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Duloxetine



Duloxetine
Systematic (IUPAC) name
N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine
Identifiers
CAS number 116539-59-4
136434-34-9 (hydrochloride)
ATC code N06AX21
PubChem 122252
DrugBank APRD00060
Chemical data
Formula C18H19NOS 
Mol. mass 297.41456 g/mol
Pharmacokinetic data
Bioavailability ~ 50% (32% to 80%)
Protein binding ~ 95%
Metabolism Liver, two P450 isozymes, CYP2D6 and CYP1A2.
Half life 12,1 hours
Excretion 70% in urine, 20% in feces
Therapeutic considerations
Licence data

EU US

Pregnancy cat.

C(US)

Legal status

-only(US)

Routes Oral

Duloxetine (brand names Cymbalta, Yentreve, and in parts of Europe, Xeristar or Ariclaim) is a drug which primarily targets major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). It is manufactured and marketed by Eli Lilly and Company.

Duloxetine has not yet been FDA approved for stress urinary incontinence or for fibromyalgia.

Duloxetine is a selective SNRI (selective serotonin-norepinephrine reuptake inhibitor). It is a systemic drug therapy which affects the body as a whole. Known also under the code name LY248686, it is a potent dual reuptake inhibitor of serotonin and norepinephrine, possessing comparable affinities in binding to norepinephrine transporter and serotonin transporter sites. It is a less potent inhibitor of dopamine reuptake.

Additional recommended knowledge

Contents

History

Duloxetine was created by Lilly researchers. The first publication of the discovery of the novel drug, then known as LY227942, was made in 1988 by David T. Wong and Frank P. Bymaster, two of the researchers behind Eli Lilly's fluoxetine (Prozac). Researchers reported: "These findings suggest that LY227942 has the pharmacological profile of an antidepressant drug and is useful to study the pharmacological responses of concerted enhancement of serotonergic and norepinephrine neurotransmission."[1]

Eli Lilly and Company had the formula for duloxetine hydrochloride patented in 1991. They began research on human subjects at 20mg by 1997. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant[2] and the dose was increased to as high as 120mg in subsequent clinical trials done by Eli Lilly.

In November 2001, Lilly filed a New Drug Application (NDA) for duloxetine for depression with the US Food and Drug Administration (FDA). The launch of duloxetine was planned for the second half of 2002. However, at the time, analysts predicted that the drug would actually be launched in the first quarter of 2003.[3]

On July 18, 2002, Eli Lilly made an agreement with Quintiles Transnational Corporation (a pharmaceutical research and marketing company) jointly to commercialize Cymbalta in the United States.[4] PharmaBio, the investment arm of Quintiles, invested $100 million to help develop Cymbalta.

Lilly received an approval letter from the FDA for Cymbalta (for depression) in September 2002. In October 2003, the FDA issued duloxetine a second approval letter saying it did not need to see any more test results before the drug got the final approval for depression. The agency said it would approve the drug once "manufacturing issues" had been resolved, as Lilly had quality control problems at two plants at the time.

Duloxetine (as Cymbalta) was approved by the FDA for MDD in August 2004, and for diabetic neuropathy in September of 2004. Lilly and Quintiles immediately began co-promoting Cymbalta. Through its contract sales organization, Innovex, Quintiles has provided more than 500 sales representatives to help Lilly's substantial sales force promote Cymbalta in the United States for five years. In exchange, Quintiles stands to earn 8.5 percent of royalties from net sales of Cymbalta for depression and other neuroscience indications for eight years.[5]

Cymbalta has not been approved for stress urinary incontinence (SUI) in the US, but Yentreve and Ariclaim have been approved for SUI in the European Union since August 2004. Yentreve, Xeristar and Ariclaim are produced by Boehringer Ingelheim and Eli Lilly and Company in a joint licensing agreement made in 2002.

In Japan, duloxetine has been jointly developed with the pharmaceutical company Shionogi Ltd. for depression since 1992, after signing a license agreement with Eli Lilly. As of January 2007, Shionogi had already received approval for the indication of depression, but is still conducting additional Phase III trials. For the treatment of pain related to diabetic peripheral neuropathy, Shionogi said it and Eli Lilly Japan K.K. will work together on the development as well as marketing. For this use, the drug is now going through Phase II clinical trials.

