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Anticholinergics Classification Essay

An anticholinergic agent is a substance that blocks the neurotransmitteracetylcholine in the central and the peripheral nervous system. These agents inhibit parasympatheticnerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, and many other parts of the body. Anticholinergics are divided into three categories in accordance with their specific targets in the central and peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.[1]

Medical uses[edit]

Anticholinergic drugs are used to treat a variety of conditions:

  • Dizziness (including vertigo and motion sickness-related symptoms)
  • Extrapyramidal symptoms, a potential side-effect of antipsychotic medications.
  • Gastrointestinal disorders (e.g., peptic ulcers, diarrhea, pylorospasm, diverticulitis, ulcerative colitis, nausea, and vomiting)
  • Genitourinary disorders (e.g., cystitis, urethritis, and prostatitis)
  • Insomnia, although usually only on a short-term basis
  • Respiratory disorders (e.g., asthma, chronic bronchitis, and chronic obstructive pulmonary disease [COPD])
  • Sinus bradycardia due to a hypersensitive vagus nerve

Anticholinergics generally have antisialagogue effects (decreasing saliva production), and most produce some level of sedation, both being advantageous in surgical procedures.[2][3]

Recreational uses[edit]

When a significant amount of an anticholinergic is taken into the body, a toxic reaction known as acute anticholinergic syndrome may result. This may happen accidentally or intentionally as a consequence of recreational drug use. Anticholinergic drugs are usually considered the least enjoyable by many recreational drug users,[4] possibly because the side effects are so unpleasant and that they do not induce euphoria. There have, however, been a few reported cases of users experiencing what they described as "euphoria" from the use of an anticholinergic drug.[citation needed] In terms of recreational use, these drugs are commonly referred to as deliriants.[5] The risk of addiction is low in the anticholinergic class, and recreational use is uncommon.

[edit]

Long-term use may increase the risk of both mental and physical decline.[6][7][8][9][10][11] It is unclear if they affect the risk of death generally.[6] However, in older adults they do appear to increase the risk of death.[12] Possible effects of anticholinergics include:

Possible effects in the central nervous system resemble those associated with delirium, and may include:

  • Confusion
  • Disorientation
  • Agitation
  • Euphoria or dysphoria
  • Respiratory depression
  • Memory problems[14]
  • Inability to concentrate
  • Wandering thoughts; inability to sustain a train of thought
  • Incoherent speech
  • Irritability
  • Mental confusion (brain fog)
  • Wakeful myoclonic jerking
  • Unusual sensitivity to sudden sounds
  • Illogical thinking
  • Photophobia
  • Visual disturbances
    • Periodic flashes of light
    • Periodic changes in visual field
    • Visual snow
    • Restricted or "tunnel vision"
  • Visual, auditory, or other sensory hallucinations
    • Warping or waving of surfaces and edges
    • Textured surfaces
    • "Dancing" lines; "spiders", insects; form constants
    • Lifelike objects indistinguishable from reality
    • Phantom smoking
    • Hallucinated presence of people not actually there
  • Rarely: seizures, coma, and death
  • Orthostatic hypotension (severe drop in systolic blood pressure when standing up suddenly) and significantly increased risk of falls in the elderly population.[15]

Older patients are at a higher risk of experiencing CNS sideffects due to lower acetylcholine production.

A common mnemonic for the main features of anticholinergic syndrome is the following:[16]

  • Blind as a bat (dilated pupils)
  • Red as a beet (vasodilation/flushing)
  • Hot as a hare (hyperthermia)
  • Dry as a bone (dry skin)
  • Mad as a hatter (hallucinations/agitation)
  • Bloated as a toad (ileus, urinary retention)
  • And the heart runs alone (tachycardia)

Toxicity[edit]

