological profiles. Until recently histamine was thought to act on three receptors - H?, H? and H?. Merely a decade back, sequencing of human genome has revealed a new histamine receptor - H? receptor. This 390 amino acid sequenced receptor has around 38% homology with histamine H? receptor besides; the pharmacological profile of the protein is quite different from other histamine receptors. H? receptor is mainly expressed in mast cells and leukocytes and involves various physiological functions related to inflammation and allergy. Potent selective H? receptor agonists and antagonists have been synthesized and in vivo studies have indicated their action on H? receptor. In this review, structure, expression, homology sequence of H? receptor among the different species has been documented. Further, structure activity relationship (SAR) of H? ligands on the basis of their nucleus has been discussed in depth. In addition, anti-inflammatory effects of H? receptor antagonists, with special emphasis to JNJ7777120, a selective H? receptor antagonist have been focused exhaustively.     

Effects of the histamine H₁ receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward

Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H? receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction.     

The case for peripheral CB₁ receptor blockade in the treatment of visceral obesity and its cardiometabolic complications

In this review, we consider the role of endocannabinoids and cannabinoid-1 (CB(1)) cannabinoid receptors in metabolic regulation and as mediators of the thrifty phenotype that underlies the metabolic syndrome. We survey the actions of endocannabinoids on food intake and body weight, as well as on the metabolic complications of visceral obesity, including fatty liver, insulin resistance and dyslipidemias. Special emphasis is placed on weighing the relative importance of CB(1) receptors located in peripheral tissues versus the central nervous system in mediating the metabolic effects of endocannabinoids. Finally, we review recent observations that indicate that peripherally restricted CB(1) receptor antagonists retain efficacy in reducing weight and improving metabolic abnormalities in mouse models of obesity without causing behavioural effects predictive of neuropsychiatric side effects in humans.     

Impact of 5-HT₃ receptor antagonists on peripheral and central diseases

In this article we discuss the novel pharmacological aspects of 5-HT(3) receptor antagonists. Commonly used to counteract chemotherapy-induced emesis, these agents now appear to be reaching out for newer indications. Studies have reported neuroprotective and anti-inflammatory properties in vitro and in vivo. 5-HT(3) receptor antagonists can modulate the immune-inflammatory axis through blockade of 5-HT(3) receptors present on immune cells. We review evidence addressing the effects of these drugs on peripheral inflammatory diseases, including asthma, rheumatoid diseases, inflammatory bowel disease and sepsis in addition to diabetes and CNS disorders, including Alzheimer's disease (AD), seizure and stroke.     

Protein kinase C-mediated phosphorylation of the μ-opioid receptor and its effects on receptor signaling

Phosphorylation of the μ opioid receptor (MOPr), mediated by several protein kinases, is a critical process in the regulation of MOPr signaling. Although G protein-coupled receptor kinases are known to play an essential role in the agonist-induced phosphorylation and desensitization of MOPr, evidence suggests that other protein kinases, especially protein kinase C (PKC), also participate in the regulation of MOPr signaling. In this study, we investigated the biochemical nature and downstream effects of PKC-mediated MOPr phosphorylation. We observed in vitro phosphorylation of the MOPr C terminus by purified PKC. Protein mass spectrometry and site-directed mutagenesis implicated Ser363 of MOPr as the primary substrate for PKC, and this was confirmed in Chinese hamster ovary cells stably expressing full-length MOPr using an antibody that specifically recognizes phosphorylated Ser363. Alanine mutation of Ser363 did not affect the affinity of MOPr-ligand binding and the efficiency of receptor G-protein coupling. However, the S363A mutation attenuated the desensitization of receptor G-protein coupling induced by phorbol 12-myristate. Our research thus has identified a specific PKC phosphorylation site in MOPr and demonstrated that PKC-mediated phosphorylation of MOPr induces receptor desensitization at the G protein coupling level.     

Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.     

Epidermal growth factor receptor – targeted molecular therapeutics for head and neck squamous cell carcinoma

Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.     

Are pharmacists and pharmaceutical care having an impact on diabetes?

This study sought to identify pharmacy services offered to patients with diabetes and demonstrate patients receiving pharmaceutical care services had better glucose control as measured by laboratory values and medication compliance. Two hundred randomly selected patients with diabetes were identified from a pharmacy benefits manager's database. Their pharmacists were mailed a survey requesting information concerning morbidity risk factors, concomitant disease states, concomitant medications, diabetes pharmacotherapy, blood glucose concentrations, and percent hemoglobin A1c values. Information concerning diabetes cognitive services offered was also requested. A statistically significant correlation between diabetes cognitive services and improved disease control was not demonstrated secondarily to the small number of responses returned with glucose control information. Our results indicate pharmacists must improve documentation of their services and the impact these interventions have on disease control in order to prepare for reimbursement for cognitive services.     

The histamine H₃ receptor as a therapeutic drug target for metabolic disorders: status, challenges and opportunities

Since the histamine-3 receptor (H?R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H?R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H?R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H?R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H?R field, together with a brief overview of the clinical trials currently running.     

