41340-25-4 Usage
Uses
Used in Pharmaceutical Industry:
Etodolac is used as an anti-inflammatory and analgesic agent for the treatment of various inflammatory conditions, such as rheumatoid arthritis and osteoarthritis. It selectively inhibits COX-2, which is responsible for prostaglandin synthesis at the site of inflammation, providing pain relief and reducing inflammation.
Used in Pain Management:
Etodolac is used for the acute and long-term management of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as for the management of pain. It is particularly suitable for elderly patients due to its rapid absorption and lack of signs of drug savings.
Used in Postoperative Pain Relief:
Etodolac is used for the alleviation of postoperative pain, providing effective pain management and promoting a smoother recovery process for patients.
Used as a Non-Steroidal Anti-Inflammatory Drug (NSAID):
Etodolac is used as an NSAID for its analgesic and anti-inflammatory effects. It can inhibit prostaglandin synthesis at the site of inflammation selectively, making it a valuable option for patients suffering from various inflammatory conditions.
Used in Drug Development:
Etodolac's unique enantioselective pharmacokinetic properties, such as the higher plasma concentration of the "inactive" (R)-enantiomer and the large volume of distribution of the active (S)-enantiomer, make it an interesting candidate for further research and development in the pharmaceutical industry. Its extensive metabolism into three major inactive metabolites also offers potential for the development of new drug formulations and delivery systems.
Non-steroidal anti-inflammatory drugs
Etodolac (trade name: Lodine), also known as ethoxycolic acid, indoleacetic acid, and rhododine, is a new generation of non-steroidal anti-inflammatory drug highly selective to COX-2. This product is a weak acidic drug, existing in a molecular form under the condition of lower pH value which is conducive to drug absorption. This product is widely used in the clinical treatment of postoperative pain. It has analgesic and anti-inflammatory effects, being able to relieve the symptoms of rheumatoid arthritis and osteoarthritis, delaying the pathological changes caused by arthritis. In inflammatory site, it can selectivity inhibit the prostaglandin synthesis to exert its anti-inflammatory effect. It is especially applicable to the elderly patients. This product appears as white crystalline powder with the melting point of 145~148 ℃.
Etodolac was first developed by a subsidiary of AHP in the United States. It had been successfully listed in the UK in 1985, followed by being listed in France, the United States, Germany, Japan and other countries.
NSAID
Etodolac (Etodolac), also known as indole acetic acid, indole acetic acid pyran and rodin etc, and the tradename is Lodine, a new generation of non-steroidal anti-inflammatory drugs which has a high selective of COX-2. This product is a kind of weak acid drug and has the form of molecular at lower pH values which is conducive to drug absorption. This product is widely used in the clinical treatment of pain after surgery, has a good effect of analgesic and anti-inflammatory that can relieve symptoms of rheumatoid arthritis and osteoarthritis, delay the bone pathology caused by arthritis and synthesis the prostaglandin at the sites of inflammation selectively. The product apply to the elderly patients. The etodolac is white crystalline powder, has the melting point of 145~148 ℃.
Etodolac was first developed by the subsidiary of AHP and successfully listed in the UK in 1985. The product have been listed in many countries like France, the United States, Germany and Japan etc.
Mechanism
This product is non-steroidal anti-inflammatory drugs. Its effects is similar to aspirin. It can inactivated the cyclooxygenase at the sites of inflammation thereby inhibit the biosynthesis of prostaglandins selectively.The product has little side effect for the gastrointestinal since its inhibition of PGE2 is mild and transient. It can be quickly absorbed by oral with a single dose of 200mg.It has the Tmax of 1 h, Cmax of 18.6 μg/ml, T1/2 of 7.4 h and PPB of 95%. The product do not accumulate in the body and 60% of the dose can be excreted after 24hr by the cellular metabolism, among the them, 74% is excreted in urine by the kidneys and 19% in feces. The product can reduce the incidence and damage of bone and joint and improce the condition of patients. The current study shows that the product has no teratogenic effect in? animal experiments and has little impact on fertility and reproductive function.
