Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates.

Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

A patient with Hypertension Uncontrolled by Previous treatment

Co-administration of antihypertensive agents with different modes of action is required in most hypertensive patients to control blood pressure. This led to the development of fixed-dose combinations of established efficacy and tolerability, with the convenience of a single tablet facilitating long-term adherence with therapy. Blockade of the renin-angiotensin system (RAS) is widely used in hypertensive patients, particularly in those at high risk of cardiovascular or renal diseases. There is therefore a strong rationale for including a blocker of the RAS in fixed combinations, together with either a diuretic or a calcium antagonist. Patient characteristics and cardiovascular risk profiles are useful in guiding the choice of combinations administered. Adding a diuretic or a calciumantagonist to aRAS blocker is a valuable option in practically all patients, whether or not they have comorbidities. Amajor task is to individualize the treatment, ie, to find a drug regimen that normalizes the patient's blood pressure while preserving his or her quality of life. This can be achieved in most patients using the fixeddose combination containing the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide. A number of trials have established the antihypertensive efficacy and the protective effects of this combination in hypertensive patients, which justifies its broad use in patients with blood pressure uncontrolled by other blood pressure-lowering agents.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

Canakinumab (ACZ885) vs triamcinolone acetonide for treatment of acute flares and prevention of recurrent flares in gouty arthritis patients refractory to or contraindicated to nsaids and/or colchicine.

Purpose: Current treatments for arthritis flares in gout (gouty arthritis) are not effective in all patients and may be contraindicated in many due to underlying comorbidities. Urate crystals activate the NALP 3 inflammasome which stimulate production of IL-1β, driving inflammatory processes. Targeted IL-1β blockade may be an alternative treatment for gouty arthritis. Canakinumab (ACZ885) is a fully human monoclonal anti- IL-1β antibody with a long half-life (28 days). Method: This was an 8-weeks, dose-ranging, multicenter, blinded, double-dummy, active-controlled trial of patients ≥18 to ≤80 y with an acute gouty arthritis flare, refractory to or contraindicated to NSAIDs and/or colchicine. Patients were randomized to 1 subcutanous (sc) dose of canakinumab (10, 25, 50, 90, or 150 mg) or 1 intra muscular (im) dose of triamcinolone acetonide (TA) [40 mg]. The primary variable was assessed 72 h post-dose, measured on a 0-100 mm VAS pain scale. Secondary variables included pain intensity 24 and 48 h post dose, time to 50% reduction in pain intensity, and time to recurrence of gout flares up to 8 weeks post dose. Results: 200 patients were enrolled (canakinumab n=143, TA n=57) and 191 completed the study. A statistically significant dose response was observed at 72 h. The 150 mg dose reached superior pain relief compared to TA starting from 24h: estimated mean difference in pain intensity on 0-100 mm VAS was -11.5 at 24 h, -18.2 at 48 h, and -19.2 at 72 h (all p<0.05). Canakinumab 150 mg provided a rapid onset of pain relief: median time to 50% reduction in pain was reached at 1 day with canakinumab 150 mg vs 2 days for the TA group (p=0.0006). The probability of recurrent gout flares was 3.7% with canakinumab 150 mg vs. 45.4% with TA 8 weeks post treatment, a relative risk reduction of 94% (p=0.006). Serious AEs occurred in 2 patients receiving canakinumab (appendicitis and carotid artery stenosis) and 1 receiving TA (cerebrovascular disorder). Investigator's reported these events as not study drug related. There were no discontinuations due to AEs. Conclusion: Canakinumab 150 mg provided faster onset and superior pain relief compared to TA for acute flares in gouty arthritis patients refractory to or contraindicated to standard treatments. The 150 mg dose of canakinumab prevented recurrence of gout flares with a relative risk reduction compared to TA of 94% at 8 weeks post-dose, and was well tolerated.

Nicotinamide phosphoribosyltransferase as a target in inflammation- related disorders.

NAD(+) biosynthesis through nicotinamide phosphoribosyltransferase (NAMPT) holds potential as a target for the treatment of inflammatory disorders due to NAD(+)'s role in immune cell signaling and metabolism. In addition to its activity as an enzyme, NAMPT is also secreted in the extracellular space where it acts as a pro-inflammatory and proangiogenic cytokine. NAMPT inhibition with FK866 has anti-inflammatory activity in different models of immune disorders and it prevents ischemia-reperfusion-induced heart damage by dampening the production of neutrophil chemoattractants. NAMPT blockade with a neutralizing antibody has beneficial effects in an acute lung injury model. Last, but not least, the anticancer activity of NAMPT inhibitors may also reflect, at least in part, their ability to modify the cancer microenvironment through their anti-inflammatory properties. Overall, NAMPT inhibition holds potential for the treatment of inflammation-related disorders and the development of effective and safe NAMPT inhibitors remains an area of strong interest in pharmaceutical research.

