Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027497 (nausea)
23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacokinetics and safety of duloxetine were evaluated in a single-blind, placebo-controlled, escalating multiple-dose study in 12 healthy male subjects. In the treatment group (n = 8), duloxetine was administered orally at a starting dose of 20 mg twice daily (bid) and escalated at weekly intervals to 30 mg bid, then to 40 mg bid. The observed plasma concentration-time data at all three dose levels were adequately described by a one-compartment model with a first-order absorption rate constant. The mean oral clearance, apparent volume of distribution, and half-life values were 114 L/h (range: 44 to 218 L/h), 1943 L (range: 803 to 3531 L), and 12.5 h (range: 9.2 to 19.1 h), respectively. Somnolence, nausea, and dry mouth were observed following the initial dose, but they resolved with continuing drug administration. Duloxetine was not associated with clinically significant changes in blood pressure (BP) or heart rate (HR) measured in the standing position. However, in recumbent position, small increases in systolic (< or = 9 mmHg) and diastolic (< or = 5 mmHg) BP and small decreases in HR (< or = 6 beats/min) were observed. Abrupt discontinuation of duloxetine was associated with a small increase in mean HR (< or = 12 beats/min). In 3 subjects, abrupt discontinuation was also associated with transient sleep disturbance. No clinically important changes in electrocardiograms, cardiac intervals, clinical laboratory tests, and neurological functions were observed. These results indicate that duloxetine exhibits linear pharmacokinetics with respect to dose and duration of treatment and that a multiple oral dose regimen starting at 20 mg bid and gradually escalating up to 40 mg bid was generally well tolerated.
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PMID:Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. 1066 22

Lilly is developing duloxetine, a 5-HT and norepinephrine uptake inhibitor as a potential treatment for depression and urinary incontinence. In Japan, it is being jointly developed with Shionogi [187401]. Phase III trials for depression and phase II trials for urinary incontinence are underway in Japan [296442,328887]. Lilly expects to file for depression in 2002 and phase III trials for urinary incontinence are planned to start enrollment by the end of 2000 [358429,370526,373870]. Duloxetine has a half-life of 10 to 15 h in humans, and parameters reach a steady-state after 3 days of daily administration. In a 6-week, open-label study duloxetine was safe and well tolerated in 79 clinically depressed patients. Clinical response occurred in 78% of patients, and remission occurred in 60%. Insomnia and nausea occurred with an incidence of 20% [300881]. Duloxetine may offer advantages over existing antidepressants, such as Lilly's fluoxetine, because of faster recovery and fewer side effects [190226]. In June 2000, Morgan Stanley Dean Witter predicted duloxetine would reach the market in 2002 with annual sales in this year of US $50 million, rising to $200 million in 2005 [373870]. In February 1999, Deutsche Bank predicted Lilly's sales at US $200 million in 2002 rising to $400 million in 2003 [316821]. In May 2000, Deutsche Bank had made further predictions, stating that filing for duloxetine is expected in the fourth quarter of 2001, and peak sales are expected to exceed US $500 million. Also in February 1999, Lehman Brothers predicted the first major launch date (US and ex-US) to be 2002, with the year of peak sales to be 2008 [319225]. In August 1999, this prediction changed, and the expected launch date became 2001, with an 80% probability of reaching the market and sales peaking at US $150 million in 2012 [349228].
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PMID:Duloxetine Eli Lilly & Co. 1124 87