Pharmacokinetics
According to the current study abroad, the drug is well absorbed orally and has the the systemic bioavailability of 80% or more. The dosage should be within 600mg every 12 hours, the area under the curve of plasma concentration-time is in direct proportion to the dosage. More than 99% of etodolac can combine with the plasma protein, the free fraction is less than 1%. The single dose is at the range of 200-600mg and the the average peak plasma concentration (Cmax) within 80 ± 30 the minute is in the scope of 14 ± 4-37 ± 9μg/ml range. The average plasma clearance rate is 47 (± 16) ml/hr/kg and the elimination half-life is 7.3 (± 4.0) hours. Etodolac can be metabolized by the liver and 16% of the dose excreted by the faeces. The dose of the product is not determined by the weight, but the recommended dosage can use the body weight as reference.
Pharmacokinetics
Etodolac is rapidly absorbed following oral administration, with maximum serum levels being achieved within 1 to 2
hours, and it is highly bound to plasma proteins (99%) with pKa 4.7. The penetration of etodolac into synovial fluid is
greater than or equal to that of tolmetin, piroxicam, or ibuprofen. Only diclofenac appears to provide greater
penetration.
Used in Particular Diseases
Acute Gouty Arthritis:
Dosage and Frequency: 300 mg twice daily
Production method
The acylation reaction of o-ethyl aniline, chloral hydrate and hydroxylamine can form the oxime, after the cyclization by using the sulfuric as the catalyst and the reduction by lithium aluminium hydride , oxime can turn into the indole derivatives. The reaction with the oxalyl chloride and ethanol can bring 1,2-carbonyl side chain in 3 bit and then be restored to hydroxyethyl by lithium aluminium hydride, after the condensation , cyclization with? ethyl propionylacetate and hydrolyzation. The final product-etodolac can be obtained.
Synthetic routes
The etodolac ester should be prepared at first, and the final product can be obtained after the hydrolyzation, acidification, crystallization of the organic phase and rectification by the toluene (or benzene)-refined petroleum ether. Using the industrial 7-Ethyl tryptophol and? ethyl propionylacetateas as the raw material to synthesis the etodolac ethyl, and get the crude etodolac by hydrolyzation and acidification. The refined etodolac can be obtained by recrystallization with isopropanol-water.
Figure 1 shows the synthetic route of etodolac
Usage and dosage
The usage are various with the different applications, as follows:
1. For pain: The recommended dose is 0.2-0.4g every 8 hours for acute pain , the maximum daily dose should not exceed 1.2g. The maximum daily dose for the patients who weight under 60kg should not exceed 20mg per kilogram of body weight. The etodolac still has analgesic effect on some patients.
2. For chronic diseases such as osteoarthritis and rheumatoid arthritis: The recommended dose of daily is 0.4-1.2g in divided doses orally, the maximum daily dose should not exceed 1.2g. The maximum daily dose for the patients who weight over 60kg should not exceed 20mg per kilogram of body weight. The daily dose for etodolac is 0.4g or less in divided doses.It has a certain effect for some patients.
Adverse drug reaction
The product may cause some side effect like the allergic symptoms include the rash, eczema, itching and redness etc; nausea, diarrhea, abdominal pain, heartburn, indigestion, bloating, abdominal pain, stomach cramps, constipation and vomiting for the gastrointestinal system; headache , dizziness, drowsiness, insomnia, nervousness, anxiety, depression, general malaise, fatigue, weakness, frequent urination, palpitations, edema and tinnitus for the central nervous system. The side effect like the increasing of the ALT, AST and BUN , the decline of the hemoglobin, white blood cells, red blood cells and thrombocytopenia are rarely.
The mechanism of action of Etodolac, the route of synthesis, adverse reactions, etc., were edited by Baoquan, lookchem. (2016-11-18)
Attention
The drug security of pregnant and lactating women has not been established and should be used with caution. The first three months of pregnancy should not use this drug. The patients who allergic to aspirin and other NSAIDs or have the active peptic ulcer can not use this product disabled. The patients with the history of gastrointestinal disease include peptic ulcer should be closely monitored and be discontinued immediately when the peptic ulcer come. Even it has no direct effect on platelets, but the inhibition of prostaglandin biosynthesis can interfere the platelet function in some ways. The patients who has liver and kidney dysfunction sjpi;d adjust the dose according to need.
Originator
Ayerst (USA)
Indications
Etodolac (Lodine) is indicated for the treatment of
osteoarthritis, rheumatoid arthritis, and acute pain. It inhibits
COX-2 with slightly more selectivity than COX-1
and therefore produces less GI toxicity than many other
NSAIDs. Common adverse effects include skin rashes
and CNS effects.
