Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Drugs
Published in: Drugs 7/2014

01-05-2014 | Leading Article

Serotonergic Therapies for Cognitive Symptoms in Alzheimer’s Disease: Rationale and Current Status

Authors: Maria J. Ramirez, Mitchell K. P. Lai, Rosa M. Tordera, Paul T. Francis

Published in: Drugs | Issue 7/2014

Login to get access

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit. Cholinesterase inhibitors for the symptomatic treatment of cognitive decline in AD have been in use for more than a decade but provide only modest benefits in most patients. Preclinical research is constantly providing new information on AD. The involvement of the serotonergic system in higher cognitive processes such as memory and learning has been widely described and extensive serotonergic denervation has been reported in AD. This review aims to explain the rationale behind testing serotonergic therapies for AD in terms of current knowledge about the pathophysiology of the disease. Based on preclinical studies, certain serotonin (5-HT) receptor ligands have been suggested to have the ability to modify or improve memory/cognition, specifically 5-HT receptors acting at 5-HT1A, 5-HT4 and 5-HT6 receptors. This article summarizes the pharmacology, efficacy, safety and tolerability data for the various serotonergic agents currently in clinical development for AD.
Literature
1.
2.
3.
Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs. 2011;25(9):765–81.CrossRefPubMed
4.
Codony X, Vela JM, Ramírez MJ. 5-HT(6) receptor and cognition. Curr Opin Pharmacol. 2011;11:94–100.CrossRefPubMed
5.
6.
Robert SJ, Zugaza JL, Fischmeister R, Gardier AM, Lezoualc’h F. The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein. J Biol Chem. 2001;276(48):44881–8.CrossRefPubMed
7.
8.
Murillo-Rodriguez E, Arias-Carrion O, Sanguino-Rodriguez K, Gonzalez-Arias M, Haro R. Mechanisms of sleep-wake cycle modulation. CNS Neurol Disord Drug Targets. 2009;8(4):245–53.CrossRefPubMed
9.
Hodges MR, Richerson GB. The role of medullary serotonin (5-HT) neurons in respiratory control: contributions to eupneic ventilation, CO2 chemoreception, and thermoregulation. J Appl Physiol. 2010;108(5):1425–32.CrossRefPubMedCentralPubMed
10.
Magalhães CP, de Freitas MF, Nogueira MI, Campina RC, Takase LF, de Souza SL, et al. Modulatory role of serotonin on feeding behavior. Nutr Neurosci. 2010;13(6):246–55.CrossRefPubMed
11.
Parent M, Wallman MJ, Gagnon D, Parent A. Serotonin innervation of basal ganglia in monkeys and humans. J Chem Neuroanat. 2011;41(4):256–65.CrossRefPubMed
12.
Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev. 1992;72(1):165–229.PubMed
13.
Meneses A, Liy-Salmeron G. Serotonin and emotion, learning and memory. Rev Neurosci. 2012;23(5–6):543–53.PubMed
14.
Wallman MJ, Gagnon D, Parent M. Serotonin innervation of human basal ganglia. Eur J Neurosci. 2011;33(8):1519–32.CrossRefPubMed
15.
Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083–152.CrossRefPubMed
16.
Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 2002;71(4):533–54.CrossRefPubMed
17.
Millan MJ, Marin P, Bockaert J, Mannoury la Cour C. Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci. 2008;29(9):454–64.CrossRefPubMed
18.
Bruinvels AT, Landwehrmeyer B, Gustafson EL, Durkin MM, Mengod G, Branchek TA, et al. Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology. 1994;33(3–4):367–86.CrossRefPubMed
19.
20.
