Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Controlled trials in patients with bulimia nervosa have demonstrated efficacy of antidepressant medications with serotonergic function (e.g. fluoxetine) as well as noradrenergic function (e.g. desipramine). Sixteen out-patients with bulimia nervosa according to DSM-IV criteria were treated in a drug surveillance with 100 mg of milnacipran, a specific serotonin and noradrenaline reuptake inhibitor (SNRI). Ten patients completed the 8-week observation period. The reasons for premature attrition were improvement in one patient (no. 12), a generalized exanthema in one patient (no. 7), severe nausea in one patient (no. 8) and non-compliance due to non-drug-related reasons in three patients (no. 1, 2, and 16). An intent-to-treat analysis exhibited a significant reduction in weekly binge eating and vomiting frequency from baseline to the end of treatment. Three patients stopped binge eating and purging completely during the last week of treatment. Furthermore, there was a concomitant decrease of depression ratings (HAMD, BDI). Our preliminary data give rise to the notion that milnacipran may be promising in the treatment of bulimia nervosa.
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PMID:Milnacipran in the treatment of bulimia nervosa: a report of 16 cases. 1265 Sep 49

Anisakis simplex IgE may bring on allergic responses such as angioedema, vomiting, and urticaria from eating seafood, but it is not the only etiology. Induced cholinergic hyperreactivity or adrenergic blockade in the target tissue can cause these diseases nonimmunologically also. Here we studied the effects on normal intestinal motility of brief A. simplex infections and in vitro exposures to the parasite's extract (CE). Each approach was evaluated according to its ability to induce cholinergic hyperreactivity or adrenergic blockade in rat duodenum (RD), jejunum (RJ), and ileum (RI) in vitro. Additionally, bolus propulsion in RD, RJ, and RI was evaluated with time in vivo utilizing animals infected 4 h previously with A. simplex larvae (L3) vs sham animals. Tissues, after inoculation of 1, 5, 10, and 20 L3, exhibited time- and dose-dependent motility changes after carbachol (Ch) and noradrenaline (NA), justifying our using herein rats from the fourth hour of infection with 20 L3. We observed a persistent, yet differential effect of the infection on RD, RJ, and RI responses to Ch or NA. It caused cholinergic (muscarinic) hyperreactivity in RD only, and adrenergic blockade in all other parts, and consequently increased the transit index in RD, not in RJ or RI. In contrast, exposing RD, RJ, and RI to CE persistently increased both parameters, amplitude of twitches and muscular tone, in all, albeit that, here also, responses to Ch and NA were CE dose dependent. Interestingly, sensitivity to CE was in the order RI > RJ > RD, the reverse situation of that observed during active infection. Thus, previously viable A. simplex L3, after digestion, can exert bystander disturbance in autonomic control in the whole intestine. Our findings demonstrate that A. simplex L3, alive or dead, can induce cholinergic hyperactivity and adrenergic blockade in the whole small intestine and, as a consequence, gastrointestinal symptoms. Significantly, they may do so long before parasite-specific IgE is detectably induced or despite the occurrence of such IgE.
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PMID:Altered autonomic control in rat intestine due to both infection with Anisakis simplex and incubation with the parasite's crude extract. 1471 23

Tramadol is a centrally acting analgesic with weak opioid agonist properties, which also has monoaminergic activity, exerted via inhibition of neuronal uptake of serotonin and norepinephrine. Tramadol is generally well tolerated and the most common adverse events are nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Currently it was examined by which principal mechanism tramadol induces oral dryness. The effects of intravenous administration (+/-)-tramadol were studied in rats on the flow of saliva in response to a peripheral cholinergic stimulus or to reflex activation involving the relay of impulses in the central nervous system. In pentobarbitone-anaesthetized rats, the salivary secretion to acetylcholine (0.1-10 micromol/kg IV) was increased by up to 110% by tramadol (1-5 mg/kg IV) and the protein concentration therein by up to 400%. The administration alpha- and beta-adrenoceptor antagonists resulted in almost identical acetylcholine-evoked responses as in the absence of tramadol. The secretory response to the application of citric acid on the tongue of the rat was reduced by 38% and by 64%, respectively, at 5 and 10 mg/kg IV of tramadol (p < 0.05-0.01). Thus, tramadol exerts its principal xerogenic effect by activating inhibitory pathways in the central nervous system and has no anticholinergic effect on the salivary glands at dosages that may be clinically relevant. Furthermore, the tramadol-induced increase of the acetylcholine-evoked secretion occurred at a glandular level and depended most likely on a release of noradrenaline from glandular nerve terminals.
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PMID:The xerogenic potency and mechanism of action of tramadol inhibition of salivary secretion in rats. 1548 38

