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)

The discovery of SP and its potent biological activities have lead to the discovery of other tachykinins and to receptors for them, including the NK1 receptor. Blockade of the NK1 receptor has a number of potentially beneficial effects in medical care including the management of drug-induced emesis and the treatment of depression. The analgesic potential of NK1 receptor antagonists that, in theory, seemed so promising has not met early expectations. However, there is still reason to predict valuable clinical uses for more potent NK1 receptor antagonists in a variety of medical conditions, including FMS.
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PMID:The promise of substance P inhibitors in fibromyalgia. 1212 21

SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).
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PMID:Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. 1223 19

PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.
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PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. 1280 93

The recombinant, humanized monoclonal antibody Herceptin is administered as an initial 4 mg/kg i.v. infusion over 90 min, followed by weekly 2 mg/kg i.v. infusions over 30 min. In pivotal clinical trials Herceptin, both as a single agent and in combination with chemotherapy, was found to produce a significant survival benefit in HER2-positive metastatic breast cancer patients. Importantly, Herceptin was well tolerated and was not associated with a poor side-effect profile, producing mainly mild to moderate side-effects. These were generally associated with the initial infusion. The incidence of adverse events was low with Herceptin therapy and severe vomiting and alopecia, typical of many chemotherapy treatment regimens, were not experienced by patients in the trials. Cardiac dysfunction was the most significant Herceptin-related adverse event but could, in most cases, be managed using standard therapy. The favourable adverse event profile seen with Herceptin is reflected in the quality of life (QoL) data. The health-related QoL of patients receiving Herceptin therapy alone or in combination with chemotherapy was found to be maintained. Previous studies have noted a deterioration of health-related QoL in patients treated with chemotherapy only. Thus, as well as providing significant survival benefit, Herceptin therapy improves patient well being.
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PMID:Anti-HER2 therapy: how to use Herceptin in clinical practice. 1284 15

Despite the widespread use of trastuzumab in the management of patients with HER2-overexpressing metastatic breast cancer, its optimal duration of administration is unknown. We retrospectively reviewed the medical records of 80 such patients who received trastuzumab monotherapy or combination chemotherapy beyond disease progression in order to register their clinical course. Median age of the patients was 54 years. Ninety-one percent had 3+ HER2 overexpression and 9% had 2+ HER2 overexpression. Fifty-six percent of patients had previously been treated with chemotherapy for advanced disease. The most commonly used combinations in first- and second-line treatments were trastuzumab with paclitaxel and trastuzumab with vinorelbine, respectively. In total, 32 responses were observed, most of them during the second or third line of treatment. Severe toxicities frequently seen (in = 5% of patients) were neutropenia (25%), thrombocytopenia (11.5%), infection (10%), peripheral neuropathy (9%), nausea/vomiting (6%), stomatitis (6%), diarrhea (6%), constipation (6%), edema (6%), and myalgias/arthralgias (5%). Median survival from diagnosis of advanced disease was 43.4 months (range, 6.4-91.7+), whereas median survival from disease progression after trastuzumab administration was 22.2 months (range, 0.01-32.9+). In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic breast cancer is feasible and safe. Randomized studies are warranted.
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PMID:Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the hellenic cooperative oncology group. 1286 40