The chemokine system as a therapeutic target in autoimmune thyroid diseases: a focus on the interferon-γ inducible chemokines and their receptor

The recruitment, trafficking, and in situ maintenance of specific subsets of activated lymphocytes constitute crucial steps for the initiation and perpetuation of chronic autoimmune inflammation. The fact that, after IFN-γ stimulation, thyrocytes secrete CXCR3- binding chemokines, which in turn recruits Th1 lymphocytes expressing CXCR3 and secreting IFN-γ, strongly supports the concept that the interferon-γ inducible chemokines (CXCL9, CXCL10, and CXCL11) and their receptor CXCR3 play an important role in the initiation of autoimmune thyroid diseases (AITD). Thus, interfering with CXCR3 might result in the abrogation of the inflammatory process. The understanding of these pathogenetic mechanisms suggested novel therapeutic approaches, with a growing interest for finding a way to interrupt the interactions between chemokines and their receptors. In this review, we focus on the efforts performed in establishing new pharmacological compounds able to target the chemokine/chemokine receptors system as well as to prevent the secretion of CXCR3-binding chemokines, induced by pro-inflammatory cytokines. The crucial issue of selecting the relevant therapeutic targets in animal models of AITD was also discussed. Although some encouraging results have been reached, major hurdles were encountered on the way to success. As a result, we are still waiting for the first anti-chemokine anti-inflammatory drug. Given the importance of leukocytes recruitment to inflammatory sites, research will continue to address the issue of developing specific chemokine-receptor antagonists. We look forward to the development of these novel pharmacological compounds which will hopefully provide a more valid alternative to the currently used lifelong replacement therapies for AITD.     

Modulation of PGC-1α activity as a treatment for metabolic and muscle-related diseases

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Could simvastatin be considered as a potential therapy for chronic lung diseases? A debate on the pros and cons

ABSTRACT

Introduction: Simvastatin (SV) is a drug from the statin class, currently used orally as an anti-cholesterolemic drug. It inhibits the 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase to reduce cholesterol synthesis. Recently, it has been found that SV also has several other protective pharmacological actions unrelated to its anti-cholesterol effects that might be beneficial in the treatment of chronic airway diseases.

Areas covered: This review summarizes the evidence relating to SV as a potential anti-inflammatory, anti-oxidant and muco-inhibitory agent, administered both orally and via pulmonary inhalation, and discusses its pro and cons. Evidence could potentially be used to support the delivery of SV as inhaled formulation for the treatment of chronic respiratory diseases.

Expert opinion: The use of SV as anti-inflammatory, anti-oxidant and muco-inhibitory agent for drug delivery to the lung is promising. Inhaled SV formulations could allow the delivery profile to be customized and optimized to take advantage of the rapid onset of action, low systemic side effect and improved physico-chemical stability. This treatment could potentially to be used clinically for the localized treatment of lung diseases where inflammation and oxidative stress production is present.     

Hyoscine butylbromide – a review on its parenteral use in acute abdominal spasm and as an aid in abdominal diagnostic and therapeutic procedures

Background: Being a quaternary ammonium compound derived from scopolamine, the alkaloid hyoscine butylbromide (HBB) exerts anticholinergic effects without side effects related to the central nervous system because it does not pass the blood–brain barrier. Clinical experience with this antispasmodic dates back to the 1950s and led to its registration for treating abdominal cramps/spasm and for diagnostic imaging purposes.

Objectives and scope: This review focuses on the therapeutic efficacy and safety of the parenteral administration of HBB for treating biliary and renal colic and acute spasm in the genito-urinary tract. In addition, its value for diagnostic or therapeutic procedures in the abdomen, as well as for labour and palliative care, is reviewed. With the generic and trade name of the drug combined with various search terms related to the relevant clinical applications, a thorough literature search was performed in the Medline and EMBASE databases in April 2008.

Findings: In most clinical studies, recommended doses of 20–40 mg HBB were injected, mainly intravenously. Fast pain reduction was achieved by HBB in renal colic; about 90% of the patients showed good to moderate analgesic responses after 30 min and the onset of action was noticeable within 10 min. Similarly, a pain reduction of 42–78% was observed in patients with biliary colic within 30 min after a single intravenous injection of 20 mg. In contrast, no analgesic efficacy of a single injection of 20 mg was found after surgical or shock-wave procedures in the urogenital area.

Administration of HBB prior to, or during, radiological imaging distended the gastrointestinal (GI) tract in double-contrast barium and computed tomographic colonography studies and reduced motion artefacts in magnetic resonance imaging. This improved diagnostic image quality and organ visualisation. Pre-medication led to shorter and easier endoscopy in some, but not all, studies. Because of cervical relaxation, HBB shortened total labour duration with 17–67%. It also relieved pain and reduced GI secretions in terminal cancer patients with inoperable bowel obstruction. With regard to its safety profile, parenteral administration of HBB is associated with mild and self-limiting adverse events, typical for anticholinergic drugs.

Conclusions: These clinical results of rapid action and beneficial efficacy combined with good tolerability support the use of HBB in a range of indications related to acute abdominal spasm, in labour and palliative care and for supporting diagnostic and therapeutic abdominal procedures, where spasm may be a problem.