A clinical study was conducted to investigate the relationship between nausea/emesis after chemotherapy for lung cancer (docetaxel 60 mg/m(2), cisplatin 80 mg/m(2)) and blood serotonin (S), blood catecholamine (adrenaline) (A), noradrenaline (NA) and dopamine (D) in effective and non-effective patients treated with anti-emetic agents. All 37 patients received preventive combination administration of granisetron (GR) 3 mg, methylprednisolone 500 mg and metoclopramide (ME) 40 mg immediately before chemotherapy, followed by GR 3 mg and ME 40 mg on Day 2 and 3. Sixteen patients who were classified as emotionally unstable according to the YG character test additionally received prochlorperazine 15 mg thrice daily starting after their last meal prior to chemotherapy, until nausea/emesis disappeared. Blood concentration was measured on the day before chemotherapy and on Day 2, 4, and 14 after administration of the anticancer agents. As a result, a significant difference was demonstrated for NA on the day before chemotherapy (p<0.05), NA on Day 14 (p<0.01) and D on Day 14 (p<0.01) between effective and non-effective patients receiving anti-emetic treatment. In addition to conventional neurotransmitters S and D, NA is also worthy of attention in connection with nausea/emesis.
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PMID:[Relationship between neurotransmitter blood noradrenalin and nausea/emesis after chemotherapy for lung cancer]. 1683 82

dl-threo-Methylphenidate is a highly efficacious drug for treating attention-deficit hyperactivity disorder (ADHD) that is currently administered as immediate- or controlled-release and osmotically controlled-released formulations. The drug exists as two enantiomers, d-threo-methylphenidate and l-threo-methylphenidate, with the former having been developed as a medication to treat ADHD in its own right. dl-threo-Methylphenidate undergoes enantioselective metabolism in the liver, which results in marked differences in the plasma concentrations of its isomers, depending on the route of administration and formulation. When dl-threo-methylphenidate is orally administered, the plasma concentrations of d-threo-methylphenidate are higher than those of l-threo-methylphenidate. However, with the recently developed methylphenidate transdermal system (MTS), 'first-pass' metabolism is circumvented and, as a consequence, plasma concentrations of d-threo-methylphenidate are consistent with those produced by oral formulations, but the relative concentrations of l-threo-methylphenidate are much higher, i.e. 50-60% of those of d-threo-methylphenidate. In this article, we review the pharmacokinetics and pharmacology of dl-threo-methylphenidate and its isomers to assess the extent to which their mechanism of action as noradrenaline (norepinephrine) and dopamine reuptake inhibitors is responsible for their efficacy and commonly occurring adverse effects. The major findings are that d-threo-methylphenidate and l-threo-methylphenidate share the same pharmacological profile as the parent racemate, i.e. catecholamine-selective reuptake inhibition with higher potency against dopamine versus noradrenaline reuptake in vivo. However, d-threo-methylphenidate is approximately 10-fold more potent than the l-isomer in this regard. For these drugs, their abilities not only to ameliorate the behavioural and cognitive dysfunctions in ADHD, but also to induce the common adverse effects of reduced appetite, nausea/vomiting and stomach ache, are almost certainly due to their ability to potentiate noradrenergic and/or dopaminergic function in the central and peripheral nervous systems. The sympathomimetic actions of ADHD drugs on cardiovascular function are currently an issue of concern. Since noradrenaline reuptake inhibition is the likely mediator for the effects of dl-threo-methylphenidate on blood pressure and heart rate, the more potent d-isomer will therefore be predominantly responsible. Motor and vocal tics are the other important adverse event to be considered in the treatment of ADHD. It is now accepted that tics are a frequently occurring behavioural manifestation of ADHD itself and the evidence for or against their exacerbation by treatment with dl-threo-methylphenidate or other stimulants remains highly contradictory. Focusing on the enantiomers of dl-threo-methylphenidate, it can be concluded that d-threo-methylphenidate, which is the more potent and abundant of the two isomers, is the major contributor of both efficacy and adverse effects, irrespective of the formulation or route of administration of the racemate. Moreover, for the oral, extended-release formulations of dl-threo-methylphenidate, the d-isomer represents the only pharmacologically active moiety when these medications are used in the clinic. With the MTS, plasma concentrations of l-threo-methylphenidate are higher than are achieved using oral formulations, but even in this case, it is likely that the contribution of this enantiomer to the efficacy and adverse effects of the racemate is no greater than 5-10% of the total.
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PMID:Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system. 1695 48