Acute anticholinergic syndrome is reversible and subsides once all of the causative agent has been excreted. Reversible Acetylcholinesterase inhibitor agents such as physostigmine can be used as an antidote in life-threatening cases. Wider use is discouraged due to the significant side effects related to cholinergic excess including: seizures, muscle weakness, bradycardia, bronchoconstriction, lacrimation, salivation, bronchorrhea, vomiting, and diarrhea. Even in documented cases of anticholinergic toxicity, seizures have been reported after the rapid administration of physostigmine. Asystole has occurred after physostigmine administration for tricyclic antidepressant overdose, so a conduction delay (QRS > 0.10 second) or suggestion of tricyclic antidepressant ingestion is generally considered a contraindication to physostigmine administration.[17]

Piracetam (and other racetams), α-GPC and choline are known to activate the cholinergic system and alleviate cognitive symptoms caused by extended use of anticholinergic drugs.[citation needed]

Pharmacology[edit]

Anticholinergics are classified according to the receptors that are affected:

Examples[edit]

Examples of common anticholinergics:

  • Antimuscarinic agents
  • Antinicotinic agents

Plants of the Solanaceae family contain various anticholinergic tropane alkaloids, such as scopolamine, atropine, and hyoscyamine.

Physostigmine is one of only a few drugs that can be used as an antidote for anticholinergic poisoning. Nicotine also counteracts anticholinergics by activating nicotinic acetylcholine receptors. Caffeine (although an adenosinereceptor antagonist) is able to counteract the anticholinergic symptoms by reducing sedation and increasing acetylcholine activity, thereby causing alertness and arousal.

Plant sources[edit]

The most common plants containing anticholinergic alkaloids (including atropine, scopolamine, and hyoscyamine among others) are:

Use as a deterrent[edit]

Several narcotic and opiate-containing drug preparations, such as those containing hydrocodone and codeine are combined with an anticholinergic agent to deter intentional misuse.[25] Examples include Hydromet/Hycodan (hydrocodone/homatropine), Lomotil (diphenoxylate/atropine) and Tussionex (hydrocodone polistirex/chlorpheniramine). However, it is noted that opioid/antihistamine combinations are used clinically for their synergistic effect in the management of pain and maintenance of dissociative anesthesia (sedation) in such preparations as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which act as strong anticholinergic agents.[26]

References[edit]