On November 1, 2007, Health Canada approved duloxetine for treatment of depression.[6] Whether the Canadian public health administrator will also approve duloxetine for treatment of diabetic neuropathy or generalized anxiety disorder is not known. As of late November 2007, duloxetine is not yet available in Canadian pharmacies.

Delivery

 

Each capsule of duloxetine contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride, equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.

Mechanism of Action

Further information: Serotonin and Norepinephrine

When serotonin and norepinephrine are released from nerve cells (neurons) in the brain they act to "lighten mood". When they are reabsorbed into the nerve cells (through reuptake), they no longer have an effect on mood. It is thought that when depression occurs, there may be a decreased amount of serotonin and norepinephrine released from nerve cells in the brain.

Duloxetine works by preventing serotonin, norepinephrine, and to a lesser extent dopamine from being reabsorbed into the nerve cells in the brain, specifically on the 5-HT and NE and D2 receptors respectively. This helps prolong the "mood lightening" effect of any released serotonin and norepinephrine. In this way, duloxetine is thought to help relieve depression.

Serotonin and norepinephrine in the brain and spinal cord are believed to mediate core depression symptoms and to help regulate the perception of pain. Disturbances of serotonin and/or norepinephrine may explain the presence of both the emotional and physical symptoms, including painful physical symptoms, of depression. Based on pre-clinical studies, duloxetine is a balanced and potent reuptake inhibitor of serotonin and norepinephrine. While the mechanism of action of duloxetine is not fully known, scientists believe its effect on both emotional symptoms and pain perception is due to increasing the activity of serotonin and norepinephrine in the central nervous system (CNS).

It may take between two and four weeks of treatment for the benefits of this medicine to appear, so it is very important for a patient to keep taking it even if it doesn't seem have much effect at first. If the patient feels that the depression has become worse, has any of the listed side effects, or has any distressing thoughts or feelings in the first few weeks, he/she should talk to the prescribing doctor.

Duloxetine is also used to treat nerve pain in the feet, legs, or hands due to nerve damage caused by poorly controlled diabetes. Duloxetine is thought to enhance the nerve signals within the central nervous system which naturally inhibit pain. Duloxetine is not effective for the numbness or tingling, nor is it effective for the other complications of diabetes. It does not treat the underlying nerve damage, but can help reduce the pain.[7]

Contraindications

  • Hypersensitivity

Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.

  • Monoamine Oxidase Inhibitors

Concomitant use in patients taking monoamine oxidase inhibitors is contraindicated.

  • Uncontrolled Narrow-Angle Glaucoma

In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.

  • CNS Acting Drugs

Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects which are known to be associated with this medicine. Simply being listed here does not mean that all people using this medicine will experience these (or any other) side effects.

Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10 to 20 percent of patients.[8]

In a trial for mild major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group[9]

Duloxetine and other SSRIs have been shown to cause sexual side effects in some patients, both males and females. Although usually reversible, these sexual side effects can sometimes last for months, years, or longer, even after the drug has been completely withdrawn.[citation needed] This disorder is known as Post SSRI Sexual Dysfunction.

Antidepressants may cause the amount of sodium in the blood to drop — a condition called hyponatraemia. This can cause symptoms such as drowsiness, confusion, muscle twitching, and convulsions. Elderly people may be particularly susceptible to this effect. There may also be an increased risk in people with cirrhosis and those who are dehydrated or taking diuretic medicines. Anyone who develops any of these symptoms while taking this medicine should consult their doctor so that their blood sodium level can be checked if necessary.

Duloxetine as Cymbalta comes with suicide risk warning for children and adolescents under 18.

Serious Adverse Effects

Since duloxetine is a newer drug (FDA approved in 2004), peer-reviewed articles have been published on its adverse effects, and the effects of long-term use are still unknown.

