Emerging therapeutic potential of transdermal clonidine: a prospective as an adaptogen

References

• Pagan N, Wargo K, Malone P, et al. The Clinical Utility of Clonidine. Vol 5. Congers, NY: US Pharm; 2006:HS–2–HS16.
   Google Scholar
• Gilman A. G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56:615–649.
   PubMed Web of Science ®Google Scholar
• Neer E, Chapham D. Roles of G protein subunits in transmembrane signaling. Nature. 1988;333:129–134.
   PubMed Web of Science ®Google Scholar
• Freissmuth M, Casey P, Gilman A. G proteins control diverse pathways of transmembrane signaling. FASEB J. 1989;3:2125–2131.
   PubMed Web of Science ®Google Scholar
• Lilmbrid L. Receptors linked to inhibition of adenylate cyclase: additional signaling mechanisms. FASEB J. 1988;2:2686–2695.
   Web of Science ®Google Scholar
• Walsh D, van Patten S. Multiple pathway signal transduction by the cAMP-dependent protein kinase. FASEB J. 1994;8:1227–1236.
   PubMed Web of Science ®Google Scholar
• Chiu P, Leung H, Ko K. Schizandrin B enhances renal mitochondrial antioxidant status, functional and structural integrity, and protects against gentamicin-induced nephrotoxicity in rats. Biol Pharm Bull. 2008;31:602–605.
   PubMed Web of Science ®Google Scholar
• Wang M, Ramos BP, Paspalas CD, et al. Alpha 2A adrenoreceptors strengthen working memory networks by inhibiting cAMP -HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410.
   PubMed Web of Science ®Google Scholar
• Isom L, Cragoe E, Limbrid L. alpha-2 adrenergic receptors accelerate Na+/H+ exchange in neuroblastoma x glioma cells. J Biol Chem. 1987;262:6720–6787.
   Web of Science ®Google Scholar
• Aghajanian G, Vander-Maelen C. Alpha 2- adrenoreceptor – mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science. 1982;215:1394–1396.
   PubMed Web of Science ®Google Scholar
• Egan TM, Henderson G, North RA, Williams JT. Noradrenalin – mediated synaptic inhibition in rat locus coeruleus neurons. J Physiol. 1983;345:477–488.
   Web of Science ®Google Scholar
• Schoffelmeer A, Mudler A. Presynaptic opioid receptor and alpha-2 adrenoreceptor mediated inhibition of noradrenaline release in the rat brain. Role of hyperpolarization? Eur J Pharmacol. 1984;105:129–135.
   Web of Science ®Google Scholar
• Williams J, North R. Catecholamine inhibition of calcium action potentials in rat locus coeruleus neurons. Neuroscience. 1985;14:105–109.
   Web of Science ®Google Scholar
• Maze M, Tranquilli W. Alpha-2 adrenoreceptor agonists: defining the role in clinical anesthesia. Anesthesiology. 1991;74:581–605.
   PubMed Web of Science ®Google Scholar
• U’Prichard D, Greenberg D, Snyder S. Binding characteristics of a radiolabeled agonist and antagonist at central nervous system alpha noradrenergic receptors. Mol Pharmacol. 1976;13:454–473.
   Web of Science ®Google Scholar
• Bylund D. Subtypes of alpa-2 adrenoreceptors. Pharmacological and biological evidence converge. Trends Pharmacol Sci. 1988;9:356–361.
   PubMed Web of Science ®Google Scholar
• Unnerstall J, Kopajtic T, Kuhar M. Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res Rev. 1984;7:69–101.
   Web of Science ®Google Scholar
• Saunders C, Limbrid L. Lacalization and trafficking of a-2 adrenergic receptor subtypes in cells and tissues. Pharmacol Ther. 1999;84:193–205.
   PubMed Web of Science ®Google Scholar
• Starke K, Gotheri M, Kiblinger H. Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev. 1989;69:864–889.
   PubMed Web of Science ®Google Scholar
• Drew G. Pharmacological characterization of presynaptic a-adrenoreceptors regulating cholinergic activity in the guinea pig ileum. Br J Pharmacol. 1978;64:293–300.
   Web of Science ®Google Scholar
• Wikberg J. Localization of adrenergic receptors in guinea pig ileum and rabbit jejunum to cholinergic neurons and to smooth muscle cells. Acta Physio Scand. 1977;99:190–207.
