Rivastigmine (S-rivastigmine; 1 µM; 24 hours) coupled with carbachol (10 µM) reduced LPS (2.5 µg/ml)-induced TNF-α and IL-6 by 50% and 46%, respectively. % without making any substantial impact. Pro-inflammatory cytokines are lowered [3]. Rivastigmine (1 µM), carbachol (10 µM), or a combination of both medications show no cytotoxic effects on activated cells [3].

An intraperitoneal injection of rivastigmine (S-rivastigmine; 0.5-2.5 mg/kg; administered 60 minutes prior to testing) markedly and dose-dependently alleviated behavioral abnormalities caused by aluminum [4]. In BALB/c OlaHsd male 8–9 week old mice weighing 200–250 grams with acute colitis, rivastigmine (0.5, 1 mg/kg/day; SC; for 8 days) decreases IL-6 concentrations by roughly 50% and 60%, respectively, but not TNF-α and IL-1β concentrations [3]. At 1 mg/kg, rivastigmine totally stopped bleeding and inhibited colonic contractions, but not at 0.5 mg/kg. While rivastigmine (1 mg/kg) reduced submucosal edema and cellular infiltration, treatment with rivastigmine (0.5 mg/kg) showed minimal change in these pathological findings. Additionally, partial recovery of the crypt architecture was observed. At the conclusion of the trial, a 4.7% weight reduction was achieved with rivastigmine (1 mg/kg) [3].

Animal/Disease Models: Male Wistar albino rat, body weight 190–240 g (90 days old) [4]
Doses: 0.5, 1, 1.5 and 2.5 mg/kg
Route of Administration: intraperitoneal (ip) injection; single dose
Experimental Results: significant and dose Dependently improves aluminum-induced behavioral disturbances (100 mg/kg/day; i.p.; for 60 days)

Absorption, Distribution and Excretion
Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. Renal excretion of the metabolites is the major route of elimination. Less than 1% of the administered dose is excreted in the feces.
1.8 to 2.7 L/kg
renal cl=2.1-2.8 L/hr

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Metabolism / Metabolites
Rivastigmine is rapidly metabolized by cholinesterase-mediated hydrolysis.

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Biological Half-Life
1.5 hours

Hepatotoxicity
In large placebo controlled trials, rivastigmine therapy was not associated with an increased rate of serum enzyme elevations compared to placebo treatment and no instances of clinically apparent liver injury with jaundice were reported. Nevertheless, since its introduction into clinical use, rivastigmine (administered by transdermal patch) has been implicated in at least one report of clinically apparent hepatotoxicity with mild jaundice. The time to onset was 2 months and the serum enzyme elevations had a mildly hepatocellular pattern. Mild rash and eosinophilia were also present, but autoimmune features were not. Recovery was complete within 5 weeks of drug discontinuation.
Likelihood score: D (possible, rare cause of clinically apparent drug-induced liver injury).

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Protein Binding
40%

[1]. Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines. J Med Chem. 2002 Aug 15;45(17):3684-91.

[2]. Efficacy and safety of switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch in patients with probable Alzheimer's disease. J Clin Neurol. 2011 Sep;7(3):137-42.

[3]. Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses. PLoS One. 2013;8(2):e57668.

[4]. Rivastigmine reverses aluminum-induced behavioral changes in rats. Eur J Pharmacol. 2011 Jun 1;659(2-3):169-76.

Rivastigmine is a carbamate ester obtained by formal condensation of the carboxy group of ethyl(methyl)carbamic acid with the phenolic OH group of 3-[(1S)-1-(dimethylamino)ethyl]phenol. A reversible cholinesterase inhibitor. It has a role as an EC 3.1.1.8 (cholinesterase) inhibitor, a neuroprotective agent and a cholinergic drug. It is a carbamate ester and a tertiary amino compound. It is a conjugate base of a rivastigmine(1+).
Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer's type. Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesterase and acetylcholinesterase.
Rivastigmine is a Cholinesterase Inhibitor. The mechanism of action of rivastigmine is as a Cholinesterase Inhibitor.
Rivastigmine is an oral acetylcholinesterase inhibitor used for therapy of Alzheimer disease. Rivastigmine is associated with a minimal rate of serum enzyme elevations during therapy and is a rare cause of clinically apparent liver injury.
A carbamate-derived reversible CHOLINESTERASE INHIBITOR that is selective for the CENTRAL NERVOUS SYSTEM and is used for the treatment of DEMENTIA in ALZHEIMER DISEASE and PARKINSON DISEASE.
See also: Rivastigmine Tartrate (narrower).

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Drug Indication
For the treatment of mild to moderate dementia associated with Parkinson's disease or of the Alzheimer's type.
FDA Label
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. , , Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease. ,
Symptomatic treatment of mild to moderately severe Alzheimer's dementia.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia. Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Treatment of dementia
Treatment of dementia

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Mechanism of Action
Rivastigmine is a carbamate derivative that is structurally related to physostigmine, but not to donepezil and tacrine. The precise mechanism of rivastigmine has not been fully determined, but it is suggested that rivastigmine binds reversibly with and inactivates chlolinesterase (eg. acetylcholinesterase, butyrylcholinesterase), preventing the hydrolysis of acetycholine, and thus leading to an increased concentration of acetylcholine at cholinergic synapses. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues.

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Pharmacodynamics
Rivastigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Tacrine is postulated to exert its therapeutic effect by enhancing cholinergic function. While the precise mechanism of rivastigmine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this proposed mechanism is correct, rivastigmine's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact.

C14H22N2O2

250.34

250.168

123441-03-2

Rivastigmine tartrate;129101-54-8;(rac)-Rivastigmine-d6;194930-04-6

77991

Colorless to light yellow liquid

1.0±0.1 g/cm3

316.2±34.0 °C at 760 mmHg

145.0±25.7 °C

0.0±0.7 mmHg at 25°C

1.518

2.14

0

3

5

18

269

1

O=C(N(C)CC)OC1=CC=CC([C@H](C)N(C)C)=C1

XSVMFMHYUFZWBK-NSHDSACASA-N

InChI=1S/C14H22N2O2/c1-6-16(5)14(17)18-13-9-7-8-12(10-13)11(2)15(3)4/h7-11H,6H2,1-5H3/t11-/m0/s1

[3-[(1S)-1-(dimethylamino)ethyl]phenyl] N-ethyl-N-methylcarbamate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~199.73 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)