Bonsi P, Cuomo D, Ding J, Sciamanna G, Ulrich S, Tscherter A, et al. Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5-HT 2C, 5-HT6, and 5-HT7 serotonin receptors: implications for extrapyramidal side effects of serotonin reuptake inhibitors. Neuropsychopharmacology. 2007;32(8):1840–54.CrossRefPubMed
21.
Borg J. Molecular imaging of the 5-HT1A receptor in relation to human cognition. Behav Brain Res. 2008;195(1):103–11.CrossRefPubMed
22.
Dawson LA, Nguyen HQ, Li P. The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. 2001;25(5):662–8.CrossRefPubMed
23.
24.
Staubli U, Xu FB. Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J Neurosci. 1995;15(3 Pt 2):2445–52.PubMed
25.
Mohler EG, Shacham S, Noiman S, Lezoualc’h F, Robert S, Gastineau M, et al. VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux. Neuropharmacology. 2007;53(4):563–73.CrossRefPubMed
26.
Meneses A. Involvement of 5-HT2A/2B/2C receptors on memory formation: simple agonism, antagonism, or inverse agonism? Cell Mol Neurobiol. 2002;22(5–6):675–88.CrossRefPubMed
27.
Hedlund PB, Sutcliffe JG. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci. 2004;25(9):481–6.CrossRefPubMed
28.
Bowen DM, Allen SJ, Benton JS, Goodhardt MJ, Haan EA, Palmer AM, Sims NR, Smith CC, Spillane JA, Esiri MM, Neary D, Snowdon JS, Wilcock GK, Davison AN. Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer’s disease. J Neurochem. 1983;41:266–72.CrossRefPubMed
29.
Chen CPLH, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, Jobst KA, Francis PT. Presynaptic serotonergic markers in community-acquired cases of Alzheimer’s disease: correlation with depression and neuroleptic medication. J Neurochem. 1996;66:1592–8.CrossRefPubMed
30.
Chen CPLH, Eastwood SL, Hope T, McDonald B, Francis PT, Esiri MM. Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer’s disease prospectively assessed for behavioural changes. Neuropathol Appl Neurobiol. 2000;26:347–55.CrossRefPubMed
31.
Palmer AM, Francis PT, Benton JS, Sims NR, Mann DM, Neary D, Snowden JS, Bowen DM. Presynaptic serotonergic dysfunction in patients with Alzheimer’s disease. J Neurochem. 1987;48:8–15.CrossRefPubMed
32.
Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, Chen CP, Francis PT, Lasheras B, Ramirez MJ. Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease. Neuropsychologia. 2005;43:442–9.CrossRefPubMed
33.
Nazarali AJ, Reynolds GP. Monoamine neurotransmitters and their metabolites in brain regions in Alzheimer’s disease: a postmortem study. Cell Mol Neurobiol. 1992;12:581–7.CrossRefPubMed
34.
Tsang SW, Keene J, Hope T, Spence I, Francis PT, Wong PT, Chen CP, Lai MK. A serotoninergic basis for hyperphagic eating changes in Alzheimer’s disease. J Neurol Sci. 2010;288:151–5.CrossRefPubMed
35.
Ouchi Y, Yoshikawa E, Futatsubashi M, Yagi S, Ueki T, Nakamura K. Altered brain serotonin transporter and associated glucose metabolism in Alzheimer disease. J Nucl Med. 2009;50(8):1260–6.CrossRefPubMed
36.
Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baaré WF, Knudsen GM, Hasselbalch SG. Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study. Neurobiol Aging. 2012;33(3):479–87.CrossRefPubMed
37.
Curcio CA, Kemper T. Nucleus raphe dorsalis in dementia of the Alzheimer type: neurofibrillary change and neuronal packing density. J Neuropathol Exp Neurol. 1984;43:359–68.CrossRefPubMed
38.