  1. ^Sharee A. Wiggins; Tomas Griebling. "Urinary Incontinence". Landon Center on Aging. Archived from the original on 2011-09-27. 
  2. ^Page 592 in: Cahalan, Michael D.; Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K. (2009). Clinical Anesthesia. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-8763-7. 
  3. ^Clinical Anesthesia. Books.google.se. Archived from the original on 20 February 2017. Retrieved 8 December 2014. 
  4. ^ abBersani, F. S.; Corazza, O.; Simonato, P.; Mylokosta, A.; Levari, E.; Lovaste, R.; Schifano, F. (2013). "Drops of madness? Recreational misuse of tropicamide collyrium; early warning alerts from Russia and Italy". General Hospital Psychiatry. 35 (5): 571–3. doi:10.1016/j.genhosppsych.2013.04.013. PMID 23706777. 
  5. ^"Erowid Dimenhydrinate (Dramamine) Vault : Dramamine (and other related Pharmaceuticals) FAQ 2.3". 2015-06-02. Archived from the original on June 2, 2015. Retrieved 2015-06-08. 
  6. ^ abFox, C; Smith, T; Maidment, I; Chan, WY; Bua, N; Myint, PK; Boustani, M; Kwok, CS; Glover, M; Koopmans, I; Campbell, N (September 2014). "Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review". Age and ageing. 43 (5): 604–15. doi:10.1093/ageing/afu096. PMID 25038833. 
  7. ^"Here's More Evidence That Common Drugs May Cause Cognition Issues". Science Daily. 2016-04-19. Archived from the original on 2016-06-11. Retrieved 2016-05-09. 
  8. ^"Popular drugs for colds, allergies, sleep linked to dementia". CBS News. 2016-04-21. Archived from the original on 2016-05-07. Retrieved 2016-05-09. 
  9. ^"Common over-the-counter drugs can hurt your brain". CNN. 2016-04-18. Archived from the original on 2016-05-06. Retrieved 2016-05-09. 
  10. ^"The Cold Medicine That's Linked to Cognitive Problems". Time.com. 2016-04-18. Archived from the original on 2016-05-10. Retrieved 2016-05-09. 
  11. ^"Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults". JAMA. 73: 721. April 18, 2016. doi:10.1001/jamaneurol.2016.0580. 
  12. ^Ruxton, K; Woodman, RJ; Mangoni, AA (2 March 2015). "Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta-analysis". British Journal of Clinical Pharmacology. 80: 209–20. doi:10.1111/bcp.12617. PMC 4541969. PMID 25735839. 
  13. ^"Study suggests link between long-term use of anticholinergics and dementia risk". Alzheimer's Society. 2015-01-26. Archived from the original on 2015-11-12. Retrieved 2015-02-17. 
  14. ^Talan, Jamie (July–August 2008). "Common Drugs May Cause Cognitive Problems". Neurology Now. 4 (4): 10–11. doi:10.1097/01.NNN.0000333835.93556.d1. Retrieved 2008-08-17. 
  15. ^"Lifeline Learning Center". Lifeline.theonlinelearningcenter.com. Retrieved 8 December 2014. 
  16. ^"Anticholinergic Toxidrome". Life in the Fast Lane. Archived from the original on 2015-05-10. Retrieved 2015-06-08. 
  17. ^Rosen, Peter, John A. Marx, Robert S. Hockberger, and Ron M. Walls. Rosen's Emergency Medicine: Concepts and Clinical Practice. 8th ed. Philadelphia, PA: Mosby Elsevier, 2014.
  18. ^Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Adv. Pharmacol. 69: 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. PMID 24484978. 
  19. ^Dwoskin, Linda P. (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 177–216. ISBN 978-0-12-420177-4. Archived from the original on 20 March 2017. 
  20. ^Tasman, Allan, Kay, Jerald, Lieberman, Jeffrey A., First, Michael B., Maj, Mario (11 October 2011). Psychiatry. John Wiley & Sons. ISBN 978-1-119-96540-4. Archived from the original on 20 March 2017. 
  21. ^Damaj, M. I.; Flood, P; Ho, K. K.; May, E. L.; Martin, B. R. (2004). "Effect of Dextrometorphan and Dextrorphan on Nicotine and Neuronal Nicotinic Receptors: In Vitro and in Vivo Selectivity". Journal of Pharmacology and Experimental Therapeutics. 312 (2): 780–5. doi:10.1124/jpet.104.075093. PMID 15356218. 
  22. ^Lee, Jun-Ho; Shin, Eun-Joo; Jeong, Sang Min; Kim, Jong-Hoon; Lee, Byung-Hwan; Yoon, In-Soo; Lee, Joon-Hee; Choi, Sun-Hye; Lee, Sang-Mok; Lee, Phil Ho; Kim, Hyoung-Chun; Nah, Seung-Yeol (2006). "Effects of dextrorotatory morphinans on α3β4 nicotinic acetylcholine receptors expressed in Xenopus oocytes". European Journal of Pharmacology. 536 (1–2): 85–92. doi:10.1016/j.ejphar.2006.02.034. PMID 16563374. 
  23. ^Hernandez, S. C.; Bertolino, M; Xiao, Y; Pringle, K. E.; Caruso, F. S.; Kellar, K. J. (2000). "Dextromethorphan and Its Metabolite Dextrorphan Block α3β4 Neuronal Nicotinic Receptors". The Journal of Pharmacology and Experimental Therapeutics. 293 (3): 962–7. PMID 10869398. 
  24. ^Shytle, RD; Penny, E; Silver, AA; Goldman, J; Sanberg, PR (Jul 2002). "Mecamylamine (Inversine): an old antihypertensive with new research directions". Journal of Human Hypertension. 16 (7): 453–7. doi:10.1038/sj.jhh.1001416. PMID 12080428. 
  25. ^"NIH DailyMed - Hydromet Syrup". Dailymed.nlm.nih.gov. Archived from the original on 2011-05-23. Retrieved 2008-08-17. 
  26. ^"Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers". Psychopharmacology. 165: 146–156. doi:10.1007/s00213-002-1245-5. Retrieved 2008-08-17. 