   PubMedGoogle Scholar
• Izumi H, Nakamura I, Karita K. Effects of clonidine and yohimbine on parasympathetic salivation and vasodilatation in cat SMG. Am J Physiol. 1995;268:R1196–R1202.
   Google Scholar
• Starke K, Montel H, Gayk W, Merker R. Comparison of the effects of clonidine on pre- and postsynaptic adrenoreceptors in the rabbit pulmonary artery. Naunyn Schmiedebergs Arch Pharmacol. 1974;285:133–150.
   Web of Science ®Google Scholar
• Ruffolo R. Distribution and function of peripheral alpha – adrenoreceptors on the cardiovascular system. Pharmacol Biochem Behav. 1985;22:327–333.
   Web of Science ®Google Scholar
• Eriksson E, Eden S, Modigh K. Inportance of norepinephrine alpha – 2 receptor activation for morphine induced ratbgrowth hormone secretion. Neuroendocrinology. 1981;33:91–96.
   PubMed Web of Science ®Google Scholar
• Grossman A, Weerasuriya K, Al-Damluji S. Alpha-2 adrenoreceptor agonists stimulate growth hormone secretion but have no acute effects on plasma cortisol under basal conditions. Horm Res. 1987;25:65–71.
   PubMedGoogle Scholar
• Garcia-Morales P, Dufrane SP, Sener A, Valverde I, Malaisse WJ. Inhibitory effect of clonidine upon adenylate cyclase activity, cyclic AMP production and insulin release in rat pancreatic islets. Biosci Rep. 1984;4:511–521.
   PubMed Web of Science ®Google Scholar
• Angel I, Langer S. Adrenergic induced hyperglycemia in anesthesized rats: involvement of peripheral alpha 2 – adrenoreceptors. Eur J Pharmacol. 1988;154:191–196.
   Google Scholar
• Mogenson G, Jones D, Yim C. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol. 1980;14:69–97.
   PubMed Web of Science ®Google Scholar
• Nauta W, Domesick V.. Neural associations of the limbic system. In: Beckman AL, editor. The Neural Basis of Behavior. Hicksville, NY: Spectrum Publications, Inc.; 1982:175–206.
   Google Scholar
• Swanson L, Mogenson G. Neural mechanisms for the functional coupling of autonomic, endocrine and somatomotor responses in adaptive behavior. Brain Res Rev. 1981;3:1–34.
   Google Scholar
• Coull JT, Frith CD, Dolan RJ, Frackowiak RS, Grasby PM. The neural correlates of the noradrenergic modulation of human attention, arousal and learning. Eur J Neurosci. 1997;9:589–598.
   Web of Science ®Google Scholar
• Dollery CT, Davies DS, Draffan GH, et al. Clinical pharmacology and pharmacokinetics of clonidine. Clin Pharmacol Ther. 1976;19(1):11–17.
   Web of Science ®Google Scholar
• Reid J, Barber N, Davies D. The clinical pharmacology of clonidine: relationship between plasma concentration and pharmacological effect in animals and men. Arch Int Pharmacodyn Ther. 1980;(Suppl):11–16.
   Google Scholar
• Frisk-Holmberg M, Faizlow L, Wibell L. Relationship between the cardiovascular effects and steady-state kinetics of clonidine in hypertension. Eur J Clin Pharmacol. 1984;26:309–313.
   PubMed Web of Science ®Google Scholar
• Shaw J, Enscore D, Chu L. Clonidine rate-controlled system: technology and kinetics. In: Weber MA, Mathias CJ, editors. Mild Hypertension. Proceedings of the International Titisee Workshop. Darmstadt: Steinkopff Verlag; 1984:134–140.
   Google Scholar
• MacGregor TR, Matzek KM, Keirns JJ, van Wayjen RG, van den Ende A, van Tol RG. Pharmacokinetics of transdermally delivered clonidine. Clin Pharmacol Ther. 1985;38:278–284.
   PubMed Web of Science ®Google Scholar
• Weber M, Drayer J, Brewer D, Lipson JL. Transdermal continous antihypertensive therapy. Lancet. 1984;1:9–11.
