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

The development of effective antiemetic prophylaxis is one of the most significant steps forward in the area of supportive care. Fifteen years ago, patients receiving chemotherapy had to face the fact that nausea and vomiting were inevitable adverse effects, which could only be partially prevented by treatment with antiemetics such as dopamine (DA) D2 receptor antagonists and corticosteroids. The first group of drugs specifically developed as antiemetics was the serotonin (5-hydroxytryptamine [5-HT](3)) receptor antagonists. These drugs have dramatically improved prophylaxis of chemotherapy-induced emesis, particularly when used in combination with a corticosteroid. This combination has resulted in a significant decrease in the number of patients vomiting, whereas the improvement in the prophylaxis of nausea has been less successful. Another group of antiemetics, the neurokinin (NK) 1 receptor antagonists, has recently been developed, and the first drug in this class, aprepitant, has been approved by the FDA and the EU authorities. Studies have showed that patients benefit from the use of this drug in combination with standard antiemetic therapy (5-HT 3 receptor antagonist plus a corticosteroid), both in the acute and delayed phase of nausea and vomiting induced by cisplatin-based chemotherapy. This development has not only led to improved efficacy but also to a decreased risk associated with the use of antiemetics. One of the problems with traditional antiemetics, for example, the DA D2 receptor antagonists, is the risk of unpleasant adverse effects including restlessness and dystonic reactions. To avoid these adverse effects, combination with benzodiazepines or antihistamines was necessary, often resulting in sedation. Modern research also includes pharmacogenomic investigations. This has led to speculation about the importance of drug-drug interactions involving antiemetics through competition for metabolism by the cytochrome P450 isoenzymes. The worst possible interaction would be a decrease in the effect of different cytotoxins but there is no evidence that such interactions are of importance in daily clinical practice. Guidelines are useful tools in the optimisation of antiemetic prophylaxis but, unfortunately, implementation of the evidence-based recommendations is far from successful. A prerequisite for further optimisation of antiemetic prophylaxis is updating of the guidelines, including recommendations for the use of NK 1 receptor antagonists (aprepitant), followed by implementation of these recommendations in the clinic. Future research must include 'the difficult trials' focusing on the remaining groups of patients with severe chemotherapy-induced nausea and vomiting, including patients with refractory and breakthrough emesis.
 ...
PMID:Risk-benefit of antiemetics in prevention and treatment of chemotherapy-induced nausea and vomiting. 1515 51

We report a 67-yr-old woman with hepatitis C-related liver cirrhosis and hepatoma who had developed severe bone marrow suppression after taking Cantharanthus roseus as an alternative anticancer treatment. The patient developed severe pancytopenia with initial presentations of vomiting, diarrhea, oral ulcer, and fever about 1 week after taking 5-days' course of Cantharanthus roseus. Bone marrow biopsy showed autolysis, which indicated massive necrosis of the hematopoietic cells. There was no malignant cell infiltration. The patient also had severe gastrointestinal disturbances, bacteremia, urinary tract infection, and impaired renal and liver function. Supportive care with broad-spectrum antibiotics, granulocyte colony-stimulating factor, repeated blood transfusions, and albumin supplement was given. She recovered and was discharged after 48 days hospitalization. Coadministration of Cantharanthus roseus and cisapride was noted, and these two drugs are both substrates of cytochrome P450 3A4 enzymes (CYP 3A4). Because the vinca alkaloids are extensively metabolized by the liver cytochrome P450 enzymes, poor hepatic function and drug-herb interaction might predispose the patient to develop the bone marrow toxicity. This case report demonstrated possible effect of oral dose of vinca alkaloids and also hinted that all the substrates and inhibitors of CYP 3A4 have propensity to interfere with metabolism of vinca alkaloids.
 ...
PMID:Severe bone marrow depression induced by an anticancer herb Cantharanthus roseus. 1546 62

