Duloxetine indications

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

Hepatotoxicity. Duloxetine is rarely associated with increases in serum transaminase levels, typically in the first 2 months of treatment. In controlled trials in major depressive disorder, elevations of alanine aminotransferase (ALT) to greater than three times the upper limit of normal occurred in 0.9% (8 of 930) of the duloxetine-treated patients and in 0.3% (2 of 652) of the placebo-treated patients. Current product labeling contains a caution regarding the use of duloxetine in patients with significant alcohol use or chronic liver disease. Postmarketing reports have indicated that increases in transaminases have occurred in some patients with chronic liver disease (Cymbalta 2005). 

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

Behavioural and electroencephalic properties of duloxetine studied in mice and rats indicated that the compound is a potential usefiil new antidepressant [108]. 

Several high quality meta-analyses of randomized controlled trials have been published on the value of antidepressants and pain control, in a variety of chronic painful musculoskeletal conditions, including low back pain, fibromyalgia, osteoarthritis, etc. [2-4]. The SNRis continue to be developed for pain indications. There is clear evidence of benefit for antidepressants in fibromyalgia, for the TCAs and the SNRis (duloxetine, miinacipran), osteoarthritis (duloxetine, venlafaxine), and low back pain (TCAs, duloxetine). 

Smith J. Duloxetine wins indication for muscoskeletal pain. Internal Medicine News. 2010 43 38-38. 

In the case of duloxetme, a benzene ring has been replaced by a thiophene nucleus which is a commonly used approach during the process of lead modification. The number of atoms is not the same hence it may be described as a non-classical isostere The phenoxy group has also been transformed, which provides an example of a ring fusion, resulting in the presence of a naphthalenyl-oxy group. This dmg is non-selective, which makes it a mixed SERT/NAT inhibitor. It is indicated for the treatment of major depression, diabetic neuropathy and urinary incontinence. Duloxetine is used as the (S)-enantiomer hydrochloride salt and is available as capsules (30 mg). A typical adult daily dose for the treatment of major depression and diabetic neuropathy is 60 mg. In case of urinary incontinence, 40 mg twice daily have been recommended. 

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