Nutrition support in gastroparesis begins with encouraging smaller volume, low-fat, low-fiber meals and, if necessary, liquid caloric supplements. There should be a low threshold for placing a jejunal feeding tube either by laparoscopy or mini-laparotomy. Parenteral nutrition should be used only briefly during hospitalization and not encouraged or sustained as an outpatient. Metoclopramide is now the prokinetic of choice for patients who can tolerate this agent; subcutaneous administration is an important method that allows for continued guaranteed absorption. Low-dosage erythromycin also has a prokinetic role alone or in combination with metoclopramide. Domperidone, a centrally acting antiemetic and prokinetic, is only be available to US citizens who can access sources in Canada or Mexico. Antiemetics should be used extensively because nausea is a very severe debilitating symptom, which is under-appreciated and under-treated by physicians. We recommend scopolamine patches to gain maximal absorption, in spite of vomiting and unpredictable oral intakes. The 5-hydroxytryptamine-3 (5-HT3) antagonists ondansetron and granisetron are the most powerful agents. Relief bands using the P6 acupuncture point are useful adjunct. Special vigilance should be paid to situations that can undermine medical therapy or result in breakthrough symptoms, such as hyperglycemic events in patients with diabetes, migraine headaches, cyclic nausea and vomiting, menstrual cycles, rumination syndrome (psychogenic vomiting), and elevated herpes simplex titers. Most excitingly, the era of gastric electrical stimulation has arrived for patients not responding to standard medical therapy. The dramatic improvement in nausea and vomiting, as well as a sustained evidence of improved quality of life, gastric emptying, nutritional status, and decreased hospitalizations by this device are documented by long-term follow-up of more than a year for patients in this country and world-wide.
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PMID:Gastric Dysmotility and Gastroparesis. 1146 76

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N = 267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD(17)), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD(17) total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.
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PMID:Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. 1239 7

>55% were observed in two of the studies, while in a third study the probability of remission with duloxetine treatment was nearly three times that observed with placebo (44% versus 16%). Duloxetine also produced significant improvement in painful physical symptoms compared with placebo, in many cases after only 2 weeks of treatment. The discontinuation rate due to adverse events (14.6%) was similar to those observed with selective serotonin reuptake inhibitors. The most frequently reported adverse events were nausea, dry mouth, fatigue, and insomnia. Conclusion. Duloxetine was demonstrated to be safe and effective in the treatment of MDD. The starting dose with the best balance of efficacy and tolerability is 60 mg QD.
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PMID:Duloxetine for the treatment of major depressive disorder. 1285 50

Stress urinary incontinence (SUI) is the accidental leakage of urine associated with physical activities such as running, jumping or lifting or with sneezing and coughing. For many patients it can be a very bothersome symptom, causing social isolation, loss of self-esteem and increased financial outlays. Although there is currently no medication approved worldwide for the treatment of SUI, a variety of off-label agents are sometimes prescribed. Duloxetine (LY-248686; Eli Lilly), a new centrally acting compound with dual activity as a serotonin and noradrenaline re-uptake inhibitor, offers a promising new approach for treatment. Due to its inhibition of presynaptic neuron re-uptake of serotonin and noradrenaline in the sacral spinal cord, duloxetine is believed to increase the strength of urethral sphincter contractions and thereby prevent accidental urine leakage by increasing urethral closure pressure. In three published trials in women with the predominant symptom of SUI, duloxetine significantly reduced the number of incontinence episodes compared to placebo. Adverse events were usually observed early in treatment, were mild-to-moderate in severity and were transient. Nausea was the most common reason for discontinuation.
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PMID:Duloxetine: a serotonin-noradrenaline re-uptake inhibitor for the treatment of stress urinary incontinence. 1294 99

BACKGROUND: Depression is underdiagnosed in the primary care setting. Physical symptoms such as aches, pains, and gastrointestinal disturbance are frequently associated with major depressive disorder (MDD) and are often the presenting symptoms. Duloxetine, a dual-reuptake inhibitor of serotonin and norepinephrine, may have a positive effect on physical symptoms in addition to efficacy in treating emotional symptoms of depression. METHOD: Efficacy was evaluated in 6 double-blind, placebo- and/or active comparator-controlled trials of duloxetine for patients with MDD (DSM-IV criteria). Efficacy in depression was determined primarily using the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Secondary efficacy measures included subscales of the HAM-D-17 and assessment of physical symptoms. Safety evaluations included adverse events, vital signs, laboratory analyses, and electrocardiograms. Safety was evaluated by pooling the data from the MDD trials and a study of duloxetine in nondepressed patients. RESULTS: Duloxetine demonstrated significant differences from placebo on core mood symptoms, physical symptoms (e.g., back pain), and global functioning as early as week 1 of treatment. The estimated probabilities of remission in the studies that demonstrated efficacy ranged from 43% to 57%. The most frequently observed adverse events for duloxetine-treated patients included nausea, dizziness, insomnia, fatigue, and somnolence. Duloxetine did not prolong corrected QT intervals, and the rate of sustained elevations of blood pressure did not differ significantly from placebo. CONCLUSION: In these studies, duloxetine was safe and effective in the treatment of both emotional and physical symptoms of MDD. Based on dose assessments, 60 mg q.d. appears to be the optimum starting and therapeutic dose.
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PMID:Duloxetine: A New Treatment for the Emotional and Physical Symptoms of Depression. 1515 43