(1) Platinum-based chemotherapy is generally used to treat advanced-stage non small-cell lung cancer (stages III and IV), but has only a modest impact on survival. There is no reference treatment. (2) Gefitinib inhibits the tyrosine kinase activity of the receptor for EGF (epidermal growth factor), which is thought to be involved in tumour growth. It has a temporary licence in France and is used on a named-patient basis, but full marketing authorisation has already been granted in Japan, the United States, and elsewhere. (3) Two double-blind dose-finding studies compared two doses of oral gefitinib monotherapy (250 mg/day and 500 mg/day) in patients in whom at least two lines of chemotherapy had failed. The results were favourable, with a median survival of 6 months and a symptomatic improvement in some patients, but they are undermined by the absence of a placebo group and by major protocol violations. (4) Two double-blind trials, each in more than 1000 patients, showed that gefitinib does not increase the efficacy of first-line platinum combinations. (5) About 15% of patients receiving gefitinib monotherapy in clinical trials stopped taking the treatment because of adverse events. The most frequent were gastrointestinal (diarrhea, nausea, vomiting) and cutaneous (rash, acne, dry skin, pruritus). (6) Interstitial pneumonitis occurred in about 1% of patients, and was fatal in about one-third of cases. (7) Gefitinib is metabolised by the cytochrome P450 isoenzyme CYP3A4, so carries a potentially high risk of interactions. (8) In practice, more thorough assessment of gefitinib is needed to determine whether this new drug is beneficial for patients with non small-cell lung cancer. Marketing authorisation is not currently justified.
 ...
PMID:Gefitinib: new preparation. Non small-cell lung cancer: stricter assessment needed. 1549 96

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.
 ...
PMID:Atazanavir for the treatment of human immunodeficiency virus infection. 1558 41

We describe a 68-year-old male patient, treated with amoxicillin-clavulanic acid for 18 days and oral anticoagulants. He developed a cholestatic hepatitis with conjugated bilirubin of 11 mg/dL and a concomitant overdose of oral anticoagulants (INR 7). Nausea, vomiting, jaundice and large ecchymoses occurred 41 days after treatment with amoxicillin-clavulanic acid; the clinical manifestations resolved within 1 week and the liver tests returned to normal 48 days after therapy withdrawal. The mechanism of the amoxicillin-clavulanate-induced hepatitis is probably immunoallergic; this complication occurs mainly in subjects with a metabolic and/or immunologic idiosyncrasy. The pharmacokinetics of this antibiotic, which is not directly metabolized by cytochrome P450, may be affected by the concomitant use of drugs under cytochrome P450 control. When using amoxicillin-clavulanic acid, one should take into account its potential hepatic toxicity and possible interaction with oral anticoagulants. However, it appears to be crucial to follow the correct indications for both drugs. In fact, in the patient described above amoxicillin-clavulanic acid was wrongly administered as prophylaxis after a cutaneous biopsy of the nose. The same occurred with the oral anticoagulants prescribed to the patient for a single episode of paroxysmal atrial fibrillation which had occurred one year previously.
 ...
PMID:[Amoxicillin-clavulanic acid and oral anticoagulants: a possible dangerous association]. 1567 8

Selective serotonin 5-HT(3) receptor antagonists have proven safe and effective for the management of postoperative nausea and vomiting. Dolasetron, granisetron, ondansetron and tropisetron selectively and competitively bind to 5-HT(3) receptors, blocking serotonin binding at vagal afferents in the gut and in the regions of the CNS involved in emesis, including the chemoreceptor trigger zone and the nucleus tractus solitarii. Despite their shared mechanism of action, 5-HT(3) receptor antagonists have different chemical structures and exhibit differences in receptor binding affinity, dose response and duration of effect. Furthermore, although dolasetron, granisetron, ondansetron and tropisetron are all extensively metabolised by the cytochrome P450 (CYP) system, different components of this system predominate in the metabolism of each of these agents. Hence, although these agents are considered equally effective in the overall population, their pharmacokinetic and pharmacodynamic differences may explain the variability in individual responses to these drugs. This review discusses the pharmacological profiles of dolasetron, granisetron, ondansetron and tropisetron, and the clinical implications of differences in their profiles.
 ...
PMID:Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? 1574 Jan 77

5-HT3-receptor antagonists are the current antiemetic 'gold standard' for chemotherapy- and radiotherapy-induced nausea and vomiting. Interestingly, studies have shown that patients experiencing poor control of acute chemotherapy-induced nausea and vomiting with one antiemetic therapy may respond well to another agent, including a drug of the same class. This review examines pharmacological differences between the 5-HT3-receptor antagonists in order to determine potential reasons for their differing efficacy, particularly in relation to refractory emesis. Differences in drug metabolism by the cytochrome P450 system, inadequate dosing of the respective agents, differences in onset and duration of action, and effects on serotonin release and reuptake are discussed.
 ...
PMID:Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? 1583 53