Role of brain alpha 1B-adrenoceptors in modafinil-induced behavioral activity.

These studies show that either central pharmacological blockade or genetic ablation of alpha(1B)-adrenoceptors markedly attenuates the behavioral activation caused by modafinil, implicating these receptors in the drug's action.

Regulation of interleukin 1α secretion by inflammasomes.

The crucial role of the proinflammatory cytokine interleukin 1β (IL-1β) in driving inflammatory disorders, such as Muckle-Wells syndrome and gout, has been extensively characterised. Owing to its high potency to induce inflammation the activation and secretion of IL-1β is tightly regulated. The sensing of various host 'dangers', including infections and metabolic deregulation, results in the formation of large protein complexes, termed inflammasomes. Formation of the inflammasomes leads to the cleavage and activation of caspase-1, which in turn proteolytically processes its substrates, including pro-IL-1β. Biologically active IL-1β is subsequently secreted by the cell. In contrast to IL-1β, little is known about mechanisms underlying the activation and secretion of its close homologue IL-1α. Moreover, the physiological role of IL-1α is still not well defined. Several studies hypothesise that IL-1α serves as a danger signal, which is passively released from dying cells. However, recent studies suggest a more complex function of this cytokine. Indeed, NLRP3 inflammasome agonists such as uric acid crystal or nigericin induce IL-1α cleavage and secretion, leading to the cosecretion of both IL-1β and IL-1α. Depending on the type of NLRP3 agonist, release of IL-1α is NLRP3-inflammasome/caspase-1 dependent or independent, but in both cases IL-1α processing depends on calpain protease activity. Taken together, these results suggest that the promotion and progression of inflammatory diseases is not solely due to IL-1β but also to its close relative IL-1α. This should be considered when IL-1 blockade is applied as a therapeutic strategy for diseases such as cryopyrin-associated periodic syndromes or gout.

Acetylcholinesterase inhibitor treatment for myasthenia gravis.

BACKGROUND: In myasthenia gravis, antibody-mediated blockade of acetylcholine receptors at the neuromuscular junction abolishes the naturally occurring 'safety factor' of synaptic transmission. Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness, but there is controversy about their long-term efficacy, dosage and side effects. OBJECTIVES: To evaluate the efficacy of acetylcholinesterase inhibitors in all forms of myasthenia gravis. SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Specialized Register (5 October 2009), The Cochrane Central Register of Controlled Trials CENTRAL) (The Cochrane Library Issue 3, 2009), MEDLINE (January 1966 to September 2009), EMBASE (January 1980 to September 2009) for randomised controlled trials and quasi-randomised controlled trials regarding usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials.Types of participants: all myasthenia gravis patients diagnosed by an internationally accepted definition.Types of interventions: treatment with any form of acetylcholinesterase inhibitor.Types of outcome measuresPrimary outcome measureImprovement in the presenting symptoms within 1 to 14 days of the start of treatment.Secondary outcome measures(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score within 1 to 14 days and more than 14 days after the start of treatment.(3) Myasthenia Gravis Association of America post-intervention status more than 14 days after start of treatment.(4) Adverse events: muscarinic side effects. DATA COLLECTION AND ANALYSIS: One author (MMM) extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials. MAIN RESULTS: We did not find any large randomised or quasi-randomised trials of acetylcholinesterase inhibitors in generalised myasthenia gravis. One cross-over randomised trial using intranasal neostigmine in a total of 10 subjects was only available as an abstract. AUTHORS' CONCLUSIONS: Except for one small and inconclusive trial of intranasal neostigmine, no randomised controlled trial has been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. Response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in the placebo arm of treatment would be difficult to justify.