  • Journalists Jeanne Lenzer and Nicholas Pyke, writing for The Independent newspaper, uncovered 41 deaths and 13 suicides for patients taking duloxetine as of June 19, 2005.[10]
  • The French journal Prescrire International published this opinion: "In practice, duloxetine currently has no place in the treatment of depression or diabetic neuropathy. Its efficacy has not yet been demonstrated to be even equivalent to that of other available drugs, and it has too many adverse effects, given this degree of uncertainty."[11]
  • The Los Angeles County Department of Coroner released a report of the first post mortem studies of duloxetine; they identified twelve cases in which duloxetine was the ultimate cause of death. Five cases were declared multiple drug intoxication, and two were declared suicide.[12]
  • A case of hyponatremia induced by duloxetine was reported by doctors at Weill Cornell Medical College in New York.[13]
  • A case of dyskinesia during treatment with duloxetine was reported in Germany.[14]
  • Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjunction with other medications.[15]
  • A case of fulminant hepatic failure involving duloxetine which resulted in death was reported by the Department of Internal Medicine, Ohio State University, Columbus, Ohio.[16]
  • An acute attack of porphyria in a patient taking duloxetine.[17]

Postmarketing spontaneous reports

Reported adverse events which were temporally correlated to Cymbalta therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens-Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.[18]

Interactions

Discontinuing Duloxetine

Further information: SSRI discontinuation syndrome

During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. This withdrawal phenomenon is known as the SSRI discontinuation syndrome.

Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate."[19] This tapering process may be ineffective for some patients.

In MDD placebo-controlled clinical trials of up to nine weeks' duration, systematically evaluating discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.[20]

Many patients on the drug longer than the nine weeks of Lilly's discontinuation test trials anecdotally report evidence of serious withdrawals from Cymbalta, lasting from weeks to many months.

Clinical Worsening and Suicide Risk

All adult and pediatric patients being treated with duloxetine for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially when decreasing the dose.[21]

Efficacy of Duloxetine (Cymbalta) versus Venlafaxine (Effexor)

A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norephinepherine (NE) and serotonin (5-HT) transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively.

Thus, duloxetine more potently blocks serotonin and norephinepherine transporters in vitro and in vivo than venlafaxine,[22] arguably making it the most potent of all commercially available SNRIs. Duloxetine and venlafaxine have not been measured against milnacipran. Milnacipran is not yet available in the United States.

Controversy

Diabetic Neuropathy

Duloxetine received a second FDA approval a month after it was approved for depression when it also became the first FDA-approved treatment for pain caused by diabetic peripheral neuropathy on September 7, 2004.[23] The approval was based on two clinical trials done by Eli Lilly between June 2001 and August 2003. At 20mg per day Cymbalta showed no clinical improvement over placebo. At 60mg per day Cymblata showed modest improvement for diabetic pain over baseline, with 51 percent of patients treated with Cymbalta reporting at least a 30 percent sustained reduction in pain. In comparison, 31 percent of patients treated with placebo reported this magnitude of sustained pain reduction. At 60mg per day 89.5% of patients had some marked treatment adverse effects in one trial, and 87% in the other trial.[24][25]

Stress Urinary Incontinence and Suicidality

Duloxetine as Yentreve and Ariclaim was approved for use of stress urinary incontinence (SUI) in the EU on August 13, 2004. In November 2002, Eli Lilly and Company and Boehringer Ingelheim, a German pharmaceutical company, signed a long-term agreement jointly to develop and commercialize duloxetine hydrochloride.

Although the FDA approved Cymbalta for MDD and diabetic neuropathy, and Yentreve was approved for use of SUI in the European Union, Eli Lilly rescinded their request for FDA approval for SUI use in the United States. In a 9,400-person trial of duloxetine for the treatment of SUI in women, eleven suicide attempts and three cases of suicidal ideation were reported.[26] Withdrawal of an application from FDA approval process is usually the result of the manufacturer's failure to demonstrate in clinical trials that the drug's risk-benefit ratio is positive.

The trials — including 19-year-old Traci Johnson[27] and four other patients who committed suicide during Lilly trials for duloxetine — were cleared by the FDA, stating that underlying depression — not the drug — causes sufferers to become suicidal. Ms. Johnson was in a Lilly trial testing duloxetine as Yentreve, a urinary stress incontinence medication, and not in an anti-depressant trial. In light of suicide risks, some critics claim that the FDA approval of duloxetine for MDD and diabetic neuropathy is irresponsible. On the other hand, the number of participants in the SUI studies was large, and trials of duloxetine for MDD and diabetic neuropathy showed no increase in suicidality.

Financial

At the time of its release in 2004, duloxetine was by far the most promising medicine in Eli Lilly's pipeline. Though it had been sitting on the shelf since 1991, the patent expiry of Prozac, combined with the commercial popularity of Wyeth's Effexor ($2 billion in sales annually since 2003), Eli Lilly went into full scale production of Cymbalta. Analysts say that Cymbalta may even outperform Effexor (Wyeth's brand name for the SNRI venlafaxine). Sales for Cymbalta could reach $2.6 billion to $3.1 billion in 2009, according to Merrill Lynch.