Halliday GM, McCann HL, Pamphlett R, Brooks WS, Creasey H, McCusker E, Cotton RGH, Broe GA, Harper CG. Brain stem serotonin-synthesising neurons in Alzheimer’s disease: a clinicopathological correlation. Acta Neuropathol (Berl). 1992;84:638–50.CrossRef
39.
Arai H, Ichimiya Y, Kosaka K, Moroji T, Iizuka R. Neurotransmitter changes in early- and late-onset Alzheimer-type dementia. Prog Neuropsychopharmacol Biol Psychiatry. 1992;16:883–90.CrossRefPubMed
40.
Stehouwer JS, Goodman MM. (11) C and (18) F PET radioligands for the serotonin transporter (SERT. J Labelled Compd Radiopharm. 2013;56(3–4):114–9.CrossRef
41.
Bowen DM, Najlerahim A, Procter AW, Francis PT, Murphy E. Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life. Proc Natl Acad Sci USA. 1989;86(23):9504–8.CrossRefPubMedCentralPubMed
42.
Lai MK, Tsang SW, Francis PT, Esiri MM, Keene J, Hope T, Chen CP. Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Res. 2003;974:82–7.CrossRefPubMed
43.
Kepe V, Barrio JR, Huang SC, Ercoli L, Siddarth P, Shoghi-Jadid K, Cole GM, Satyamurthy N, Cummings JL, Small GW, Phelps ME. Serotonin 1A receptors in the living brain of Alzheimer’s disease patients. Proc Natl Acad Sci USA. 2006;103:702–7.CrossRefPubMedCentralPubMed
44.
Garcia-Alloza M, Hirst WD, Chen CP, Lasheras B, Francis PT, Ramirez MJ. Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer’s disease. Neuropsychopharmacology. 2004;29:410–6.CrossRefPubMed
45.
Palmer AM, Wilcock GK, Esiri MM, Francis PT, Bowen DM. Monoaminergic innervation of the frontal and temporal lobes in Alzheimer’s disease. Brain Res. 1987;401:231–8.CrossRefPubMed
46.
Francis PT, Pangalos MN, Stephens PH, Bartlett JR, Bridges PK, Malizia AL, Neary D, Procter AW, Thomas DJ, Bowen DM. Antemortem measurements of neurotransmission: possible implications for pharmacotherapy of Alzheimer’s disease and depression. J Neurol Neurosurg Psychiatry. 1993;56(1):80–4.CrossRefPubMedCentralPubMed
47.
Dijk SN, Francis PT, Stratmann GC, Bowen DM. NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT 1A antagonist. Br J Pharmacol. 1995;115:1169–74.CrossRefPubMedCentralPubMed
48.
Schechter LE, Smith DL, Rosenzweig-Lipson S, Sukoff SJ, Dawson LA, Marquis K, Jones D, Piesla M, Andree T, Nawoschik S, Harder JA, Womack MD, Buccafusco J, Terry AV, Hoebel B, Rada P, Kelly M, Abou-Gharbia M, Barrett JE, Childers W. Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. J Pharmacol Exp Ther. 2005;314:1274–89.CrossRefPubMed
49.
Raje S, Patat AA, Parks V, Schechter L, Plotka A, Paul J, Langstrom B. A positron emission tomography study to assess binding of lecozotan, a novel 5-hydroxytryptamine-1A silent antagonist, to brain 5-HT1A receptors in healthy young and elderly subjects, and in patients with Alzheimer’s disease. Clin Pharmacol Ther. 2008;83:86–96.CrossRefPubMed
50.
Skirzewski M, Hernandez L, Schechter LE, Rada P. Acute lecozotan administration increases learning and memory in rats without affecting anxiety or behavioral depression. Pharmacol Biochem Behav. 2010;95:325–30.CrossRefPubMed
51.
Patat A, Parks V, Raje S, Plotka A, Chassard D, Le Coz F. Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects. Br J Clin Pharmacol. 2009;67:299–308.CrossRefPubMedCentralPubMed
52.
53.
Lai MK, Tsang SW, Esiri MM, Francis PT, Wong PT, Chen CP. Differential involvement of hippocampal serotonin 1A receptors and re-uptake sites in non-cognitive behaviors of Alzheimer’s disease. Psychopharmacology. 2011;213:431–9.CrossRefPubMed
54.