Biological Activity
Non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2) (IC 50 values are 53 and >100 μ M for COX-2 and COX-1 respectively). Displays anti-inflammatory effects in both adjuvant arthritic and normal rats.
Biochem/physiol Actions
Non-steroidal anti-inflammatory compound that is a non-selective inhibitor of COX-1 and COX-2.
Mechanism of action
The primary mechanism of action appears to be
inhibition of the biosynthesis of prostaglandins at the cyclooxygenase step, with no inhibition of the lipoxygenase
system. Etodolac, however, possesses a more favorable ratio of inhibition of prostaglandin biosynthesis in human
rheumatoid synoviocytes and chondrocytes than by cultured human gastric mucosal cells compared to ibuprofen,
indomethacin, naproxen, diclofenac, and piroxicam.
Clinical Use
Etodolac is promoted as the first of a new chemical class of anti-inflammatory drugs, the pyranocarboxylic acids.
Although not strictly an arylacetic acid derivative (because there is a two-carbon atom separation between the
carboxylic acid function and the hetero-aromatic ring), it still possesses structural characteristics similar
to those of the heteroarylacetic acids and is classified here. It was introduced in the United States in 1991 for acute
and long-term use in the management of osteoarthritis and as an analgetic. It also possesses antipyretic activity.
Etodolac is marketed as a racemic mixture, although only the S-(+)-enantiomer possesses anti-inflammatory activity
in animal models. Etodolac also displays a high degree of enantioselectivity in its inhibitory effects on the
arachidonic acid cyclooxygenase system.
Veterinary Drugs and Treatments
Etodolac is labeled for the management of pain and inflammation
associated with osteoarthritis in dogs. It may find uses, however, for
a variety of conditions where pain and/or inflammation
should be
treated.
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect, increased risk of
nephrotoxicity and hyperkalaemiaAnalgesics: avoid concomitant use of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac, increased risk of side effects and
haemorrhage.Antibacterials: possibly increased risk of convulsions
with quinolones.Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparin, dabigatran and edoxaban -
avoid long term use with edoxaban.Antidepressants: increased risk of bleeding with
SSRIs and venlafaxine.Antidiabetic agents: effects of sulphonylureas
enhanced.Antiepileptics: possibly increased phenytoin
concentration.Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavirCiclosporin: may potentiate nephrotoxicityCytotoxic agents: reduced excretion of methotrexate;
increased risk of bleeding with erlotinib.Diuretics: increased risk of nephrotoxicity;
antagonism of diuretic effect; hyperkalaemia with
potassium-sparing diuretics.Lithium: excretion decreased.Pentoxifylline: increased risk of bleedingTacrolimus: increased risk of nephrotoxicity.
Metabolism
Etodolac is metabolized to three hydroxylated metabolites and to glucuronide conjugates, none of which
possesses important pharmacological activity. Metabolism appears to be the same in the elderly as in the general
population, so no dosage adjustment appears necessary.
Etodolac is indicated for the management of the signs and symptoms of osteoarthritis and for the management of
pain.
references
[1] kumagai k1, kubo m, imai s, toyoda f, maeda t, okumura n, matsuura h, matsusue y.the cox-2 selective blocker etodolac inhibits tnfα-induced apoptosis in isolated rabbit articular chondrocytes. int j mol sci. 2013 sep 30;14(10):19705-15. [2] hakozaki m1, hojo h, kikuchi s, abe m. etodolac, a selective cyclooxygenase-2 inhibitor, induces apoptosis by activating caspases in human malignant rhabdoid tumor cells (frtk-1). oncol rep. 2007 jan;17(1):169-73.
Check Digit Verification of cas no
The CAS Registry Mumber 41340-25-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 4,1,3,4 and 0 respectively; the second part has 2 digits, 2 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 41340-25:
(7*4)+(6*1)+(5*3)+(4*4)+(3*0)+(2*2)+(1*5)=74
74 % 10 = 4
So 41340-25-4 is a valid CAS Registry Number.