Did you know that common over-the-counter drugs or prescriptions can cause memory loss and cognitive impairment?

Mild cognitive impairment is a common, age-linked condition that is often an early sign of Alzheimer's disease. Its cardinal symptom is forgetfulness or impairment of short-term memory.

Numerous drugs have been shown to produce mild cognitive impairment (MCI). They may create or aggravate Alzheimer's-type symptoms.

(NOTE: You should NOT stop taking medications without first consulting your physician.)

Most of the drugs that cause MCI have a property called "anti-cholinergic." They inhibit activity of the neurotransmitter acetylcholine, which plays a critical role in memory and cognitive function.

Here's the problem: only a few of these drugs are officially classified as anti-cholinergic. The official anti-cholinergic drugs are mostly used for relieving intestinal cramps or bladder irritability and are labeled "anti-spasmodic." They're at the top of the list below.

But there are 17 additional types of drugs used for many other purposes that may also have anti-cholinergic effects. The list includes commonly used drugs like antihistamines, acid blockers and antidepressants. Unfortunately, many doctors and pharmacists are unaware of the anti-cholinergic properties of these medications.

In an address to the American Academy of Neurology at the 60th Annual Meeting, Dr. Jack Tsao, associate professor of neurology at Uniformed Services University in Bethesda, Maryland, said, "... a lot of medicines that are not advertised as anti-cholinergic in nature actually have anti-cholinergic properties." Dr. Tsao and his colleagues followed a group of nuns and clergy from the Rush Religious Orders for about eight years and found an accelerated rate of cognitive decline in those who began using anti-cholinergic drugs.

Several published studies have also shown that people taking drugs with hidden anti-cholinergic effects are at increased risk for MCI.

It is likely that these drugs have additive effects: the more anti-cholinergic drugs a person takes at one time, the greater the risk of side effects.

Because the list is long and includes drugs used for many different purposes, it is possible for an individual's total burden of anti-cholinergic drug activity to be much higher than expected.

In addition, advanced age is associated with increased susceptibility to anti-cholinergic drugs because of a reduction in acetylcholine activity with age.

If you're concerned about MCI in yourself or someone you know, check the list of drugs below to see if medication might be contributing to the problem.

Drugs with Anti-cholinergic Properties

Some of these are available without prescription and may be found alone or combined with other drugs, especially in over-the-counter cold and headache remedies. Don't just rely on the product's name. Check all ingredients. Bring this information to your doctor. Do not discontinue the use of any prescription drug without your doctor's approval.

Antispasmotics: used to relieve intestinal cramps or bladder symptoms, these are also found in numerous over-the-counter and prescription combination products used for colds and coughs, with various brand names:

o Atropine
o Belladonna (Donnatal and others)
o Clidinium (Quarzan)
o Dicyclomine (Bentyl and others)
o Flavoxate (Urispas)
o Glycopyrrolate (Robinul)
o Hyoscyamine (Levsin, NuLev, Cystospas and many others)
o Oxybutynin (Ditropan and others)
o Solifenacin (VesiCARE)
o Propantheline (ProBanthine and others)
o Scopolamine (Transderm-Scop and others)
o Tolterodine (Detrol)
o Trospium (Regurin and others)

Antihistamines: these are used in numerous over-the-counter and prescription products alone or in combination with other drugs for relieving symptoms of allergies, colds, dizziness or improving sleep:

o Azatadine (Optimine and others)
o Chlorpheniramine (Chlortimeton and others)
o Clemastine (Contac, Tavist and others)
o Cyproheptadine (Periactin)
o Desloratadine (Clarinex and others)
o Dimenhydrinate (Dramamine and others)
o Diphenhydramine (Benadryl and many others)
o Doxylamine (Unisom and others)
o Hydroxyzine (Atarax, Vistaryl)
o Loratadine (Claritin and others)
o Meclizine (Antivert and others)
o Pyrilamine

Note: Fexofenadine (Allegra) and cetirizine (Zyrtec) are antihistamines without anti-cholinergic effects, but may cause sedation.