Canakinumab (Acz885) Relieves Pain And Controls Inflammation Rapidly In Patients With Difficult-To-Treat Gouty Arthritis : Comparison With Triamcinolone Acetonide

Background : Monosodium urate (MSU) crystals stimulate the productionof interleukin-1b (IL-1b), a potent inflammatory cytokine. Targeted IL-1b blockade with canakinumab, a fully human monoclonal anti-IL-1b antibody, is a novel treatment for gouty arthritis. Its effects on pain and inflammation in acute gouty arthritis flares were compared with triamcinolone acetonide (TA). TA has been shown to be effective in the treatment of acute gouty arthritis flares.Methods : This was an 8-week, dose-ranging, multicenter, blinded, active-controlled trial. Patients _18 to _80 years with an acute gouty arthritis flare, refractory to or contraindicated to NSAIDs and/or colchicine were randomized to one subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n¼143) or one intramuscular dose of TA (40 mg; n¼57). Primary outcome was pain intensity at 72 hours post dose on VAS scale (0-100 mm). Secondary outcomes included Creactive protein (CRP), serum amyloid A (SAA), and physician's assessment of tenderness, swelling and erythema of target joint at 72 hours, 7 days, 4 and 8-weeks post dose.Results : 191/200 patients completed the study. Canakinumab showed a statistically significant dose response at 72 hours. The 150mg dose group reached superior pain relief compared to TA group starting from 24 hours as previously reported. At 72 hours post dose, 78% of canakinumab 150mg treated patients achieved _75% and 96% achieved _50% reduction in pain from baseline. In contrast, 45% and 61% of patients treated with TA achieved _75% and _50% pain reduction, respectively. Median CRP/SAA levels were normalized by Day 7 for all canakinumab doses above 10mg and remained below the upper limit of normal [(ULN): CRP 3.0 mg/L; SAA 6.7 mg/L)] for rest of the study. In TA group, median CRP levels remained above the ULN throughout the study while median SAA levels decreased below ULN only 28 days after first dose. At 72 hours post dose, canakinumab 150mg group was 3.2 (95% CI, 1.27-7.89) times more likely to have less joint tenderness and 2.7 (95% CI, 1.09-6.5) times more likely to have less joint swelling than TA group (p<0.05). At 72 hours post dose, erythema disappeared in 74.1% of patients receiving canakinumab150mg and 69.6% of patients receiving TA. At 7 days post dose, erythema was absent in 96.3% of canakinumab 150mg treated patients vs. 83.9% of patients receiving TA. The overall incidence of AEs was similar for canakinumab (41%) and triamcinolone acetonide (42%). Serious AEs (canakinumab treatment groups n¼4, TA n¼1) were not considered treatment-related by investigators. No discontinuationsdue to AEs occurred.Conclusions : Canakinumab 150mg provided superior pain relief compared to TA for acute flares in difficult-to-treat gouty arthritis patients. Canakinumab provided rapid normalization of markers of inflammation accompanied by reduction of clinical signs and symptoms of inflammation.Disclosure statement : U.A., V.M., D.R. and P.S. are shareholders and employees of Novartis Pharma AG. A.P. has received research support from Novartis Pharma AG. N.S. has received research support from and acts as a consultant for Novartis Pharmaceuticals Corporation, has served on advisory boards for Novartis, Takeda, Savient, URL Pharma and Enzyme Rx, and is/has been a member of a speakers' bureau for Takeda. A.S. has received consultancy fees from Novartis Pharma AG, Abbott, Wyeth, UCB, Roche, MSD, Pfizer, Essex and Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Fixed-dose combinations as initial therapy for hypertension : a review of approved agents and a guide to patient selection.

Recent guidelines recommend initiation of antihypertensive therapy with fixed-dose combinations in high-risk patients because such patients usually need two or more blood pressure (BP)-lowering agents in order to normalize their BP. Agents that block the renin-angiotensin system (ACE inhibitors or angiotensin II receptor antagonists [angiotensin receptor blockers; ARBs]) are preferred for the management of hypertension in most patients exhibiting subclinical target organ damage, or established cardiovascular or renal diseases. Unless contraindicated they should be one of the components of fixed-dose combinations, whereas the other component may be either a calcium channel antagonist or a thiazide diuretic. Fixed-dose combinations containing an ACE inhibitor or ARB plus a calcium channel antagonist appear particularly effective in preventing complications of coronary heart disease.

Inhibition of the renin-angiotensin system does not reduce platelet activity at rest or during stress in hypertension.