   PubMed Web of Science ®Google Scholar
• Klein C, Morton N, Kelley S, Metz S. Transdermal clonidine therapy in elderly mild hypertensives: effect on blood pressure, plasma, norepinephrine and fasting plasma glucose. J Hypertens Suppl. 1985;3:S81–S84.
   Google Scholar
• Weber M. Transdermal antihypertensive therapy: clinical and metabolic considerations. Am Heart J. 1986;112:905–912.
   Web of Science ®Google Scholar
• McChesney J, Ryan C, Shaw R, Fishman-Rosen J, Murphy MC. Transdermal clonidine for the treatment of essential hypertension. Compr Ther. 1987;13:49–53.
   Google Scholar
• Arndts D, Doevendans J, Kirsten R, Heintz B. New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man. Eur J Clin Pharmacol. 1983;24:21–30.
   PubMed Web of Science ®Google Scholar
• Claessens AJ, Risler LJ, Eyal S, Shen DD, Easterling TR, Hebert MF. CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance. Drug Metab Dispos. 2010;38:1393–1396.
   PubMed Web of Science ®Google Scholar
• Schaller M, Nussberger J, Weber B. Transdermal clonidine therapy in hypertensive patients. JAMA. 1985;253:233–235.
   PubMed Web of Science ®Google Scholar
• Golub M, Thananopavarn C, Sambhi M. Transdermal clonidine in elderly patiemts with mild hypertension: effects on blood pressure and catecholamines. In: Weber MA, Drayer JIM, editors. Low Dose Oral and Transdermal Therapy of Hypertension. International Symposium on Clonidine in Hypertension. Darmstadt: Steinkopff Verlag; 1985:16–21.
   Google Scholar
• Popli S, Stroka G, Ing TS, et al. Transdermal clonidine for hypertensive patients. Clin Ther. 1983;5:624–628.
   Web of Science ®Google Scholar
• Gosse P, Wicker P, Roudaut R, Danays T, Dallocchio M. Treatment of hypertension by a new transdermal form of clonidine. J Hypertension. 1985;3:565–567.
   Web of Science ®Google Scholar
• Burris J, Mroczek W. Transdermal administration of clonidine: a new approach to antihypertensive therapy. Pharmacotherapy. 1986;6:30–34.
   PubMed Web of Science ®Google Scholar
• Hollifield J. Clinical acceptability of transdermal clonidine: a large – scale evaluation by practitioners. Am Heart J. 1986;112:900–906.
   Web of Science ®Google Scholar
• Houston M. Clonidine hydrochloride: review of pharmacologic and clinical aspects. Prog Cardiovasc Dis. 1981;23:337–350.
   PubMed Web of Science ®Google Scholar
• Kolloch R, Finster H, Overlack A, et al. Low dose oral and transdermal application of clonidine in mild hypertension: hemodynamic and biochemical correlates. In: Weber MA, Drayer JIM, Kolloch R, editors. Low Dose Oral and Transdermal Therapy of Hypertension. International Symposium on Clonidine in Hypertension. Darmstadt: Steinkopff Verlag; 1985:71–80.
   Google Scholar
• Fillingim JM, Matzek KM, Hughes EM, Johnson PA, Sharon GS. Long term treatment with transdermal clonidine in mild hypertension. Clin Ther. 1989;11:398–408.
   Web of Science ®Google Scholar
• Sclar DA, Skaer TL, Chin A, Okamoto MP, Gill MA. Utility of transdermal delivery system for antihypertensive therapy. Am J Med. 1991;91(1A):50S–56S.
   Google Scholar
• Ross E, Pittman T, Koo L. Strategy for the treatment of noncompliant hypertensive hemodyalysis patients. Int J Artif Organs. 2002;25:1061–1065.
   Web of Science ®Google Scholar
• Burris JF, Papademetriou V, Wallin JD, Cook ME, Weidler DJ. Therapeutic adherence in the elderly: transdemal clonidine compared to oral verapamil for hypertension. Am J Med. 1991;91(Suppl 1A):22S–28S.
   Google Scholar
• McMahon FG, Jain AK, Vargas R, Fillingim J. A double – blind comparison of transdermal clonidine and oral captopril in essential hypertension. Clin Ther. 1990;12:88–100.
   Web of Science ®Google Scholar
• Kellaway G, Lubbe W. A community – based trial of transdermal antihypertensive therapy with clonidine (Catapres – TTS). N Z Med J. 1986;99:711–714.