Postoperative pain after laparoscopic cholecystectomy is an ongoing problem. To relieve this pain, practitioners have used many anesthetic and analgesic drugs. This study was undertaken to assess the effects of incisional and intraperitoneal administration of ropivacaine on postoperative pain and stress response in patients undergoing laparoscopic cholecystectomy. In this prospective, single-blinded, randomized study, 45 patients with ASA (American Society of Anesthesiologists) scores I and II who were about to undergo laparoscopic cholecystectomy were divided into 3 groups. After cholecystectomy, a total of 40 mL of 3.75% ropivacaine was administered pre-incisionally and intraperitoneally to patients in group 1 (n=14); pre-incisionally and intraperitoneally to patients in group 2 (n=17); and intraperitoneally and locally at incision sites to patients in group 3 (n=14). Blood levels of epinephrine and norepinephrine were examined preoperatively, 15 min after insufflation, and at the end of the operation. Visual analog pain scale scores and analgesic requirements were used for 24-h postoperative follow-up of pain levels reported by patients. No statistically significant difference was found among the 3 groups with respect to visual analog pain scale scores, total analgesic requirements, and accompanying pain, nausea, and vomiting. The earliest analgesic requirements were seen in group 2 (P<.005), and less shoulder pain was noted in group 3 (P<.005). Norepinephrine and epinephrine levels showed no statistically significant differences between the 3 groups. Administration of ropivacaine preoperatively and postoperatively for laparoscopic cholecystectomy has similar effects on postoperative pain and the stress response of patients.
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PMID:Effects of ropivacaine on pain after laparoscopic cholecystectomy: a prospective, randomized study. 1756 14

The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT3 receptor antagonist, a glucocorticoid, and an NK1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P<0.001) and 61% (P<0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P<0.01) and 66% (P<0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by approximately 70-90% (P<0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P<0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P<0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P<0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P>0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.
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PMID:Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret. 1867 89

Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year.
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PMID:Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. 1944 48

When attention deficit-hyperactivity disorder in children is truly problematic, methylphenidate, an amphetamine, can be tried as a last resort. Methylphenidate has short-term symptomatic efficacy but also many adverse effects, including a risk of sudden death. After having been evaluated, unsuccessfully, in depression, atomoxetine, a noradrenaline reuptake inhibitor, was authorised in some EU member states for use in attention-deficit/hyperactivity disorder. In France it has only received temporary authorisation for prescription on a named-patient basis. Two double-blind trials comparing atomoxetine versus methylphenidate provided somewhat different results, based on a symptom rating scale completed by the investigator after an interview with the parents. In a trial in 516 children treated for 6 weeks, the "response" rate was statistically higher than with methylphenidate (56% versus 45%). In the other trial in 330 children treated for 8 weeks, the response rate was about 80% in both groups. A meta-analysis of 9 placebo-controlled trials in a total of 1828 children showed that atomoxetine was more effective than placebo in the short term. The main adverse effects identified in clinical trials and pharmacovigilance studies conducted in the United Kingdom and the United States were gastrointestinal disorders (abdominal pain, reduced appetite, vomiting, and weight loss) and neuropsychological disorders (drowsiness, irritability, mood swings, aggressive behaviour). A meta-analysis of 12 trials and pharmacovigilance studies showed an increased risk of suicide. Atomoxetine also provokes seizures, arterial hypotension, tachycardia, and hepatic disorders. Little is known about the risk of abuse or dependence, or the long-term efficacy of treatment. Atomoxetine carries a risk of multiple drug interactions due to its metabolism by the cytochrome P450 isoenzyme 2D6 and its inhibitory effect on noradrenaline reuptake. In practice, atomoxetine has a similar safety profile to methylphenidate and is probably less effective. When drug therapy is warranted, it is better to continue to use methylphenidate, despite its adverse effects.
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PMID:Atomoxetine. Attention-deficit/hyperactivity disorder: no better than methylphenidate. 2045 29

Over the past two decades, the clinical management of depression has been revolutionized by the introduction of selective serotonin re-uptake inhibitors and serotonin/noradrenaline re-uptake inhibitors. However, despite this progress, several unmet medical needs remain. These challenges, which collectively represent the next frontier for antidepressant drug discovery, range from improving efficacy in treatment-resistant patients, to accelerating onset of therapeutic activity, to reducing deleterious side effects such as emesis or sexual dysfunction. The present review addresses some of the innovative approaches designed to create novel therapies that improve in one or more of these areas. Additionally, the authors propose that to discover truly novel disease-modifying agents we must improve our appreciation of disease etiology, pathophysiology and genetics. Therefore, while it is still very early in the characterization of these strategies - as well as our general understanding of disease progression - the next several years should allow sufficient time for one (or more) of these approaches to differentiate themselves from current therapies.
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PMID:Innovations in CNS drug discovery: differentiating strategies to treat depression. 2348 32


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