With Cymbalta's patents set to expire on June 11, 2008, Lilly says it is working on at least two new antidepressants to ensure its place in the SSRI antidepressant market. Eli Lilly originally patented duloxetine on June 11, 1991, and has asked the U.S. Patent and Trademark Office for an extension on the exclusivity of the chemical compound beyond 2008 (to June 11, 2013) with an official patent extension application on January 5, 2006.[28]

As of Feb. 28, 2005, more than 1 million Cymbalta prescriptions have been dispensed since FDA approval in August 2004.[29] For the year 2006, Cymbalta outperformed all branded antidepressants in the U.S. in terms of market growth as measured by both new prescriptions and total prescriptions. "Globally, the Cymbalta launch has been one of the most successful in both Lilly's history and that of the entire antidepressant market."[30] Worldwide sales for Cymbalta grew at 91 percent in the third quarter compared with the same period last year. Eli Lilly is estimated to generate over $1 billion in annual sales in only its second full year with the drug on the market.

Recent News

Generalized Anxiety Disorder

On May 11 2006, Eli Lilly and Company announced the recent submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for Cymbalta for the treatment of generalized anxiety disorder (GAD). Approximately 6.8 million American adults, or about 3.1 percent of people age 18 and over, have GAD in a given year.[31]

Eli Lilly said the FDA has approved Cymbalta for the treatment of GAD in February 2007.[32] Eli Lilly said that in clinical trials patients treated with Cymbalta for GAD experienced a 46% improvement in anxiety symptoms, compared to 32% for those who took placebo, as measured by the Hamilton Anxiety Scale.

Fibromyalgia

On October 19 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta, at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgia (FM), with and without major depression, according to 12-week data presented at the annual meeting of the American College of Rheumatology. Eli Lilly is in Phase III of its FM trials and is expected to submit a sNDA to the FDA for approval of Cymbalta for FM within the next 12 months.

Critics argue that randomized controlled trials of FM are difficult due to factors such as a lack of understanding of the pathophysiology and a heterogeneous FM patient population. Although there is a lack of understanding of what causes FM, it is estimated that approximately 5-7% of the U.S. population has FM,[33] representing a large patient clientele. Eli Lilly hopes Cymbalta will be the first FDA approved medication for FM and had been promoting Cymbalta for FM since 2004.[34]

In the study testing the efficacy of Cymbalta for FM, participants completed several questionnaires to measure the amount of pain and discomfort the disease caused them at the beginning of the study, and then at the end of each of the first two weeks and every second week for the remaining 12 weeks of the study. Researchers also tested the participants for depression.

Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11 percent of the study, there was no effect from taking the medication compared with a placebo. Reportedly, depression played no part in whether or not the drug worked to control pain. The change in the level of women's pain was particularly pronounced after a month of taking the drug, then leveled off a bit before dropping again near the end of the study.

However, in one of the primary measures of pain there was no significant difference between the two groups at the end of the 12-week trial. Also, because the trial lasted only 12 weeks, it is impossible to tell how well the drug would control treatment for a longer period of time. Lastly, the primary researcher on the project has received more than $10,000 in consulting fees from Eli Lilly, the manufacturer of Cymbalta, all other researchers also had ties to the company, reflecting a conflict of interest.

Chronic Fatigue Syndrome

As of January 11 2007, Eli Lilly is currently enrolling patients for double blind Phase II and Phase III trials of Cymbalta for the use of Chronic Fatigue Syndrome (CFS) in conjunction with the University of Cincinnati.[35] CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition. Eli Lilly has not publicly stated their hypothesis for use of Cymbalta for CFS.[citation needed]

