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duloxetine Cymbalta
What is Cymbalta? Cymbalta is a newly approved antidepressant believed to affect the levels of the neutrotransmitters serotonin and norepinephrine both involved in depression and anxiety associated with depression. Studies show that Cymbalta might help with physical symptoms like back pain and joint aches that can accompany depression. Its competitor is Effexor which targets also serotin and norepinephrine.Lilly said Cymbalta comes in a capsule and can be taken once a day. The recommended daily dose is 60 milligrams. Lily is also possibly filing Cymbalta for stress urinary incontinence but is calling the drug Yentreve for that.
J Clin Psychopharmacol. 2004 Aug;24(4):389-99. : Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine.
Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C, Demitrack MA.
PRN Consulting, Indianapolis, IN, USA.
CONTEXT: Major depressive disorder causes significant morbidity and mortality. Current therapies fail to fully treat both emotional and physical symptoms of major depressive disorder. OBJECTIVE: To evaluate duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on improvement of emotional and painful physical symptoms. DESIGN: Randomized, double-blind, evaluation of duloxetine at 40 mg/d (20 mg twice daily) and 80 mg/d (40 mg twice daily) versus placebo and paroxetine 20 mg/d in depressed outpatients. MAIN OUTCOME MEASURES: The primary efficacy measure was the 17-item Hamilton Depression Rating Scale. Visual Analog Scales for pain, Clinical Global Impression of Severity, Patient's Global Impression of Improvement, and Quality of Life in Depression Scale were also used. Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. RESULTS: Duloxetine 80 mg/d was superior to placebo on mean 17-item Hamilton Depression Rating Scale total change by 3.62 points (95% CI 1.38, 5.86; P = 0.002). Duloxetine at 40 mg/d was also significantly superior to placebo by 2.43 points (95% CI 0.19, 4.66; P = 0.034), while paroxetine was not (1.51 points; 95% CI -0.55, 3.56; P = 0.150). Duloxetine 80 mg/d was superior to placebo for most other measures, including overall pain severity, and was superior to paroxetine on 17-item Hamilton Depression Rating Scale improvement (by 2.39 points; 95% CI 0.14, 4.65; P = 0.037) and estimated probability of remission (57% for duloxetine 80 mg/d, 34% for paroxetine; P = 0.022). The only adverse event reported significantly more frequently for duloxetine 80 mg/d than for paroxetine was insomnia (19.8% for duloxetine 80 mg/d, 8.0% for paroxetine; P = 0.031). Hypertension incidence was not affected by any treatment. CONCLUSION: Duloxetine therapy was efficacious for emotional and physical symptoms of depression, with a selective serotonin reuptake inhibitor-like profile of side effects. Copyright 2004 Lippincott Williams and Wilkins PMID: 15232330 [PubMed - in process]
Desipramine ( Norpramine, Pertofrane ).
Psychopharmacology (Berl). 2004 Jul 28 [Epub ahead of print] : Comparative effects of duloxetine and desipramine on sleep EEG in healthy subjects.
Chalon S, Pereira A, Lainey E, Vandenhende F, Watkin JG, Staner L, Granier LA.
Lilly Research Laboratories, 46285, Indianapolis, IN, USA.

RATIONALE. Antidepressants are known to modify human sleep patterns. OBJECTIVES. Duloxetine is a new antidepressant with a mechanism of action involving reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE). In this study, the effects of two dosing regimens of duloxetine on sleep electroencephalography (EEG) were investigated at steady-state plasma concentrations in young, healthy, male subjects. METHODS. Placebo ( n=12), desipramine (50 mg BID; n=12) and two regimens of duloxetine (80 mg QD, n=6; or 60 mg BID, n=6) were compared in a randomized, double-blind, three-period crossover study, each treatment being administered from day 1 to day 7. Sleep polygraphic recordings took place at baseline (day -1) and day 6 of each period. The Leeds sleep evaluation questionnaire (LSEQ) was also administered on the morning of day 7. RESULTS. Both regimens of duloxetine produced a significant increase in the onset latency of REM sleep as well as a significant mean decrease in total REM sleep duration. Desipramine exhibited comparable effects. When compared to placebo, sleep continuity was significantly reduced with desipramine and duloxetine 60 mg BID whereas a significant improvement was observed with duloxetine 80 mg QD. On the LSEQ, duloxetine 80 mg QD produced a significant improvement in the "getting to sleep" subscale compared to placebo, whereas desipramine demonstrated a significant reduction (worsening) in the "quality of sleep" score versus placebo. CONCLUSIONS. The two dose regimens of duloxetine (80 mg QD and 60 mg BID) produced a REM sleep pattern comparable to that of most antidepressant medications. Duloxetine 80 mg QD appeared to exhibit less impact upon sleep quality than duloxetine 60 mg BID in healthy subjects.
