Memantine Amantadine

Moryl E, Danysz W, Quack G (1993) Potential antidepressive properties of amantadine, memantine and bifemelane. Pharmacol Toxicol 72 394-397 NaassUa M, Hammoumi S, Legrand E, et al (1998) Mechanism of action of acamprosate. Part 1. Characterization of spermidine-sensitive acamprosate binding site in rat brain. Alcoholism 22 802-809... 

SLC22A1 OCTl Organic cations (e.g., TEA, Amantadine, memantine, metformin, acyclovir. Liver Dresser et al., 2001 ... 

Moryl, E., Danysz, W.. and Quack, G. (199.3). Potential antidepres-sivc properties of amantadine, memantine and hil cmelanc. Pharmacol. Toxicol. 72, 394-397. 

Low affinity use-dependent NMDA recqrtor antagonists meet the criteria for safe administration into patients. Drugs like amantadine and memantine have modest effects on Parkinson s disease and are used as initial therapy or as adjunct to l-DOPA. Their adverse effects include dizziness, lethargy and sleep disturbance. 

In pharmacology, two adamantane derivatives. Amantadine (1-adamanta-neamine hydrochloride) and Rimantadine (a-methyl-1-adamantane methyla-mine hydrochloride) (see Fig. 24), have been well known because of their antiviral activity [129]. The main application of these drugs is prophylaxis (treatment to prevent the onset of a particular disease) and treatment of influenza-A viral infections. They are also used in the treatment of parkinsonism and inhibition of hepatitis-C virus. Memantine (1-amino-3,5-dimethyladaman-tane) (see Fig. 24) has been reported effective in slowing the progression of Alzheimer s disease [130]. 

The site of action for Memantine is the central nervous system (CNS) and it has CNS affinity. Amantadine and Rimantadine can penetrate to the CNS and cause some adverse effects. 

Figure 24. Chemical structures of (a) Amantadine, (b) Rimantadine, and (c) Memantine.

Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C et al. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol 1998 54(2) 342—352. 

NMDA antagonists The combined use of memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated. Approach such use with caution. 

Memantine (Namenda) [Anti Alzheimer Agent/NMDA Receptor Antagonist] Uses Mod/ evere Alzheimer Dz Action N-methyl-D-aspartate recqjtor antagonist Dose Target 20 mg/d, start 5 mg/d, t 5 mg/d to 20 mg/d, wait >1 wk before t dose use doses if >5mg/d Caution [B, /-] Hqjatic/mild-mod renal impair Disp Tabs, sol SE Dizziness Interactions t Effects W amantadine, carbonic anhydrase inhibitors, dextromethorphan, ketamine, Na bicarbonate t effects W/ any drug, herb, food that alkalinizes urine EMS Use NaHCOs w/ caution OD May cause restlessness, hallucinations, drowsiness, and fainting symptomatic and supportive... 

Amantadine has a long history in the symptomatic treatment of Parkinson s disease. Several recent double-blind, placebo-controlled studies have confirmed the impressive acute antidyskinetic effects of amantadine (Rajput et al. 1998 Verhagen Metman et al. 1998 Luginger et al. 2000 Del Dotto et al. 2001 Shoghi-Jadid et al. 2002). One study also indicates that amantadine s antidyskinetic benefit is maintained for at least 1 year (Metman et al. 1999). The related compound memantine was found, as in the MPTP monkey, to have no effect on dyskinesia in a double-blind study but it did improve parkinsonian symptoms (Merello et al. 1999). This indicates that the antidyskinetic effects of amantadine may be unrelated to NMDA receptor antagonism (Danysz et al. 1997). 

In humans, the antidepressant activity of NMDA receptor antagonists has not been evaluated extensively (Skohiick 1999). In animal models of depression, NMDA receptor antagonists have been reported to exert positive effects in most studies (Trullas 1997). This concerns mainly the forced swim test (Maj 1992 Moryl et al. 1993 PrzegaUnski et al. 1997) and stress-induced anhe-donia (Papp and Moryl 1994). Amantadine but not memantine was effective against reserpine-induced hypothermia (Moryl et al. 1993). In the forced swim test, both amino-adamantanes produced specific antidepressive-like activity (Moryl et al. 1993). 

Danysz W, Parsons CG, Mobius HJ, et al (2000) Neuroprotective and symptomatological action of memantine relevant for Alzheimer s disease—an unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2 85-97 Davis SM, Lees KR, Albers GW, et al (2000) Selfotel in acute ischemic stroke possible neurotoxic effects of an NMDA antagonist. Stroke 31 347-354 DeKeyser J (1991) Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol 14 562-565 Del Dotto P, Pavese N, Gambaccini G, et al (2001) Intravenous amantadine improves levodopa-induced dyskinesias an acute double-blind placebo-controlled study. Mov Disord 16 515-520... 

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

Fig. 10.3 Chemical structures of low affinity NMDA antagonists used for the treatment of AD, AD, AIDS dementia, and migrane. Memantine (a) Amantadine (b) (R,S)-N-2-(4-(3-thienyl)phenyl)-2-propanesulfonamide (LY392098) (c) and (R)-4 -[l-fluoro-l-methyl-2-(propane-2-sulphonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430) (d)...

Ketamine also shares a close chemical kinship to prescription drugs Tiletamine and Memantine. Tileta-mine is used in combination with zolazepam as a veterinary anesthetic under the brand names Zoletic and Tela-zol. Memantine is derived from the anti-influenza drug amantadine, and also works to block NDMA receptors. Memantine has been approved for use in Parkinson s disease and dementia in the elderly. It is also being used experimentally with AIDS patients for the treatment of HIV encephalopathy. 

MEMANTINE ANTIPARKINSON S DRUGS- AMANTADINE t CNS side-effects Additive effects on NMDA receptors Manufacturers recommend avoiding co-administration of amantadine and memantine... 

Danysz, W., Gossel, M., Zajaczkowski, W., Dill, D., Quack, G. (1994). Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats Case of amantadine and memantine. J. Neurol. Transm. Park. Dis. Dement. Sect. 1 155-66. 

Memantine is an amantadine derivative that has been studied in patients with Parkinson s disease. Its adverse effects include agitation, restlessness, insomnia, pronounced delirious states, and muscular hypotonia. All were reversible after dosage reduction or withdrawal. 

Oct2 (Slc22a2) Rat TEA, MPP, adrenaline, agmatine, creatinine, monoamine neurotransmitters Drugs amantadine, cimetidine, memantine Corticosterone, dexoycorticosterone, p-estradiol, NMN, progesterone, monoamine neurotransmitters Drugs cimetidine, dsplatin, procainamide, quinine... 

Blanpied, T, A., Bocckman, F. A.. Aizenman, E., and Johnson, J. W. (1997), Trappipg channel block of NMDA-activaied re.sponsc,s by amantadine and memantine. J. Neurophysial. 77,. 309-323. Bormann, J. (1989). Memantine is a potent blocker of N-mcthyl-D-aspartate (NMDA) receptor channels. Eur. J. Pharmacol 591-592. 

Sobtilevsky. A. I., Koshelev, S. C., and Khodorov, B. 1. (1998). Interaction of memantine and amantadine with agonist-unbound NMDA-receptor channels in acutely isolated rat hippocampal neurons. J. Physiol. 512(Pt, 1), 47-60. 

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