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:C0042963 (vomiting)
31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Little information exists on the functional impact of effective antiemetic protection. In the present study, the Functional Living Index-Emesis (FLIE), was used to assess patient-reported impact of chemotherapy-induced nausea and vomiting (CINV) after administration of a new NK-1 receptor antagonist (aprepitant). Cisplatin-treated patients in a double-blind randomised trial received either aprepitant+dexamethasone+ondansetron on day 1 and aprepitant+dexamethasone on days 2-5 or standard antiemetic therapy (dexamethasone and ondansetron on day 1 and dexamethasone on days 2-5). Emetic events, nausea ratings and rescue medications were recorded in a 5-day diary and the FLIE was completed on day 6. Compared with standard therapy, significantly more patients treated with the high dose aprepitant regimen achieved a Complete Response (71 vs 44%, P<0.001) and also reported no impact on daily life as indicated by the FLIE total score (84 vs 66%, P<0.01). Use of the FLIE demonstrated that improved control of emesis was highly effective in reducing the impact of CINV on patients' daily lives.
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PMID:Functional relevance of antiemetic control. Experience using the FLIE questionnaire in a randomised study of the NK-1 antagonist aprepitant. 1282 42

The role of peptides as signalling molecules in the nervous system has been studied for more than 30 years. Neuropeptides and their G-protein-coupled receptors are widely distributed throughout the body and they commonly occur with, and are complementary to, classic neurotransmitters. The functions of neuropeptides range from neurotransmitter to growth factor. They are present in glial cells, are hormones in the endocrine system, and are messengers in the immune system. Much evidence indicates that neuropeptides are of particular importance when the nervous system is challenged (eg, by stress, injury, or drug abuse). These features and the large number of neuropeptides and neuropeptide receptors provide many opportunities for the discovery of new drug targets for the treatment of nervous-system disorders. In fact, receptor-subtype-selective antagonists and agonists have been developed, and recently a substance P receptor (neurokinin 1) antagonist has been shown to have clinical efficacy in the treatment of major depression and chemotherapy-induced emesis. Several other neuropeptide receptor ligands are in clinical trials for various indications.
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PMID:Neuropeptides: opportunities for drug discovery. 1287 34

The anti-emetic activity of selective NK-1 receptor antagonism is well established. However, little is known of the possibility that other NK receptors might also be involved in the emetic reflex. Given the reported location of NK-3 receptors within the rat brainstem vagal motor and sensory nuclei, we investigated the ability of SB-222200, a brain-penetrant NK-3 receptor antagonist, to interfere with emesis evoked in ferrets by the emetogenic cytotoxic agent cisplatin. In contrast to control anti-emetic experiments using the 5-HT3 receptor antagonist ondansetron, SB-222200 was found to have no effects on cisplatin-induced vomiting or on the associated reductions in feeding and drinking behaviors at any dose tested. We suggest that if NK-3 receptors are involved in the mechanisms of cisplatin-induced nausea and vomiting, they play only a minor role, relative to the major anti-emetic activity exhibited by 5-HT3 or NK-1 receptor antagonism.
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PMID:Effect of a selective and potent central nervous system penetrant, neurokinin-3 receptor antagonist (SB-222200), on cisplatin-induced emesis in the ferret. 1569 64

Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. 'analgesic tolerance'. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.
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PMID:Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? 1621 2

In advanced stages of polycystic liver disease, often associated with polycystic kidney disease, a curative therapy is liver or combined liver-kidney transplantation. However, little is known about long-term outcome and quality of life. Between 1990 and 2003, 36 patients (32 female, 4 male) with polycystic liver or combined liver-kidney disease underwent liver (n = 21) or liver-kidney (n = 15) transplantation at our center. Main indications for liver transplantation were cachexia, muscle atrophy, loss of weight, recurrent cyst infections, portal hypertension, and ascites. Apart from clinical parameters, 2 anonymous questionnaires (standard short form 36 and self-designed) addressing quality of life and social status were evaluated. Five patients (14 %) died due to sepsis or myocardial infarction with pneumonia, all within 61 days after transplantation. The follow-up time of the remaining 31 patients ranged from 5 to 156 months, with a mean of 62 months. Of the 23 (74%) answered the questionnaires, 91% of patients felt "much better" or "better," only 9% felt "worse" than before, and 52% of patients participated in sports regularly. Fatigue, physical fitness, loss of appetite, and vomiting improved significantly after transplantation. Physical attractiveness and interest in sex increased as well. Professional occupation did not change for 71% of patients. Family situation before and after transplantation changed in 1 case only. Finally, 78% of patients said they would opt for transplantation again, while 17% were undecided; 1 patient would not repeat transplantation. In conclusion, patients with advanced polycystic liver or polycystic liver-kidney disease have an excellent survival rate and an improved quality of life after liver or combined liver-kidney transplantation.
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PMID:Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation. 1686 56