J Pharmacol Exp Ther. 2004 Jul 13 [Epub ahead of print] : Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.
Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM. Eli Lilly & Co.
Serotonin (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in parachloramphetamine (p-CA)-treated rats was comparable to paroxetine, a selective serotonin reuptake inhibitor (SSRI), while its ability to antagonize NE depletion in alpha-methyl-m-tyrosine (alpha-MMT)-treated rats was similar to norepinephrine reuptake inhibitors (NRI), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI, paroxetine or the NRI, thionisoxetine, alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg, intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg, oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve-ligation model of neuropathic pain. Duloxetine (3-30 mg/kg, oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.
J Urol. 2004 Jul;172(1):27-33. : Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women.
Thor KB, Donatucci C.
Dynogen Pharmaceuticals, Inc., Durham, North Carolina 27708, USA.
kthor@dynogenpharma.com
PURPOSE: Despite the prevalence of stress urinary incontinence in women there are no approved drugs for the disease. MATERIALS AND METHODS: Designing medical therapies requires a comprehensive understanding of how the internal and external sphincters are neurologically controlled. In this review recent advances in mapping storage and micturition reflexes, and the association of serotonergic and noradrenergic systems with these reflexes are discussed. RESULTS: Urine storage and micturition are controlled by a series of hard wired reflexes that are under the modulatory influence of serotonin and norepinephrine. Augmentation of the serotonergic and noradrenergic systems with duloxetine increases bladder capacity and urethral rhabdosphincter activity. The increase in sphincter activity is mediated by alpha1 adrenergic receptors and 5-hydroxytryptamine receptors. CONCLUSIONS: Increasing rhabdosphincter activity with duloxetine may offer a therapeutic benefit in women with stress urinary incontinence.
Gynecol Obstet Fertil. 2004 Jun;32(6):556-61. : [Update on medical treatment of female stress urinary incontinence]
[Article in French]
Yazbeck C, Dhainaut C, Batallan A, Thoury A, Madelenat P.
Service de gynecologie-obstetrique, hopital Bichat-Claude-Bernard, Paris, France.
chayaz@cyberia.net.lb
A reasonable assumption is that incontinence would be relieved by increasing urethral resistance through stimulating alpha-adrenergic receptors in urethral smooth muscle. A review of available medical treatment of stress urinary incontinence is done. Alpha-receptor agonists are not in common use because of systemic side-effects. Estrogens do not seem to have beneficial effect on stress urinary incontinence. Currently, new molecules such as duloxetine, are uptake inhibitor of serotonin and noradrenaline could provide a noninvasive therapy for patients with urinary incontinence. Further studies to identify clinical applications are required.
J Clin Psychiatry. 2004 Apr;65(4):521-30. : The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates?
Fava M, Mallinckrodt CH, Detke MJ, Watkin JG, Wohlreich MM.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
BACKGROUND: Depression is a chronic disease consisting of emotional/psychological and physical symptoms. Emotional symptoms have been shown to respond to currently available antidepressants; however, physical symptoms may not be as responsive. It was hypothesized that resolution of both psychological and physical symptoms of depression would predict a higher percentage of patients achieving remission. METHOD: Efficacy data were pooled from 2 identical, but independent, 9-week randomized, double-blind clinical trials of duloxetine 60 mg q.d. (N = 251) and placebo (N = 261). All patients met diagnostic criteria for DSM-IV major depressive disorder, which was confirmed by the Mini-International Neuropsychiatric Interview. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score, the HAM-D-17 Maier subscale, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the Patient Global Impression of Improvement (PGI-I) scale, the Somatic Symptom Inventory, the Quality of Life in Depression Scale, and Visual Analog Scales (VAS) for pain (overall pain, headaches, back pain, shoulder pain, interference with daily activities, and time in pain while awake). RESULTS: Duloxetine-treated patients demonstrated significantly greater improvement in overall pain (p =.016), back pain (p =.002), and shoulder pain (p =.021) at week 9 compared with patients receiving placebo. When treatment effects were pooled over all visits, patients receiving duloxetine, 60 mg q.d., exhibited significantly greater improvement than placebo-treated patients in 5 of the 6 assessed VAS pain measures. Approximately 50% of the improvement in overall pain was independent of improvement in HAM-D-17 total score. Assuming the same level of improvement in core emotional symptoms of depression (Maier subscale), improvement in overall pain severity was associated with higher estimated probabilities of remission (p <.001). The week 9 means for VAS overall pain severity were 13.0 for remitters (last observed value for HAM-D-17 was < or = 7) compared with 22.7 for nonremitters (p <.001), respectively, representing a greater than 3-fold improvement from baseline in remitters. The remission rate for pain responders (improvement in VAS overall pain from baseline to last observation > or = 50%) was twice that observed for pain nonresponders (36.2% vs. 17.8%, p <.001). Greater improvements in pain outcomes were associated with more favorable endpoint outcomes on the CGI-S and PGI-I scales. In addition, early favorable responses in VAS overall pain severity were associated with favorable endpoint outcomes. CONCLUSIONS: Treatment with duloxetine, 60 mg q.d., significantly reduced pain compared with placebo. Improvements in pain severity were attributable equally to the direct effect of duloxetine and to associated changes in depression severity. Improvement in painful physical symptoms was associated with higher remission rates even after accounting for improvement in core emotional symptoms.