Sato S, Mizukami K, Asada T. A preliminary open-label study of 5-HT1A partial agonist tandospirone for behavioural and psychological symptoms associated with dementia. Int J Neuropsychopharmacol. 2007;10:281–3.CrossRefPubMed
55.
Salzman C. Treatment of the agitation of late-life psychosis and Alzheimer’s disease. Eur Psychiatry. 2001;Suppl 1:25s–8s.CrossRef
56.
Shen F, Smith JA, Chang R, Bourdet DL, Tsuruda PR, Obedencio GP, Beattie DT. 5-HT(4) receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: a pharmacodynamic and pharmacokinetic assessment. Neuropharmacology. 2011;61:69–79.CrossRefPubMed
57.
Sawant-Basak A, Coffman KJ, Walker GS, Ryder TF, Tseng E, Miller E, Lee C, Vanase-Frawley MA, Wong JW, Brodney MA, Rapp T, Obach RS. Metabolism of a serotonin-4 receptor partial agonist 4-{4-[4-tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol (TBPT): identification of an unusual pharmacologically active cyclized oxazolidine metabolite in human. J Pharm Sci. 2013;102(9):3277–93.CrossRefPubMed
58.
Fujiuchi A, Sugiura A, Ohshiro H, Watanabe S, Yamamoto T, Take Y. RQ-00000009, a selective 5-HT4 receptor partial agonist, suppressed brain amyloid-β protein levels and improved memory and cognitive performances in rodents. Alzheimer’s Dementia. 2010;6:S538.CrossRef
59.
Marcos B, Gil-Bea FJ, Hirst WD, García-Alloza M, Ramírez MJ. Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci. 2006;24:1299–306.CrossRefPubMed
60.
Ivachtchenko AV, Ivanenkov YA, Tkachenko SE. 5-hydroxytryptamine subtype 6 receptor modulators: a patent survey. Expert Opin Ther. 2010;20:1171–96.CrossRef
61.
Witty D, Ahmed M, Chuang TT. Advances in the design of 5-HT6 receptor ligands with therapeutic potential. Prog Med Chem. 2009;48:163–224.CrossRefPubMed
62.
Martarello L, Parker C, Cunningham V, Searle G, Rabiner E, Gee A, Davy M, Laruelle M. First evaluation in humans of [11C]GSK215083 as a probe to image the 5-HT6 receptors. J Nucl Med. 2008;49:79P.
63.
Meneses A, Pérez-García G, Ponce-Lopez T, Castillo C. 5-HT6 receptor memory and amnesia: behavioral pharmacology—learning and memory processes. Int Rev Neurobiol. 2011;96:27–47.CrossRefPubMed
64.
Hirst WD, Stean TO, Rogers DC, Sunter D, Pugh P, Moss SF, Bromidge SM, Riley G, Smith DR, Bartlett S, Heidbreder CA, Atkins AR, Lacroix LP, Dawson LA, Foley AG, Regan CM, Upton N. SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur J Pharmacol. 2006;553:109–19.CrossRefPubMed
65.
Da Silva Costa-Aze V, Dauphin F, Boulouard M. 5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice. Psychopharmacology. 2012;2221:99–115.CrossRef
66.
de Bruin NM, Prickaerts J, van Loevezijn A, Venhorst J, de Groote L, Houba P, Reneerkens O, Akkerman S, Kruse CG. Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol Learn Mem. 2011;96:392–402.CrossRefPubMed
67.
Maher-Edwards G, Dixon R, Hunter J, Gold M, Hopton G, Jacobs G, Hunter J, Williams P. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011;26(5):536–44.CrossRefPubMed
68.
69.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, Dimebon Investigators. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo controlled study. Lancet. 2008;372:207–15.CrossRefPubMed
70.
MacMillan KS, Naidoo J, Liang J, Melito L, Williams NS, Morlock L, Huntington PJ, Estill SJ, Longgood J, Becker GL, McKnight SL, Pieper AA, De Brabander JK, Ready JM. Development of proneurogenic, neuroprotective small molecules. J Am Chem Soc. 2011;133(5):1428–37.CrossRefPubMedCentralPubMed
71.