The present study characterizes the safety, pharmacokinetics, and anti-emetic effects of the selective NK-1 receptor antagonist maropitant in the cat. Safety of maropitant was determined following 15 days of subcutaneous (SC) administration at 0.5-5 mg/kg. Maropitant was well tolerated in cats at doses that exceeded the efficacious anti-emetic dose range of the drug by at least a factor of 10 and adverse clinical signs or pathological safety findings were not noted at any dose.The pharmacokinetics of maropitant in cats were determined following single dose oral (PO), intravenous (IV) and SC administration. Maropitant had a terminal half-life of 13-17 h and a bioavailability of 50 and 117% when administered PO and SC, respectively. Efficacy was determined against emesis induced either by xylazine or by motion. A dosage of 1 mg/kg maropitant administered IV, SC or PO prevented emesis elicited by xylazine. The compound had good oral antiemetic activity and a long (24 h) duration of action. Maropitant (1.0 mg/kg) was highly effective in preventing motion-induced emesis in cats. These studies indicate that the NK-1 receptor antagonist maropitant is well tolerated, safe and has excellent anti-emetic properties in cats.
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PMID:Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia) for the prevention of emesis and motion sickness in cats. 1847 Nov 43

Neurokinin-1 (NK-1) receptor antagonists are a new class of antiemetic agents that have activity in controlling cisplatin-induced acute and delayed emesis. Preclinical data in animal models show that the NK-1 receptor antagonists have broad antiemetic activity. The NK-1 receptor antagonists have activity in controlling emesis induced by peripherally acting and centrally acting emetogens, suggesting a mechanism of action at multiple sites. The effects at central and peripheral sites to control acute and delayed emesis cannot be determined at this time based on available studies. When added to a standard regimen of a 5-hydroxytryptamine-3 (5- HT3) receptor antagonist and dexamethasone, the NK-1 receptor antagonists improve control of acute emesis. The NK-1 receptor antagonists improve delayed emesis compared with placebo, and when used in combination with dexamethasone, compared with dexamethasone alone. Acute and delayed nausea may also be improved by the NK-1 receptor antagonists when they are used in combination with a 5-HT3 receptor antagonist and dexamethasone prechemotherapy or with daily dosing for 5 days after chemotherapy. The current data suggest that the mechanism of action of the NK-1 receptor antagonists appears to be different from that of the 5-HT3 receptor antagonists. Future studies may consider using NK-1 receptor antagonists with moderately emetogenic chemotherapy as well as bone marrow transplantation.
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PMID:Inhibiting substance p pathway for prevention of chemotherapy-induced emesis: preclinical data, clinical trials of neurokinin-1 receptor antagonists. 1862 85

Despite significant advances in supportive care in oncology, many patients with cancer still experience chemotherapy- induced nausea and vomiting (CINV). Historically, there were only 3 neurotransmitter receptors (dopamine D2, cannabinoid- 1, and 5-hydroxytryptamine-3) that were the known targets for antiemetic therapy. Major advances in the management of chemotherapy-induced emesis were seen with the introduction of 5-hydroxytryptamine-3 receptor antagonists, which include palonosetron, ondansetron, tropisetron, dolasetron, and granisetron. However, recently, selective inhibitors of substance P have shown promising activity in the management of CINV in patients with cancer. Substance P mediates a number of biologic effects by binding to a specific neuroreceptor, neurokinin-1 (NK-1). Among the NK-1 receptor antagonists, aprepitant has been approved for the treatment of CINV. Currently, several other NK-1 receptor antagonists, including casopitant, vestipitant, netupitant, and SCH619734, are undergoing clinical evaluation for the prevention of CINV in patients with a variety of malignancies. The clinical potential of these novel NK-1 receptor antagonists and their respective ongoing clinical trials for the management of chemotherapy-induced emesis are discussed briefly herein.
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PMID:Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. 1863 87

This multicenter study was intended to validate the French version of the M. D. Anderson Symptom Inventory (MDASI-Fr) in French cancer patients (n=162) with solid tumors or hematological malignancies. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used as a part of the validation. Factor analysis showed three underlying constructs for symptom items: general symptoms (pain, fatigue, disturbed sleep, shortness of breath, drowsiness, dry mouth, and numbness or tingling items); emotional and cognitive components (distress, sadness, and remembering items); and a gastrointestinal component (nausea, vomiting, and lack of appetite items), with Cronbach's alphas of 0.79, 0.73, and 0.71, respectively. Convergent validity was established by comparing MDASI-Fr items with the EORTC QLQ-C30 scale and the Brief Pain Inventory (BPI). Overall, the 19-item MDASI-Fr score correlated well with the QLQ-C30 global health status, and the pain item of the MDASI-Fr was highly correlated with the short form of the BPI. The most prevalent symptoms were fatigue, distress, dry mouth, and pain. Twenty-five percent of patients reported moderate or severe pain (numeric rating scale >4 on 0-10 severity ratings). Physician ratings of global change on a second visit were significantly associated with changes in patient ratings on the MDASI-Fr, supporting the sensitivity of the measure. Symptoms interfered most with work and general activity. The MDASI-Fr is a valid and reliable tool for measuring symptom severity and interference in French cancer patients.
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PMID:Cancer-related symptom assessment in France: validation of the French M. D. Anderson Symptom Inventory. 2041 59

Palonosetron is the only 5-HT(3) receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT(3) cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT(3) receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.
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PMID:The antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses in vitro and in vivo. 2072 84


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