Br J Clin Pharmacol. 2004 Jan;57(1):54-61. : Effect of age on the pharmacokinetics of duloxetine in women.
Skinner MH, Kuan HY, Skerjanec A, Seger ME, Heathman M, O'Brien L, Reddy S, Knadler MP.
Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, Indianapolis, IN 46202, USA.
AIMS: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence. METHODS: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24-77 years) who received duloxetine 20 mg day(-1), 30 mg day(-1), or 40 mg day(-1) in Study 2A and 128 women (28-64 years) who received duloxetine 20 mg day(-1), 40 mg day(-1), or 80 mg day(-1) in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed-effects modelling program (NONMEM). RESULTS: In Study 1, the elderly (> or = 65 years) exhibited a statistically significant slower elimination rate constant lambdaz compared with younger subjects [elderly-younger difference = -0.022 h(-1)[95% confidence interval (CI) -0.036, -0.008]]. However, no statistically significant differences in either CL/F [elderly-younger difference = -17.4 l h(-1) (95% CI -41.1, 6.23)] or V/F [elderly-younger difference = 115.9 l (95% CI -168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non-elderly participants in these studies. CONCLUSIONS: Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower lambdaz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.
J Clin Psychiatry. 2004;65 Suppl 4:46-52. : Newer antidepressants: review of efficacy and safety of escitalopram and duloxetine.
Hirschfeld RM, Vornik LA.
Department of Psychiatry and Behavioral Sciences, University of Texas-Medical Branch, Galveston 77555-0188, USA.
rohirsch@utmb.edu
BACKGROUND: Two antidepressants with different mechanisms of action, escitalopram and duloxetine, have recently been developed for the treatment of major depressive disorder. This article reviews the available controlled data on these agents with regard to efficacy, safety, and tolerability. METHOD: We identified four 8-week, double-blind, placebo-controlled studies of escitalopram in the acute treatment of major depression. Three of the studies involved an active comparator, citalopram. We identified 6 placebo-controlled studies of duloxetine in major depressive disorder. Two of the studies included fluoxetine as an active comparator, and 2 included paroxetine as an active comparator. RESULTS: A review of the data from the controlled studies supports the efficacy of both escitalopram and duloxetine in the treatment of patients with major depression. Three of the 4 escitalopram studies were positive, and 1 was a failed study. Four of the 6 duloxetine studies were positive. Both escitalopram and duloxetine performed better than at least 1 selective serotonin reuptake inhibitor comparator. The safety and tolerability profiles of both drugs are quite benign. The reported incidence of treatment-emergent adverse events was somewhat lower with escitalopram than with duloxetine, with the possible exception of sexual dysfunction. Discontinuations due to adverse events were lower for escitalopram than for duloxetine, although rates were comparable with higher doses of escitalopram (20 mg/day). CONCLUSION: Both escitalopram and duloxetine are useful in the treatment of major depressive disorder.
J Psychosoc Nurs Ment Health Serv. 2003 Dec;41(12):13-8. :ks Physical symptoms comorbid with depression and the new antidepressant duloxetine.
Bailey KP.
Yale University School of Nursing, New Haven, Connecticut, USA.
katharine.bailey@yale.edu
Most general descriptions of depression that date back to Hippocrates, including the DSM-IV, have listed gastrointestinal problems, sleep disturbances, headaches, appetite changes, and aches and pains of a diffuse nature as common features of the disorder. In addition, physical symptoms have a strong association with psychiatric disorders, and the presence of any physical symptom may increase the likelihood of a mood or anxiety disorder by two-fold or three-fold. A growing body of evidence suggests that serotonin and norepinephrine may share neurochemical mechanisms that tie depression and physical symptoms together. Both selective serotonin reuptake inhibitors alone and antidepressant agents that incorporate both serotonin and norepinephrine reuptake inhibition have shown evidence of relieving physical symptoms. Given the additional disease burden caused by physical symptoms in depression, it is vital that antidepressant agents that effectively treat the physical symptoms and chronic pain associated with depression be used
J Clin Psychiatry. 2003 Oct;64(10):1237-44. : Duloxetine in the long-term treatment of major depressive disorder.
Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB.
Lilly Research Laboratories, Eli Lilly Canada, 3650 Danforth Avenue, Scarborough, Ontario, Canada M1N 2E8.
raskin_joel@lilly.com
BACKGROUND: Depression is a chronic recurring disorder and guidelines recommend long-term therapy. This clinical trial evaluated the long-term (1 year) safety and efficacy of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, in patients with DSM-IV major depressive disorder. METHOD: This was an open-label, 52-week, multinational clinical trial in outpatients (age > or = 18 years) who received duloxetine at 80 mg/day (administered 40 mg twice daily) to 120 mg/day (administered 60 mg twice daily) for up to 1 year. RESULTS: A total of 1279 patients had postbaseline data. Of these, 520 were exposed to duloxetine for at least 360 days, yielding approximately 808 patient-years of total exposure. Mean changes in Clinical Global Impressions-Severity of Illness scale (CGI-S) score, 17-item Hamilton Rating Scale for Depression total score and subfactor scores, Beck Depression Inventory-II score, and Sheehan Disability Scale score and mean Patient Global Impression-Improvement scale (PGI-I) scores all showed highly significant (p <.001) improvements at all assessment times. The estimated probabilities of improvement in CGI-S and PGI-I scores at week 1 were 40.4% and 59.2%, respectively, and at week 2 were 70.0% and 78.3%. The estimated probabilities of remission at weeks 6, 28, and 52 were 50.8%, 75.6%, and 81.8%, respectively. Adverse events led to discontinuation in 218 patients (17.0%). The most frequent specific events leading to discontinuation were nausea (1.5%), somnolence (1.4%), vomiting (0.9%), hypomania (0.8%), pregnancy (0.8%), dizziness (0.6%), insomnia (0.6%), and hypertension (0.5%). Treatment-emergent adverse events that were reported by > 10% of patients included nausea, insomnia, headache, somnolence, dry mouth, dizziness, constipation, sweating increase, anxiety, diarrhea, and fatigue. Most events occurred early in the study. Of those events that first occurred or worsened after discontinuation, only dizziness (8.3%) occurred in more than 5% of patients. Mean changes from baseline to last observation for standing and supine pulse were less than 2 b.p.m. Mean changes in blood pressure (< 1.0 mm Hg), corrected QT interval (< 1 msec), and body weight (2.4 kg [5.3 lb]) were not clinically significant. Laboratory analyses varied across visits, and mean changes after 52 weeks were generally close to zero. The incidence of laboratory values above or below normal limits at any time during treatment was low. CONCLUSION: Duloxetine was effective, safe, and well tolerated in the long-term treatment of major depression at a dose of 80 to 120 mg/day in this study.
: Drug Metab Dispos. 2003 Sep;31(9):1142-50. : Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects.
Lantz RJ, Gillespie TA, Rash TJ, Kuo F, Skinner M, Kuan HY, Knadler MP
. Department of Drug Disposition, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 microCi) oral dose of [14C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (+/- S.E.M.) after 312 h was 90.5% (+/-0.4%) with 72.0% (+/-1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [14C]duloxetine administration, Cmax was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).
Prim Care Companion J Clin Psychiatry. 2003 Jun;5(3):118-123. : Antidepressant Use in Chronic Pain Management: Is There Evidence of a Role for Duloxetine?
Leo RJ, Barkin RL.
Department of Psychiatry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo; and the Departments of Anesthesiology, Family Medicine, and Pharmacology, The Rush North Shore Pain Center of Rush Presbyterian St. Luke's Medical Center, Chicago, Ill.
BACKGROUND: Duloxetine is a novel antidepressant that is anticipated to be clinically available soon. It exerts simultaneous noradrenergic and serotonergic neurotransmitter effects. Because of these influences, it is postulated to have a role in management of pain. DATA SOURCES: An Index Medicus search from 1997 to 2003 was conducted using the search terms duloxetine, Cymbalta, and pain. DATA ANALYSIS: Preclinical animal studies suggest that duloxetine may have a direct analgesic role. Premarketing studies have emphasized its utility in alleviating somatic, specifically pain, complaints among patients with major depression. CONCLUSION: Although promising, these results cannot be generalized to patients with pain disorders; the reasons for this are discussed herein. While duloxetine may be useful among somatizing depressed patients and possibly chronic pain patients with comorbid depression, its analgesic role has yet to be elucidated in future research.