Woods S, Clarke NN, Layfield R, Fone KC. 5-HT(6) receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms. Br. J. Pharmacol. 2012;167(2):436–49.CrossRefPubMedCentralPubMed
72.
Kendall I, Slotten HA, Codony X, Burgueño J, Pauwels PJ, Vela JM, Fone KC. E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat. Psychopharmacology. 2011;213:413–30.CrossRefPubMed
73.
Mowla A, Mosavinasab M, Haghshenas H, Borhani Haghighi A. Does serotonin augmentation have any effect on cognition and activities of daily living in Alzheimer’s dementia? A double-blind, placebo-controlled clinical trial. J Clin Psychopharmacol. 2007;27:484–7.CrossRefPubMed
74.
Mowla A, Mosavinasab M, Pani A. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J Clin Psychopharmacol. 2007;27:67–70.CrossRefPubMed
75.
Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil. Int J Geriatr Psychiatry. 2004;19:9–18.CrossRefPubMed
76.
Drye LT, Ismail Z, Porsteinsson AP, Rosenberg PB, Weintraub D, Marano C, Pelton G, Frangakis C, Rabins PV, Munro CA, Meinert CL, Devanand DP, Yesavage J, Mintzer JE, Schneider LS, Pollock BG, Lyketsos CG, CitAD Research Group. Citalopram for agitation in Alzheimer’s disease: design and methods. Alzheimers Dement. 2012;8:121–30.CrossRefPubMedCentralPubMed
77.
Munro CA, Longmire CF, Drye LT, Martin BK, Frangakis CE, Meinert CL, Mintzer JE, Porsteinsson AP, Rabins PV, Rosenberg PB, Schneider LS, Weintraub D, Lyketsos CG, Depression in Alzheimer’s Disease Study-2 Research Group. Cognitive outcomes after sertraline treatment in patients with depression of Alzheimer disease. Am J Geriatr Psychiatry. 2012;20:1036–44.CrossRefPubMedCentralPubMed
78.
Rosenberg PB, Drye LT, Martin BK, Frangakis C, Mintzer JE, Weintraub D, Porsteinsson AP, Schneider LS, Rabins PV, Munro CA, Meinert CL, Lyketsos CG; DIADS-2 Research Group. Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry. 2010;18:136–45.CrossRefPubMedCentralPubMed
79.
Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D’Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci USA. 2011;108(36):14968–73.CrossRefPubMedCentralPubMed
80.
Martisova E, Aisa B, Guereñu G, Ramírez MJ. Effects of early maternal separation on biobehavioral and neuropathological markers of Alzheimer’s disease in adult male rats. Curr Alzheimer Res. 2013;10(4):420–32.CrossRefPubMed
Metadata
Title
Serotonergic Therapies for Cognitive Symptoms in Alzheimer’s Disease: Rationale and Current Status
Authors
Maria J. Ramirez
Mitchell K. P. Lai
Rosa M. Tordera
Paul T. Francis
Publication date
01-05-2014
Publisher
Springer International Publishing
Published in
Drugs / Issue 7/2014
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-014-0217-5

Other articles of this Issue 7/2014

Drugs 7/2014 Go to the issue

Current Opinion

Defining Phenotypes in Asthma: A Step Towards Personalized Medicine

Adis Drug Evaluation

Canagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus

Adis Drug Evaluation

Sevelamer Carbonate: A Review in Hyperphosphataemia in Adults with Chronic Kidney Disease

Adis Drug Evaluation

Ponatinib: A Review of Its Use in Adults with Chronic Myeloid Leukaemia or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia

Review Article

Management of Asthma and Chronic Obstructive Pulmonary Disease with Combination Inhaled Corticosteroids and Long-Acting β-Agonists: A Review of Comparative Effectiveness Research

R&D Insight Report

Apremilast: First Global Approval