   Web of Science ®Google Scholar
• Burris J. Transdermal clonidine dermatitis. JAMA. 1987;258:1819–1820.
   Google Scholar
• Groth H, Greminger P, Vetter H, Knüsel J, Baumgart P, Siegenthaler W. Transdermal clonidine: a new approach to therapy in essential hypertension. Schweizerishe Rundshau fur Medizin Praxis. 1985;74:10–14.
   Google Scholar
• Maibach H. Clonidine irritant and allergic contact dermatitis assays. Contact Dermatitis. 1985;12:192–195.
   PubMed Web of Science ®Google Scholar
• Maibach H. Oral substitution in patients sensitized by transdermal clonidine treatment. Contact Dermatitis. 1987;16:1–8.
   Web of Science ®Google Scholar
• Giugliano D, Acampora R, Marfella R, et al. Hemodynamic and metabolic effects of transdermal clonidine in patients with hypertension and non-insulin-depenedent diabetes mellitus. Am J Hypertens. 1998;11:184–189.
   PubMed Web of Science ®Google Scholar
• Khandker SK, Mukerjee D, Gurtu S, Pant KK, Dhawan KN, Sinha JN. Modification of reserpine – induced emetic response in pigeons by a2-adrenoreceptors. Pharmacol Res. 1994;29(4):383–387.
   Web of Science ®Google Scholar
• Robichaud A, Savoie C, Stamatiou PB, Tattersall FD, Chan CC. PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway. Neuropharmacology. 2001;40:262–269.
   PubMed Web of Science ®Google Scholar
• Oddby-Muhrbeck E, Eksborg S, Bergendahl HT, Muhrbeck O, Lönnqvist PA. Effects of clonidine on postoperative nausea and vomiting in breast cancer surgery. Anesthesiology. 2002;96:1109–1114.
   PubMed Web of Science ®Google Scholar
• Mikawa K, Nishina K, Maekawa N, Asano M, Obara H. Oral clonidine premedication reducesvomiting in children after strabismus surgery. Can J Anaesth. 1995;4:977–981.
   Google Scholar
• Maina A, Arrotta M, Cicogna L, et al. Transderma clonidine in the treatment of severe hyperemesis. A pilot randomised control trial: CLONEMESI. BJOG. 2014;121(12):1556–1562.
   Web of Science ®Google Scholar
• Rosa-e-Silva L, Troncon LE, Oliveira RB, Iazigi N, Gallo L Jr, Foss MC. Treatment of diabetic gastroparesis with oral clonidine. Aliment Pharmacol Ther. 1995;9:179–183.
   PubMed Web of Science ®Google Scholar
• Gullikson GW, Virina MA, Loeffler R, Erwin WD. Alpha-2 – adrenergic model of gastroparesis: validation with renzapride, a simulator of motility. Am J Physiol. 1991;261:G426–G432.
   PubMed Web of Science ®Google Scholar
• Tack J, Wood J. Actions of noradrenaline on myenteric neurons on the guinea pig gastric antrum. J Auton Nerv Syst. 1992;41:67–78.
   Google Scholar
• Chang E, Field M, Miller R. Alpha-2 adrenergic receptors regulation of ion transport in rabbit ileum. Am J Physiol. 1982;242:G237–G242.
   Google Scholar
• Chang E, Field M, Miller R. Enterocyte alpha-2 adrenergic receptors: yohimbine and p-aminoclonidine binding relative to ion transport. Am J Physiol. 1983;244:G75–G82.
   Google Scholar
• Doherty N, Hancock A. Role of alpha-2 adrenergic receptors in the control of diarrhea and intestinal motility. J Pharmacol Exp Ther. 1983;225:269–274.
   Web of Science ®Google Scholar
• Schiller LR, Santa Ana CA, Morawski SG, Fordtran JS. Studies of the antidiarrheal action of clonidine. Gastroenterology. 1985;89:982–988.
   Web of Science ®Google Scholar
• Viramontes BE, Malcolm A, Camilleri M, et al. Effects of an a2 – adrenergic agonist on gastrointestinal transit, colonic motility, and sensation in humans. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1468–G1476.
   PubMed Web of Science ®Google Scholar
• Bharucha AE, Camilleri M, Zinsmeister AR, Hanson RB. Adrenergic modulation of human colonic motor and sensory function. Am J Physiol. 1997;273:G997–G1006.