Antacids: these are histamine H2 antagonists, used to relieve heartburn and stomach pain. For more on acid suppressing drugs, see my article "Stomach Acid and the Future of Health Care":

o Cimetidine (Tagamet)
o Famotidine (Pepcid)
o Nizatadine (Axid)
o Ranitidine (Zantac)

Note: Although these drugs have relatively weak anti-cholinergic activity, their use is associated with MCI in older adults.

Antidepressants:

o Amitriptyline (Elavil and others)
o Amoxapine (Asendin)
o Citalopram (Celexa)
o Clomipramine (Anafranil)
o Desipramine (Norpramin)
o Doxepin (Sinequan and others)
o Duloxetine (Cymbalta)
o Escitalopram (Lexapro)
o Fluoxetine (Prozac)
o Imipramine (Tofranil)
o Lithium
o Nortriptyline (Pamelor, Aventyl)
o Paroxetine (Paxil and others)
o Protriptyline (Vivactil)

Muscle relaxants:

o Carisoprodal (Soma and others)
o Chlorzoxazone (Parafon Forte and others)
o Cyclobenzaprine (Flexeryl and others)
o Methocarbamol (Robaxin and others)
o Orphenadrine (Norflex and others)

Antiarrythmics: used to treat cardiac arrhythmias:

o Digoxin
o Disopyramide (Norpace and others)
o Procainamide
o Quinidine (Quinaglute and others)

Antiemetics: used to suppress nausea or vomiting:

o Promethazine (Phenergan and others)
o Prochlorperazine (Compazine and others)
o Trimethobenzamide (Tigan)

Antipsychotics: used for severe psychiatric disorders:

o Chlorpromazine (Thorazine and others)
o Clozapine (Clopine and others)
o Mesoridazine (Serentil)
o Olanzapine (Zyprexa)
o Promazine
o Quetiapine (Seroquel)
o Thioridazine (Mellaril)

Antiparkinsonian: used in the treatment of Parkinson's disease and related disorders:

o Amantadine (Symmetrel)
o Benztropine (Cogentin)
o Biperiden (Akineton)
o Procyclidine (Kemadrine)
o Trihexyphenidyl (Artane and others)

Miscellaneous:

These drugs were shown to have anti-cholinergic effects at high concentration. They may exert clinically significant anti-cholinergic side effects when used at high doses or in people with impaired kidney function or a heightened susceptibility to anti-cholinergic side effects:

o Amoxicillin (an antibiotic)
o Carbamazepine (Tegretol, a drug for controlling seizures or chronic pain)
o Celecoxib (Celebrex, an anti-inflammatory pain reliever)
o Cephalexin (Keflex, an antibiotic)
o Diazepam (Valium, a tranquilizer)
o Diphenoxylate (Lomotil, a drug for diarrhea)
o Fentanyl (Duragesic, a narcotic pain reliever)
o Furosemide (Lasix, a diuretic used for fluid retention)
o Hydrocodone (a narcotic pain reliever, found in Vicodin)
o Lansoprazole (Prevacid, a proton pump inhibitor, used to reduce stomach acid)
o Levofloxacin (Levaquin, an antibiotic)
o Metformin (Glucophage, a drug that reduces blood sugar, used by diabetics)
o Phenytoin (Dilantin, a drug for controlling seizures)
o Temazepam (Restoril, a sleeping pill)
o Topiramate (Topimax, a drug used for preventing migraine headaches)

A medication does not have to be swallowed or injected to exert systemic effects.