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplasms. Loss in Rb function occurs by the hyperactivation of the cyclin-dependent kinases (cdk's). Therefore, modulation of cdk's may have an important use for the therapy and prevention of human neoplasms. Efforts to obtain small-molecule cdk modulators yielded two classes of modulators: direct and indirect modulators. Direct cdk modulators are small molecules that specifically target the ATP binding site of cdk's. Examples for this group include flavopiridol, roscovitine and BMS-387032. In contrast, indirect cdk modulators affect cdk function due to modulation of upstream pathways required for cdk activation. Some examples include perifosine, lovastatin, and UCN-01. The first example of a direct small-molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. Clinical trials with this agent were performed with at least three different schedules of administration: 1-, 24- and 72-h infusions. The main toxicities for infusions >/=24-h are secretory diarrhea and proinflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. A phase II trial of patients with advanced non-small-cell lung carcinoma using the 72-h infusion every 2 weeks was recently completed. The median overall survival for the 20 patients who received treatment was 7.5 months, a survival similar to that obtained in a randomized trial of four chemotherapy regimens containing platinum analogues in combination with taxanes or gemcitabine, or with gefitinib, a recently approved EGFR inhibitor for the treatment of advanced lung cancer. Based on these encouraging results, a phase III trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small-molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca(2+)-dependent PKCs, promotes apoptosis, arrests cell cycle progression at G(1)/S, and abrogates checkpoints upon DNA damage. The first phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72-h continuous infusion every 4 weeks (in second and subsequent cycles UCN-01 is administered as a 36-h infusion). Other shorter schedules (i.e. 3 h) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia, and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, phase I trials with two novel small-molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability. In summary, novel small-molecule cdk modulators are being tested in the clinic with interesting results. Although these small molecules are directed towards a very prevalent cause of carcinogenesis, we need to test them in advanced clinical trials to determine the future of this class of agents for the prevention and therapy of human malignancies.
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PMID:Small-molecule cyclin-dependent kinase modulators. 1452 86

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300-1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration-time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses > or = 750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.
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PMID:Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. 1593 65

Staphylococcal enterotoxin (SE) activities remain after boiling or treating with proteases. The main symptoms such as vomiting and diarrhea, are caused by the ingestion of SEs. Among SEs, SEA has been reported to be the major and most toxic protein. A highly specific and simple assay system is required to diagnose staphylococcal food poisoning. Therefore, the development of a suitable assay system is strongly anticipated. In this study, we have established a highly specific and sensitive avidin-biotin sandwich ELISA (ABS-ELISA) system for SEA, SEB, and SEC1 using newly-developed monoclonal antibodies. The linearity of these systems obtained was in the range of 0.78-25 ng/ml for each SE, and furthermore, the lower concentrations of SEs could also be detected. The recoveries of SEs from murine serum, skim milk solution, and raw milk were found to be over 90%, suggesting that our systems could detect SEs without any interventions, such as these from milk or serum proteins. We were also able to quantify SEs in 22 specimens of culture supernatants of S. aureus isolated in past occurrences. Our established system should be very useful not only in the clinical field but also in various fields of investigation because of its quantifi-cation and simplicity in detecting SEs.
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PMID:Establishment of highly specific and quantitative immunoassay systems for staphylococcal enterotoxin A, B, and C using newly-developed monoclonal antibodies. 1603 1

The occurrence of Staphylococcus aureus strains producing enterotoxins of types SEA and SEB, which isolated from patients of different profile and caused the infectious process accompanied by pronounced intoxication without vomiting and enteric disturbances, was determined by means of the indirect hemagglutination test. The collection included 28 strains isolated in sepsis, 38 strains isolated in pneumonia, 57 strains isolated from patients with burns and 23, from the hands and nasopharynx of the medical staff. Among the staphylococcal strains isolated in sepsis, 75.6% synthesized SEA and 5.4%, SEB. The occurrence of SEA- and SEB-positive strains isolated in pneumonia was, respectively, 42.1% and 2.6%. From patients with burns SEA-positive staphylococci were mainly isolated (92.9%). Only 3% of the cultures isolated in wound infections produced SEA. From the medical staff, 13.4% of SEA-positive strains and 17.3% of SEB-positive strains were isolated. The data obtained from this study indicate the expediency of the determination of the enterotoxigenic properties of S. aureus clinical isolates in medical institutions for prophylactic measures with a view to the prevention of the spread of pathogenic clones.
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PMID:[Isolation rate of enterotoxigenic staphylococci in patients with sepsis, pneumonia and burns]. 1627 24


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