   PubMed Web of Science ®Google Scholar
• Brarucha A, Seide B, Zinmeister A. Effect of clonidine on symptoms and anorectal sensorimotor function in women with fecal incontinence. Ailment Pharmacol Ther. 2010;32(5):681–688.
   Web of Science ®Google Scholar
• Durbin T, Rosenthal L, McArthur K, Anderson D, Dharmsathaphorn K. Clonidine and lidamidine stimulate sodium and chloride absorption in the rabbit intestine. Gastroenterology. 1982;82:1352–1358.
   Web of Science ®Google Scholar
• Sundaram U. Mechanism of intestinal absorption: effect of cloninide on rabbit ileal villus and crypt cells. J Clin Invest. 1995;95:2187–2194.
   Web of Science ®Google Scholar
• Camilleri M, Kim DY, McKinzie S, et al. A randomized, controlled exploratory study of clonidine in diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2003;1:111–121.
   PubMed Web of Science ®Google Scholar
• McDoniel K, Taylor B, Huey W, et al. Use of clonidine to decrease intestinal fluid losses in patients with high-output short – bowel syndrome. JPEN J Parenter Enteral Nutr. 2004;28:265–268.
   Web of Science ®Google Scholar
• Buchman AL, Fryer J, Wallin A, Ahn CW, Polensky S, Zaremba K. Clonidine reduces diarrhea and sodium loss in patients with proximal jejunostomy: a controlled study. JPEN J Parenter Enteral Nutr. 2006;30:487–491.
   PubMed Web of Science ®Google Scholar
• Fedorak R, Field M, Chang E. Treatment of diabetic diarrhea with clonidine. Ann Intern Med. 1985;102:197–199.
   PubMed Web of Science ®Google Scholar
• Furlan R, Ardizzone S, Palazzolo L, et al. Sympathetic overactivity in active ulcerative colitis: effects of clonidine. Am J Physiol Regul Integr Comp Physiol. 2006;290(1):R224–R232.
   Web of Science ®Google Scholar
• Rabbani G, Butler T, Patte D, et al. Clinical trial of clonidine hydrochloride as an antisecretory agent in cholera. Gastroenterology. 1989;97(2):321–325.
   Web of Science ®Google Scholar
• Riedl MS, Schnell SA, Overland AC, et al. Coexpression of alpha-2 adrenergic and delta-opioid receptors in substance P-containing terminals in rat dorsal horn. J Comp Neurol. 2009;513:385–398.
   Web of Science ®Google Scholar
• Campbell J, Meyer R. Mechanisms of neuropathic pain. Neuron. 2006;52:77–92.
   PubMed Web of Science ®Google Scholar
• Campbell CM, Kipnes MS, Stouch BC, et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain. 2012;153(9):1815–1823.
   PubMed Web of Science ®Google Scholar
• Byas-Smith M, Max M, Muir J. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage “enriched enrollment” design. Pain. 1995;60:267–274.
   PubMed Web of Science ®Google Scholar
• Zemlan F, Corrigan S, Pfaff D. Noradrenergic and serotonergic mediation of spinal analgesia mechanisms. Eur J Pharmacol. 1980;61:111–124.
   Web of Science ®Google Scholar
• Kuraishi Y, Harada Y, Takagi H. Noradrenaline regulation of pain transmission in the spinal cord mediated by a-adrenoreceptors. Brain Res. 1979;174:333–336.
   PubMed Web of Science ®Google Scholar
• Kuraishi Y, Hirota N, Sato Y, et al. Transmission of pain information and neuropeptides – with special reference to substance P in the primary afferents. Jpn J Pharmacol. 1984;34(Suppl):38.
   Google Scholar
• Kuraishi Y, Hirota N, Sato Y, Kaneko S, Satoh M, Takagi H. Noradrenergic inhibition of the release of substance P from the primary afferents in the rabbit spinal dorsal horn. Brain Res. 1985;359:177–182.
   PubMed Web of Science ®Google Scholar
• Fleetwood-Walker SM, Mitchell R, Hope PJ, Molony V, Iggo A. An a-2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones. Brain Res. 1985;334:243–254.