The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5-3 hours) with an elimination half-life of approximately 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of approximately 40%, and a reliable dose-correspondence of 80 mg/m2 oral form --> 30 mg/m2 i.v. and 60 mg/m2 oral --> 25 mg/m2 i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic-pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m2/week for the first 3 administrations and then increased to 80 mg/m2/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.
 ...
PMID:Oral versus intravenous vinorelbine: clinical safety profile. 1611 53

We investigated the efficacy of granisetron and dolasetron in preventing postoperative nausea and vomiting. Because the metabolism of the various antiemetic 5-hydroxytryptamine type 3 (5-HT3) antagonists involves different isoforms of the hepatic cytochrome P450 system, we examined the relationship between the clinical efficacy of these drugs and polymorphic cytochrome P450 2D6 (CYP2D6) genotype. This prospective, randomized, double-blind study involved 150 adult patients with a moderate to high risk for postoperative nausea and vomiting. All subjects received dexamethasone at induction of anesthesia followed by either 12.5 mg of dolasetron or 1 mg of granisetron. We analyzed the number of complete responders (no vomiting or rescue medication) during the first 24 hours after surgery. CYP2D6 genotyping was performed using a TaqMan real-time polymerase chain reaction. A complete response was more frequent in the granisetron group (54.7%) compared with the dolasetron group (38.7%, P < 0.05). In subjects receiving dolasetron, carriers of the duplication of the CYP2D6 allele predicting ultrarapid metabolizer status had more frequent vomiting episodes (P < 0.05) than patients in the granisetron group. It is postulated that the difference in the antiemetic efficacy between two investigated 5-HT3 receptor antagonists may be associated with differences in the carrier status for the duplication of the CYP2D6 allele.
 ...
PMID:Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype. 1751 73

Chagas' disease (American trypanosomiasis) is an endemic parasitic disease in some areas of Latin America. About 16-18 million persons are infected with the aetiological agent of the disease, Trypanosoma cruzi, and more than 100 million are living at risk of infection. There are different modes of infection: (1) via blood sucking vector insects infected with T. cruzi, accounting for 80-90% of transmission of the disease; (2) via blood transfusion or congenital transmission, accounting for 0.5-8% of transmission; (3) other less common forms of infection, eg, from infected food or drinks or via infected organs used in transplants. The acute phase of the disease can last from weeks to months and typically is asymptomatic or associated with fever and other mild nonspecific manifestations. However, life-threatening myocarditis or meningoencephalitis can occur during the acute phase. The death rate for persons in this phase is about 10%. Approximately 10-50% of the survivors develop chronic Chagas' disease, which is characterized by potentially lethal cardiopathy and megacolon or megaoesophagus. There are two drugs available for the aetiological treatment of Chagas' disease: nifurtimox (Nfx) and benznidazole (Bz). Nfx is a nitrofurane and Bz is a nitroimidazole compound. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs are a major drawback in their use, frequently forcing the physician to stop treatment. The most frequent adverse effects observed in the use of Nfx are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations such as nausea or vomiting, and occasionally intestinal colic and diarrhoea. In the case of Bz, skin manifestations are the most notorious (e.g., hypersensitivity, dermatitis with cutaneous eruptions, generalized oedema, fever, lymphoadenopathy, articular and muscular pain), with depression of bone marrow, thrombocytopenic purpura and agranulocytosis being the more severe manifestations. Experimental toxicity studies with Nfx evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of Bz, deleterious effects were observed in adrenals, colon and oesophagus. Bz also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and its reactive metabolites react with fetal components in vivo. Both drugs exhibited significant mutagenic effects and were shown to be tumorigenic or carcinogenic in some studies. The toxic side effects of both nitroheterocyclic derivatives require enzymatic reduction of their nitro group. Those processes are fundamentally mediated by cytochrome P450 reductase and cytochrome P450. Other enzymes such as xanthine oxidoreductase or aldehyde oxidase may also be involved.
 ...
PMID:Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis). 1693 19


<< Previous 1 2 3 4 5 6 Next >>