Anti-cholinergic eye drops may affect the brain. They are used to dilate the pupils. These include:

o Cyclopentolate
o Homatropine
o Tropicamide

Anti-cholinergic Herbs: Numerous herbs and natural products have anti-cholinergic effects and may be more hazardous than medications. Here are those that have been studied the most:

o Amanita muscaria (fly agaric)
o Amanita pantherina (panther mushroom)
o Arctium lappa (burdock root)
o Atropa belladonna (deadly nightshade)
o Cestrum nocturnum (night blooming jessamine)
o Datura metel (yangjinhua, used in traditional Chinese remedies)
o Datura suaveolens (angel's trumpet)
o Datura stramonium (jimson weed)
o Hyoscyamus niger (black henbane)
o Lantana camara (red sage)
o Phyllanthus emblica (Indian gooseberry)
o Solanum carolinensis (wild tomato)
o Solanum dulcamara (bittersweet)
o Solanum pseudocapsicum (Jerusalem cherry)

Learn more about herbs, traditional uses and side effects in my Herb Guide

In addition to memory loss and cognitive impairment, anti-cholinergic drugs may cause nervousness, confusion, disorientation, hallucinations, restlessness, irritability, dizziness, drowsiness, blurred vision and light sensitivity.

Know What You Are Taking

You should know everything that you or people in your family are taking: drugs and supplements and their potential side effects and interactions. If cognitive impairment is a problem and you're taking one or more of the substances listed above, what you're taking may be a cause or contributor.

And to get information on vitamins, nutrition and brain health read my articles:

"Leptin Fights Alzheimer's Disease"

"Metabolic Syndrome Linked to Memory Loss"

"To B or Not to B Vitamins?" which looks at the complex relationship between B Vitamins and the brain.

Now I'd like to hear from you. Have you experienced any symptoms of cognitive impairment? Are you taking medications or herbs? Did you have any side effects?

Please let me know your thoughts by posting a comment below.

Best Health,
Leo Galland, M.D.

Important: "Share the health" with your friends and family by forwarding this article to them, and sharing on Facebook.

Leo Galland, M.D. is a board-certified internist, author and internationally recognized leader in integrated medicine. Dr. Galland is the founder of Pill Advised, a web application for learning about medications, supplements and food. Sign up for FREE to discover how your medications and vitamins interact. Watch his videos on YouTube and join the Pill Advised Facebook page.

References:

J Am Geriatr Soc. 2008 Jul;56(7):1333-41. "Anticholinergic activity of 107 medications commonly used by older adults." Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, Kirshner MA, Sorisio DA, Bies RR, Gharabawi G.

Eur J Pharmacol. 2005 Jan 4;506(3):257-64. "Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models." Orzechowski RF, Currie DS, Valancius CA.

Pharmacoepidemiol Drug Saf. 2004 Nov;13(11):781-7. "Histamine2 receptor antagonist use and decline in cognitive function among community dwelling elderly." Hanlon JT, Landerman LR, Artz MB, Gray SL, Fillenbaum GG, Schmader KE.

Clin Interv Aging 2009.:225-33. Campbell N, Boustani M, Limbil T, Ott C, Fox C, Maidment I, Schubert CC, Munger S, Fick D, Miller D, Gulati R "The cognitive impact of anticholinergics: a clinical review."

Arch Intern Med. 2009;169(14):1317-1324. "Drugs With Anticholinergic Properties, Cognitive Decline, and Dementia in an Elderly General Population The 3-City Study." Isabelle Carrière, PhD; Annie Fourrier-Reglat, PhD; Jean-François Dartigues, MD; Olivier Rouaud, MD; Florence Pasquier, MD; Karen Ritchie, PhD; Marie-Laure Ancelin, PhD

Psychogeriatrics. 2010 Mar;10(1):34-8. "Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease." Konishi K, Hori K, Uchida H, Watanabe K, Tominaga I, Kimura M, Hosoyamada M, Shibasaki T, Kataoka A, Hachisu M.

This information is provided for general educational purposes only and is not intended to constitute (i) medical advice or counseling, (ii) the practice of medicine or the provision of health care diagnosis or treatment, (iii) or the creation of a physician-patient relationship. If you have or suspect that you have a medical problem, contact your doctor promptly.

Follow Leo Galland, M.D. on Twitter: www.twitter.com/leogallandmd

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