   Web of Science ®Google Scholar
• Kuraishi Y, Fukui K, Shiomi H, Akaike A, Takagi H. Microinjection of opioids into the nucleus reticularis gigantocellularisof the rat: analgesia and increase in the normetanephrine level in the spinal cord. Biochem Pharmacol. 1978;27:2756–2758.
   Google Scholar
• Yaksh T. Direct evidence that spinal serotonin and adrenaline terminals mediate the spinal antinociceptive effects of morphine in the periaqueductal gray. Brain Res. 1979;160:180–185.
   PubMed Web of Science ®Google Scholar
• Yaksh T, Hammond D, Tyce G. Functional aspects of bulbospinal monoaminergic projections in modulating processing of somatosensory information Fe ? Fed Proc. 1981;40:2786–2794.
   Google Scholar
• Morton C, Johnson S, Duggan A. Lateral reticular regions and the descending control of dorsal horn neurons of the cat: selective inhibition by electrical stimulation. Brain Res. 1983;275:13–21.
   Web of Science ®Google Scholar
• Kuraishi Y, Harada Y, Aratani S, Satoh M, Takagi H. Separate involvement of the spinal noradrenergic and serotonergic systems in morphine analgesia: the differences in mechanical and thermal analgesic tests. Brain Res. 1983;273:245–252.
   PubMed Web of Science ®Google Scholar
• Kuraishi Y, Hirota N, Sugimoto M, Satoh M, Takagi H. Effects of morphine on noxious stimuli –induced release of substance P from rabbit dorsal horn in vivo. Life Sci. 1983;33(Suppl 1):693–696.
   Google Scholar
• Shiomi H, Takagi H. Morphine analgesia and the bulbospinal noradrenergic system: increase in the concentration of normetanephrine in the spinal cord of the rat caused by analgesics. Br J Pharmacol. 1974;52:519–526.
   Web of Science ®Google Scholar
• Takagi H, Shiomi H, Kuraishi Y, Fukui K, Ueda H. Pain and the bulbospinal noradrenergic system: pain induced increase in normetanephrine content in the spinal cord and its modification by morphine. Eur J Pharmacol. 1979;54:99–107.
   Web of Science ®Google Scholar
• Osipov M, Suarez L, Spaulding T. Antinociceptive interactions between alpha-2 adrenergic and opiate agonists at the spinal level in rodents. Anesth Analg. 1989;68:194–200.
   Web of Science ®Google Scholar
• Eisenach J, Lysack S, Viscomi C. Epidural clonidine analgesia following surgery: phase 1. Anesthesiology. 1989;71:640–646.
   Web of Science ®Google Scholar
• Eisenach J, Rauck L, Buzzanell C, et al. Epidural clonidine analgesia for intractable cancer pain: phase 1. Anesthesiology. 1989;71:647–652.
   PubMed Web of Science ®Google Scholar
• Wallet F, Clement H, Bouret C. Effects of a continuous low-dose clonidine epidural regimen on pain, satisfaction and adverse events during labour: a randomized, double – blind, placebo-controlled trial. Eur J Anaesthsiol. 2010;27:441–447.
   Web of Science ®Google Scholar
• Segal IS, Jarvis DJ, Duncan SR, White PF, Maze M. Clinical efficacy of oral-transdermal clonidine conbinations during the perioperative period. Anesthesiology. 1991;74:220–225.
   PubMed Web of Science ®Google Scholar
• Owen MD, Fibuch EE, McQuillan R, Millington WR. Postoperative analgesia using a low-dose, oral-transdermal clonidine combination: lack of clinical efficacy. J Clin Anesth. 1997;9:8–14.
   Web of Science ®Google Scholar
• D’Andrea G, Perini F, Granella F, Cananzi A, Sergi A. Efficacy of transdermal clonidnie in short-term treatment of cluster headache: a pilot study. Cephalalgia. 1995;15:430–433.
   PubMed Web of Science ®Google Scholar
• Leone M, Attanasio A, Grazzi L, et al. Transdermal clonidine in the prophylaxis of episodic cluster headache: an open study. Headache. 1997;37:559–560.
   PubMed Web of Science ®Google Scholar
• Aoki C, Go CG, Venkatesan C, Kurose H. Perikaryal and synaptic localization of a -2a-adrenergic receptor- like immunoreactivity. Brain Res. 1994;650:181–204.