Duloxetine is a potent and balanced dual serotonin and norepinephrine reuptake inhibitor (SNRI) that enhances urethral rhabdosphincter activity and bladder capacity in a cat irritated bladder model. Whether this is beneficial in women suffering from stress urinary incontinence (SUI) has been investigated in one phase 2 and three phase 3 placebo-controlled clinical trials with very comparable inclusion and exclusion criteria and outcome variables. In addition, one phase 3 study was performed in women with SUI awaiting incontinence surgery. These trials involved investigational centers in 5 continents: North America, Europe, Australia, South America and Africa. Duloxetine 80 mg per day (40 mg twice daily) decreased the frequency of incontinence episode frequency (IEF) and improved incontinence-related quality of life (I-QOL) independent of baseline incontinence severity and also in patients awaiting surgery. In the trial in patients awaiting surgery, onset of action was closely monitored and all patients who responded to duloxetine did so within 1-2 weeks. The decrease in IEF and improvement in I-QOL were not due to more frequent voiding, as the mean time between voids increased. Nausea was the most common treatment emergent adverse event. This was mostly experienced early after the start of duloxetine (usually within the first few days) and was usually mild or moderate and non-progressive in severity. The majority of patients reporting nausea continued treatment with duloxetine and in most of these patients the nausea resolved within 1 to 4 weeks. It can, therefore, be concluded that duloxetine 40 mg twice daily is a new and promising pharmacological treatment approach for women with SUI.
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PMID:Duloxetine: a new approach for treating stress urinary incontinence. 1530 67

Duloxetine is an orally administered, balanced, dual serotonin and norepinephrine (noradrenaline) reuptake inhibitor that increases neural input to the urethral sphincter, thereby relieving the symptoms of stress urinary incontinence (SUI). Duloxetine 40 mg twice daily for 12 weeks reduced the median incontinence episode frequency (IEF) to a significantly greater extent than placebo in women with predominant symptoms of SUI. In most studies, Incontinence Quality of Life (I-QOL) questionnaire total scores were significantly improved compared with placebo. In a dose-escalation study in women with severe SUI scheduled for continence surgery, duloxetine 80-120 mg/day for 8 weeks significantly reduced IEF and increased I-QOL total scores compared with placebo, and caused 20% of recipients to reconsider their willingness to undergo surgery. Duloxetine or duloxetine plus pelvic floor muscle training (PFMT) were more effective in reducing the median IEF than PFMT alone or no treatment in women with SUI. Mean I-QOL total scores suggested that combination therapy was more effective than either therapy alone. Nausea was the most frequent adverse event and was the main cause for discontinuing duloxetine therapy.
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PMID:Duloxetine: in stress urinary incontinence. 1551 54

The action of domperidone (1 mg/kg, i.p.) on spontaneous behaviour and the emesis and behavioural change induced by apomorphine (0.25 mg/kg, s.c.) were studied in the ferret. Domperidone was inactive to modify spontaneous behaviour but apomorphine-induced emesis and increased locomotor activity (distance travelled and velocity of movement; P<0.05); the emesis, but not the modification of locomotor activity was antagonized significantly (P<0.01) by domperidone. However, apomorphine did not modify significantly other behavioural measures (i.e. lip licking, rearing, burrowing, backward walking, curling-up activity, or defecatory frequency; P>0.05). The action of apomorphine to modify behaviour and its interaction with domperidone in this species is discussed in relation to animal models of nausea.
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PMID:Differential action of domperidone to modify emesis and behaviour induced by apomorphine in the ferret. 1596 78


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