See also

References

  1. ^ Wong DT, Robertosn DW, Bymaster FP, Krushinski JH, Reid LR. "LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug." Life Sci. 1988;43(24):2049-57.
  2. ^ [1]Turcotte JE, Debonnel G, de Montigny C, Hebert C, Blier P. "Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects." Neuropsychopharmacology. 2001 May;24(5):511-21.
  3. ^ [2]Antilla S, Leinonen "Duloxetine Eli Lilly". Curr Opin Investig Drugs. 2002 Aug;3(8):1217-21
  4. ^ [3] NovaQuest Press Release 2002
  5. ^ [4] Triangle Business Journal February 20, 2004
  6. ^ Health Canada Notice of Compliance Database - duloxetine. November 1, 2007, retrieved November 24, 2007.
  7. ^ Essential Science Indicators
  8. ^ Cymbalta® package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.
  9. ^ D. G. S. Perahia1, D. K. Kajdasz, D. J. Walker, J. Raskin, A. Tylee. "Duloxetine 60 mg once daily in the treatment of milder major depressive disorder". International Journal of Clinical Practice (Vol, 60 Issue 5 Pg 613 - May 2006)
  10. ^ The Independent 19 June 2005
  11. ^ "Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects." Prescrire International. (2006 Oct;15(85):168-72)
  12. ^ Anderson D, Reed S, Lintemoot J, Kegler S, DeQuintana S, Sandberg M, Muto J. "A first look at duloxetine (Cymbalta) in a postmortem laboratory. Journal of Annual Toxicology. (2006 Oct;30(8):576-480)
  13. ^ Safdieh JE, Rudominer R. "A case of hyponatremia induced by duloxetine". J Clin Psychopharmacol. 2006 Dec;26(6):675-6.
  14. ^ Deuschle M, Mase E, Zink M. "Dyskinesia during treatment with duloxetine". Pharmacopsychiatry. 2006 Nov;39(6):237-8.
  15. ^ J Clin Psychopharmacol. 2006 Dec;26(6):681-683, Anesth Analg. 2006 Dec;103(6):1466-8.
  16. ^ Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB. "Case report: fulminant hepatic failure involving duloxetine hydrochloride". Clin Gastroenterol Hepatol. 2006 Jul;4(7):912-7. Epub 2006 Jun 22.
  17. ^ Loper T, Touchet B. Psychosomatics. 2007 Mar-Apr;48(2):179-80
  18. ^ [5] Cymbalta Side Effects, and Drug Interactions - RxList Monographs
  19. ^ Cymbalta® patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006
  20. ^ Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. "Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder". J Affect Disord. 2005 Dec;89(1-3):207-12. Epub 2005 Nov 2.
  21. ^ Cymbalta® patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006
  22. ^ Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT. "Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors". Neuropsychopharmacology. 2001 Dec;25(6):871-80
  23. ^ [6] FDA News
  24. ^ Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. "Duloxetine vs. placebo in patients with painful diabetic neuropathy". Pain. 2005 Jul;116(1-2):109-18.
  25. ^ Raskin J, Pritchett YL, Wang F, D'Souza DN, Waninger AL, Iyengar S, Wernicke JF. "A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain". Pain Med. 2005 Sep-Oct;6(5):346-56.
  26. ^ FDA Historical Information on Duloxetine
  27. ^ [7] Alliance for Human Research Protection. "19 year old volunteer suicided in Eili Lilly laboratory". February 11, 2004.
  28. ^ 2006E-0004: Patent Extension Application for CYMBALTA (duloxetine hydrochloride), U.S. Patent No. 5,023,269
  29. ^ Cymblata Healthcare Professional Website
  30. ^ CNNMoney.com December 07, 2006
  31. ^ [8] NIMH: The Numbers Count
  32. ^ [9] News-Medical.Net February 26, 2007
  33. ^ [10] National Fibromyalgia Association Brochure
  34. ^ [11] Duloxetine Effective in Fibromyalgia Arthritis Rheum. 2004;50:2974-2984
  35. ^ [12] Clinicaltrials.gov
  • Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. "Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial". J Clin Psychiatry 2002;63(3):225-31.
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  • Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. "Duloxetine in the long-term treatment of major depressive disorder". J Clin Psychiatry 2003;64(10):1237-44.
  • Bailey KP. Yale University School of Nursing, New Haven, Connecticut, USA. "Physical symptoms comorbid with depression and the new antidepressant duloxetine". J Psychosoc Nurs Ment Health Serv. 2003 Dec;41(12):13-8.
  • Gutman DA, Owens MJ.Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA. "Serotonin and norepinephrine transporter binding profile of SSRIs". Essent Psychopharmacol. 2006;7(1):35-41.
  • Raskin J, Wang F, Pritchett YL, Goldstein DJ. "Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study". Pain Med. 2006 Sep-Oct;7(5):373-85.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Duloxetine". A list of authors is available in Wikipedia.
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