   PubMed Web of Science ®Google Scholar
• Arnsten A, Steere J, Hunt R. The contribution on a-2 noradrenergic mechanisms to prefrontal cognitive function. Arch Gen Psychiatry. 1996;53(5):448–455.
   PubMed Web of Science ®Google Scholar
• Coull JT, Büchel C, Friston KJ, Frith CD. Noradrenergically mediated plasticity in a human attentional neuronal network. Neuroimage. 1999;10:710–715.
   Web of Science ®Google Scholar
• Coull JT, Middleton HC, Robbins TW, Sahakian BJ. Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search. Psychopharmacology. 1995;121:222–230.
   Web of Science ®Google Scholar
• Jackson W, Buccafusco J. Clonidine enhances delayed matching – to – sample performance by young and aged monkeys. Pharmacol Biochem Behav. 1991;39:79–84.
   Web of Science ®Google Scholar
• Franowicz J, Phil M, Arnsten A. Treatment with the noradrenergic alpha-2 agonist clonidine, but not doazepam, improves spatial working memory in normal young rhesus monkeys. Neuropsychopharmacology. 1999;21:611–621.
   Web of Science ®Google Scholar
• Brozoski TJ, Brown RM, Rosvold HE, Goldman PS. Cognitive deficit caused by regional depletion of dopamine in the prefrontal cortex of the rhesus monkey. Science. 1979;205:929–932.
   PubMed Web of Science ®Google Scholar
• Arnsten A, Goldman – Rakic P. Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science. 1985;230:1273–1276.
   PubMed Web of Science ®Google Scholar
• Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW. Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia. 1990;28(10):1021–1034.
   PubMed Web of Science ®Google Scholar
• Coull JT. Neural Correlates of Attention and Arousal. Insights from Electrophysiology, Functional Neuroimaging and Psychopharmacology. Prog in Neurobiology. 1998;55:343–351.
   PubMed Web of Science ®Google Scholar
• Arnsten A, Li B. Neurobiology of executive functions: cathecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377–1384.
   PubMed Web of Science ®Google Scholar
• Beversdorf DQ, Hughes JD, Steinberg BA, Lewis LD, Heilman KM. Noradrenergic modulation of cognitive flexibility in problem solving. Neuroreport. 1999;10:2763–2767.
   PubMed Web of Science ®Google Scholar
• Silver JA, Hughes JD, Bornstein RA, Beversdorf DQ. Effect of anxiolytics on cognitive flexibility in problem solving. Cogn Behav Neurol. 2004;17:93–97.
   PubMedGoogle Scholar
• Arnsten A, Goldman–Rakic P. Analysis of alpha-2 adrenergic agonist effects on the delayed nonmatch-to-sample performance of aged rhesus monkeys. Neurobiol Aging. 1990;11:583–590.
   Web of Science ®Google Scholar
• Arnsten A, Contant T. Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performimg the delayed response task. Psychopharmacology. 1992;108:159–169.
   PubMed Web of Science ®Google Scholar
• Cai J-X, Ma Y, Hu X. Reserpine impairs spatial working memory performance in monkeys: reversal by the a-2 adrenergic agonist clonidine. Brain Res. 1993;614:191–196.
   PubMed Web of Science ®Google Scholar
• Coull JT, Middleton HC, Robbins TW, Sahakian BJ. Contrasing effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology. 1995;120(3):311–321.
   Web of Science ®Google Scholar
• Mair R, McEntee W. Cognitive enhancement in Korsakoff’s psychosis by clonidine: a comparison with L-Dopa and Ephedrine. Psychopharmacology. 1986;88:374–380.
   PubMed Web of Science ®Google Scholar
• Riekkinen P, Riekkinen M. THA improves word planning and clonidine enhances fluency and working memory in Alzheimer’s disease. Neuropsychopharmacology. 1999;20:357–364.
   Web of Science ®Google Scholar
• Mohr E, Schlegel J, Fabbrini G, et al. Clonidine treatment of Alzheimer’s disease. Arch Neurol. 1989;46:376–378.
   PubMedGoogle Scholar
• Groch S, Wilhelm I, Diekelmann S, Sayk F, Gais S, Born J. Contribution of norepinephrine to emotional memory consolidation during sleep. Psychoneuroendocrinology. 2011;36:1342–1350.
   Web of Science ®Google Scholar
• Bondareff W, Mountjoy C, Roth M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia. Neurology. 1982;32:164–168.