OBJECTIVES: We investigated the influence of angiotensin receptor blockade and angiotensin-converting enzyme inhibition on stress-induced platelet activation in hypertensive patients. Secondary aims were effects on inflammation, coagulation, and endothelial function. METHODS: Following a 4-week placebo period, 25 hypertensive patients entered a double-blind, crossover study comparing enalapril (20 mg once daily) and losartan (100 mg once daily) treatment (each for 8 weeks). Patients were studied at rest and after a standardized exercise test. RESULTS: Mean arterial pressure was reduced from 119 ± 2 to 104 ± 2 (enalapril) and 106 ± 2 (losartan) mmHg (both P <0.001). Plasma angiotensin II decreased from 2.4 ± 0.4 to 0.5 ± 0.1 pmol/l with enalapril, and increased to 7.2 ± 1.3 pmol/l with losartan (both P <0.001). Exercise-evoked platelet activation, as evidenced by increased numbers of P-selectin-positive platelets (P <0.01), elevated circulating platelet-platelet aggregates (P <0.01) and soluble P-selectin levels (P <0.001), and increased platelet responsiveness to adenosine diphosphate and thrombin (both P <0.05). Neither drug influenced these markers of platelet activation at rest or following exercise. Markers of inflammation (high-sensitivity C reactive protein, interleukin-6, tissue necrosis factor-α), coagulation (tissue plasminogen activator antigen, prothrombin fragment F1+2), and endothelial function (von Willebrand factor, soluble vascular cellular adhesion molecule-1, and intercellular adhesion molecule-1) were also uninfluenced by treatment. CONCLUSION: Enalapril and losartan failed to reduce platelet activity both at rest and during exercise in hypertensive patients. Markers of inflammation, coagulation, and endothelial function were similarly unaffected. Inhibition of the renin-angiotensin system promotes its beneficial effects in hypertension through mechanisms other than platelet inhibition.

Programming of marginal zone B-cell fate by basic Kruppel-like factor (BKLF/KLF3).

Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.

Pre- and postsynaptic effects of SKF64139, a phenylethanolamine N-methyltransferase inhibitor, in conscious normotensive rats

We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent phenylethanolamine N-methyltransferase (PNMT) inhibitor, on blood pressure responses to norepinephrine (40, 80, and 160 ng i.v.); methoxamine (2.5, 5 and 10 micrograms i.v.), a directly active sympathomimetic agent that is not taken up by adrenergic nerves; and tyramine (20, 40, and 80 micrograms i.v.), an indirectly acting sympathomimetic amine. The pressor effect of norepinephrine was not changed by 2 mg of SKF64139, while those of methoxamine and tyramine were significantly reduced. The dose-response curve to exogenous norepinephrine was also evaluated following blockade of norepinephrine uptake in the nerve endings using 0.25 mg desipramine i.v. This dose of desipramine had no effect on blood pressure increase induced by methoxamine. In rats pretreated with the neuronal uptake inhibitor desipramine in a dose that did not affect alpha-adrenoceptors, SKF64139 significantly decreased the pressor responses to norepinephrine. Increasing the dose of SKF64139 to 8 mg i.v. resulted in a significant fall in base-line blood pressure and in a blunted blood pressure response to norepinephrine. These data demonstrate that in vivo the PNMT inhibitor SKF64139 blocks alpha-adrenoceptors and inhibits neuronal uptake. The alpha-adrenoceptor blocking properties of SKF65139 are masked by simultaneous blockade of norepinephrine uptake when agonists with affinity for the uptake system are used. These findings need to be taken into account when interpreting cardiovascular effects of the PNMT inhibitor SKF64139.

Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12.

Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12-CXCR4 axis have emerged as additional or alternative agents for neo-adjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of "selective blockade" of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression.

Pharmacokinetic evaluation of losartan.

Introduction: Blockade of the renin-angiotensin system is one of the major therapeutic strategies in the management of patients with essential hypertension, congestive heart failure and diabetic as well as non-diabetic renal diseases. As the first angiotensin II receptor blocker (ARB) on the market, losartan belongs to the most frequently prescribed ARB. Area covered : The present review examines the pharmacokinetics of losartan with a special discussion on the dose of losartan that should be used in clinical practice to obtain the maximal benefits of the drug. Readers are provided with arguments suggesting that the dose of 50 mg losartan is probably too low and that losartan should preferably be prescribed at the dose of 100 mg/day or higher. Expert opinion : Losartan is an effective antagonist of angiotensin II AT(1) receptors which has been shown to provide important clinical benefits in patients with hypertension, congestive heart failure and renal diseases. Losartan should be prescribed at the dose of 100 mg/day and the use of higher doses should be reconsidered in future studies to improve its clinical efficacy.