Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Duloxetine: a serotonin-noradrenaline re-uptake inhibitor for the treatment of stress urinary incontinence. 1294 99

The serotonin (5-hydroxytryptamine [5-HT]) and noradrenalin (NA) reuptake inhibitor duloxetine is currently the only widely approved pharmacological treatment option for women with stress urinary incontinence (SUI). The rationale for employing duloxetine in SUI is based on the role of 5-HT and NA in the neurological control of the lower urinary tract. Animal studies have shown that duloxetine increases the concentration of 5-HT and NA in the sacral spinal cord, thereby facilitating an increased activity of the external urethral sphincter (rhabdosphincter) and preventing urine leakage during the storage phase of the micturition cycle. Importantly, 5-HT and NA exert only a modulatory effect as they are not able to directly excite motor neurons. Glutamate is the key descending neurotransmitter and can be considered as the "on/off" switch for micturition. In the absence of glutamate, no rhabdosphincter activity is observed, irrespective of the presence of 5-HT and NA. Hence, duloxetine enhances sphincter activity during urine storage when glutamate is released but allows complete relaxation of the rhabdosphincter once glutamate release is inhibited during the voiding phase. The efficacy of duloxetine for treating women with SUI, as shown in several double-blind, placebo-controlled randomised clinical trials, has suggested a similar mode of action, although no direct evidence for this pathway in humans was available until recently. Two recent studies provide support for duloxetine's mechanism of action in humans. Duloxetine was shown to have a significant effect on the excitability of pudendal motor neurons and on sphincter contractility in healthy women. In contrast, no relevant effect was observed on urethral resting tone. Another study reported important increases in Valsalva leak point pressure and in the rhabdosphincter electrical activity at rest and with coughing in women with SUI who responded to duloxetine. These studies support the hypothesis that duloxetine in women with SUI enhances urethral closure through neuromodulation of the rhabdosphincter.
 ...
PMID:What do we know about duloxetine's mode of action? Evidence from animals to humans. 1652 63

Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the United States. There is currently no globally approved pharmacological drug for the treatment of patients with SUI. Therefore, a new pharmacological treatment option is required. TAS-303 [4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-day7 )acetate hydrochloride] is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters. In this report, we describe the pharmacological properties of TAS-303 and its effects on urethral function, using preclinical in vitro and in vivo studies. Radioligand-binding studies showed that TAS-303 selectively and potently inhibited [3H]norepinephrine binding to the human NET. Oral administration of TAS-303 (3 mg/kg) significantly increased norepinephrine levels in the plasma, whereas it did not significantly affect epinephrine, dopamine, and serotonin levels. TAS-303 (0.3, 1, and 3 mg/kg) dose-dependently increased basal urethral pressure in normal rats and leak point pressure in vaginal distention rats, exhibiting a maximal effect comparable to duloxetine. In the forced swimming test, TAS-303 (100 mg/kg) showed no significant effects on immobility time in rats, raising the possibility that this agent would have minimal central nervous system side effects at an effective dose for urethral function. These results demonstrate that TAS-303 has therapeutic potential for the treatment of patients with SUI.
 ...
PMID:TAS-303, a Novel Selective Norepinephrine Reuptake Inhibitor that Increases Urethral Pressure in Rats, Indicating Its Potential as a Therapeutic Agent for Stress Urinary Incontinence. 2987 27