   PubMed Web of Science ®Google Scholar
• Perry E, Tomlinson B, Blessed G, Perry RH, Cross AJ, Crow TJ. Neuropathological and biochemical observations on the noradrenergic system in Alzheimer’s disease. J Neurol Sci. 1981;51:279–287.
   PubMed Web of Science ®Google Scholar
• Rossor M, Iversen L. Non-cholinergic neurotransmitter abnormalities in Alzheimer’s disease. Br Med Bull. 1986;42:70–74.
   PubMed Web of Science ®Google Scholar
• Robertson D, Goldberg MR, Hollister AS, Wade D, Robertson RM. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. Am J Med. 1983;74:193–200.
   PubMed Web of Science ®Google Scholar
• Eason M, Liggett S. Subtype selective desensitization of alpha-2 adrenergic receptors. Different mechanisms control short and long term agonist-promoted desensitization of Alpha 2C10, Alpha 2C4, and alpha 2C2. J Biol Chem. 1992;267:225479–254873.
   Web of Science ®Google Scholar
• Daunt DA, Hurt C, Hein L, Kallio J, Feng F, Kobilka BK. Subtype specific intracellular trafficking of alpha -2 adrenergic receptors. Mol Pharmacol. 1997;51:711–720.
   Web of Science ®Google Scholar
• Zubenko G, Cohen B, Lipinski J, Jonas JM. Clonidine in the treatment of mania and mixed bipolar disorder. Am J Psychiatry. 1984;141:617–618.
   Web of Science ®Google Scholar
• Liebowitz M, Fyer A, McGarth P, et al. Clonidine treatment of panic disorder. Psychopharmacol Bull. 1981;17:122–123.
   PubMedGoogle Scholar
• Nishikawa T, Tanaka M, Koga I, Uchida Y. Combined treatment of tardive dyskinesia with clonidine and neuroleptics: a follow up study of three cases for three years. Psychopharmacology. 1983;80:374–375.
   Web of Science ®Google Scholar
• Nishikawa T, Tanaka M, Tsuda A, Koga I, Uchida Y. Clonnidine therapy for tardive dyskinesia and related syndromes. Clin Neuropharmacol. 1984;7:239–245.
   PubMed Web of Science ®Google Scholar
• Zubenko GS, Cohen BM, Lipinski JF Jr, Jonas JM. Use of clonidine in the treatment of akathisia. Psychiatry Res. 1984;13:253–259.
   PubMed Web of Science ®Google Scholar
• Adler LA, Angrist B, Peselow E, Reitano J, Rotrosen J. Clonidine in neuroleptic – induced akathisia. Am J Psychiatry. 1987;144:235–236.
   Web of Science ®Google Scholar
• Svensson T, Bunney B, Aghajanian G. Inhibition of both noradrenergic and serotonergic neurons in brain by the a-adrenergic agonist clonidine. Brain Res. 1975;92(2):291–306.
   Web of Science ®Google Scholar
• Goldenberg G, Bharathan T, Shifrin I. Transdermal clonidine in patients with swallowing dysfunction. J Palliat Med. 2014;17(9):1042–1044.
   Web of Science ®Google Scholar
• Panossian A, Wikman G, Wagner H. Plant adaptogens. III. Earlier and more recent concepts of their mode of action. Phytomedicine. 1999;6(4):287–300.
   PubMed Web of Science ®Google Scholar
• Selye H. Stress. Montreal: Acta Medical Publisher; 1950.
   Google Scholar
• Samuelson G, Bohlin L. Drugs of Natural Origin. A Ttreatise of Pharmacology. 6th ed. Stokholm: Swedish Academy of Pharmaceutical Sciences; 2009.
   Google Scholar
• Panossian A, Hamm R, Kadioglu O, Wikman G, Efferth T. Synergy and antagonism of active constituens of ADAPT -232 on transcriptional level of metabolic regulation of isolated neuroglial cells. Front Nerosci. 2013;7:Article16.
   Google Scholar
• Von Zastrow M. Regulation of G protein coupled receptors by phopshorilation and endocytosis. In: Davis K, Charney D, Coyle J, Nmeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress. (Chap 5). Philadelphia: Lipppincott Williams & Wilkins; 2002:59–70.
   Google Scholar