InChI:InChI=1/C17H21NO3/c1-3-11-6-5-7-12-13-8-9-21-17(4-2,10-14(19)20)16(13)18-15(11)12/h5-7,18H,3-4,8-10H2,1-2H3,(H,19,20)
41340-25-4Relevant articles and documents
HPLC monitoring of acid catalyzed conversion of 7-ethyltryptophol to methyl ester of etodolac
Habinovec, Iva,Car, Zeljka,Ribic, Rosana,Galic, Nives,Novak, Predrag,Mestrovic, Ernest,Tomic, Srdanka
, (2017/05/29)
Small scale experimental model for the preparation of methyl ester of etodolac, the key intermediate in the synthesis of nonsteroidal drug etodolac, is thoroughly investigated in order to define the key parameters needed for its large scale production. Ox
Direct racemization of indole derivatives
-
Page/Page column 9, (2008/06/13)
The present invention discloses processes for the racemization of enantiomers of etodolac and other tetra-hydropyrano indole derivatives.
Method for the racemization of etodolic acid
-
Page 2, (2008/06/13)
A method for the resolution of etodolic acid by crystallization of its salt with optically active 1-phenylethylamine and subsequent recovery of the (R,S) etodolic acid from the mother liquors of crystallization by racemization and crystallization is described.
Process for the resolution of etodolac using glucamine derivatives
-
, (2008/06/13)
The subject invention pertains to a process for the resolution of etodolac comprising the use of the resolving agent glucamine or a N-(C1-4 alkyl)-glucamine. The subject invention also concerns a process for converting a single enantiomer of etodolac into the racemate. The method comprises forming all ester of the carboxylate function of the enantiomer and treating with an acid or base.
Enzymatic resolution of new anti-inflammatory drug etodolac
Mizuguchi, Eisaku,Itanami, Makiko,Achiwa, Kazuo
, p. 149 - 152 (2007/10/03)
Optically active etodolac (1) was easily prepared by lipase-catalyzed kinetic resolution. The unnecessary enantiomer as a by-product of the resolution could be racemized and was converted to a repeated substrate for the enzymatic reaction.
Process for preparing 1,8-diethyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetic acid, etodolac
-
, (2008/06/13)
A process for preparing 1,8-diethyl-1,3,4,9-tetrahydro[3,4-b]-indole-1-acetic acid (etodolac) is disclosed. Etodolac is a useful antiinflammatory and analgesic agent.
Process for the resolution of pyrano[3,4-b]indole-1-acetic acids
-
, (2008/06/13)
Mixtures of racemic (±)pyrano[3,4-b]indole-1-acetic acids are resolved with (-)-borneol to obtain the substantially pure (+) and (-)-enantiomers. The resolution involves the formation of a mixture of the diastereoisomeric pyrano[3,4-b]indole-1-acetic acid, (-)-borneol esters, separation of the diastereoisomeric esters, and hydrolysis of the latter esters.
Esters and amides containing the 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetyl moiety
-
, (2008/06/13)
Compounds of the formula STR1 wherein each X, which may be identical or different from the other X, is oxygen or imino; R1 is hydrogen, fluorine, chlorine or bromine; R2 and R3, which may be identical or different from each other, are each hydrogen; unsubstituted or mono-substituted alkyl of 1 to 6 carbon atoms, where the substituent is phenyl or dialkylamino with 1 to 3 carbon atoms in each alkyl moiety; pyridyl; or cycloalkyl of 5 to 7 carbon atoms; R2 and R3, together with each other and the nitrogen atoms to which they are attached, are pyrrolidino, piperidino, hexamethyleneimino, morpholino, N-aryl-piperazino or N-(alkyl of 1 to 3 carbon atoms)-piperazino; A is cycloalkylene of 5 to 7 carbon atoms; unsubstituted or substituted alkylene of 2 to 10 carbon atoms, where the substituents are one to two alkyls of 1 to 3 carbon atoms each, one to two carbalkoxys of 2 to 4 carbon atoms each, one to two phenyls, one to four hydroxyls, one halomethyl, one hydroxymethyl, one alkanoyloxy of 1 to 18 carbon atoms, one alkanoyloxymethyl of 1 to 18 carbon atoms in the alkanoyl moiety or one STR2 where R1, R2 and R3 have the meanings previously defined; or alkylene of 2 to 10 carbon atoms interrupted by oxygen, sulfur, sulfoxide, sulfonyl, phenyl, cyclohexyl, pyridyl, piperazino or unsubstituted or substituted imino, where the substituent on the imino group is alkyl of 1 to 6 carbon atoms, phenyl or phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety; B is the acyl residue of an antiphlogistic carboxylic acid; and their non-toxic, pharmacologically acceptable acid addition salts. The compounds as well as their salts are useful as anti-inflammatories.
