Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixty-nine patients with malignant tumors receiving cancer chemotherapy, 90% including cis-platinum, were evaluated in a randomized crossover study for the antiemetic efficacy and the side effects of two antiemetic regimens: chlorpromazine (CPM) 2.5 mg/kg in 5 doses plus dexamethasone (DXM) 0.2 mg/kg in 2 doses, and high-dose metoclopramide (HD-MCP) 10 mg/kg in 5 doses plus the same dose of DXM. In 69% of 173 courses of chemotherapy, antiemetic response was achieved, and in 26% emesis was completely prevented. There was no statistical difference in the response to the antiemetic regimens, but 65% of the patients who completed 3 courses of chemotherapy preferred HD-MCP plus DXM. The main side effects of the treatment were drowsiness, nervousness, diarrhea and extrapyramidal reactions. HD-MCP plus DXM is recommended as a first line antiemetic treatment in patients receiving cancer chemotherapy. Patients resistant to this treatment should receive CPM plus DXM treatment.
 ...
PMID:Chlorpromazine and dexamethasone versus high-dose metoclopramide and dexamethasone in patients receiving cancer chemotherapy, particularly cis-platinum: a prospective randomized crossover study. 265 92

Forty-six outpatients with breast cancer who had experienced severe emesis as a result of chemotherapy were evaluated for the antiemetic efficacy of high-dose metoclopramide (HD-MCP) and dexamethasone (DXM). Chemotherapy consisted of: cyclophosphamide 600, methotrexate 40 and 5-fluorouracil 600 mg/m2 (CMF) given intravenously every 3 weeks. The dosage of antiemetic drugs was MCP 2 mg/kg and DXM 0.2 mg/kg given by slow intravenous drip 0.5 h before the administration of chemotherapy. 138 courses of combined chemotherapy--HD-MCP and DXM--were administered, with a mean of 3 courses and a range of 1-10 courses per patient. Complete protection--no nausea and no vomiting--was achieved in 17.7% of the courses. Partial protection--no vomiting with mild nausea or 1-3 episodes of vomiting--in 45.3% of the courses. The total antiemetic efficacy was 63%. The most common side effects were: drowsiness, dry mouth, restlessness and diarrhea. Sixteen patients (35%) refused to continue the antiemetic regimen because of the side effects. HD-MCP and DXM have antiemetic efficacy, but because of these side effects, further studies are required to determine the optimal dose of each of these drugs.
 ...
PMID:High-dose metoclopramide and dexamethasone as an antiemetic in outpatients receiving chemotherapy for breast cancer. Second study. 361 13

Twenty-six patients with breast carcinoma who experienced severe emesis due to chemotherapy were evaluated for the antiemetic efficacy of high-dose metoclopramide (HD-MCP) and dexamethasone (DXM). Most of the patients received the CMF (cyclophosphamide, methotrexate and 5-fluorouracil) combination chemotherapy. The MCP and DXM dosage were: 2 X 2 mg/kg and 2 X 0.2 mg/kg, respectively. In 41% of eighty evaluable courses, nausea and vomiting were eliminated altogether. The common side effects were: drowsiness, restlessness and diarrhea. HD-MCP and DXM are recommended in modified dose for preventing CMF chemotherapy induced emesis.
 ...
PMID:High-dose metoclopramide and dexamethasone as an antiemetic in chemotherapy of breast cancer. 375 27

A randomized clinical trial was carried out to compare a locally available maize-cowpea-palm oil diet (group MCP) with a commercially produced lactose-free, soy protein isolate formula (group SF) for the dietary management of 69 Nigerian boys, 6-24 months of age, hospitalized for acute, watery diarrhea. Although the treatment groups were generally similar initially, the children in group SF had slightly lower mean weight-for-age z scores (p = 0.08), lower serum bicarbonate levels (p = 0.04) and greater stool outputs during the period of rehydration before the diets were initiated (p = 0.01). Rates of treatment failure in group MCP (5.7%) and group SF (8.8%) were similar (p = 0.67). There were no significant differences in the adjusted mean stool outputs by study group on days 1-5, but the children in group SF had slightly lower fecal weights on day 6 (p = 0.05). Children in group MCP had a substantially reduced duration of liquid stool excretion (estimated median duration 42 h versus 140 h; p < 0.001). On the other hand, children in group SF consumed considerably more of their diet, had greater net absorption of macronutrients and greater rates of weight gain than those in group MCP. We conclude that children can safely consume the MCP diet during acute, watery diarrhea without increasing their risk of treatment failure or augmenting stool output. However, the diet may not be adequate as a sole source of nutrients beyond the period of acute illness.
 ...
PMID:Evaluation of a maize-cowpea-palm oil diet for the dietary management of Nigerian children with acute, watery diarrhea. 798 59

(1) First-line treatment of multiple myeloma depends first and foremost on the patient's age. There is no standard treatment for relapses and the median survival time after the first relapse is only 12 to 15 months. (2) Bortezomib, a cytotoxic agent, inhibits the 26S proteasome involved in protein breakdown in mammalian cells. It is licensed for use in myeloma after multiple treatment failure. (3) Three dose-finding studies showed some effects of 1 mg/m2 and 1.3 mg/m2 bortezomib administered twice a week for two weeks, with each course followed by a 10-day treatment-free period. It is not known whether 1.3 mg/m2 is more effective than 1 mg/m2. (4) In a non comparative trial that included 202 patients with multidrug-resistant myeloma, progression-free survival time increased to a median of 6.6 months (compared to 3.3 months after previous relapses), and the median overall survival time was 7 months in the 75% of patients who did not respond and more than 15 months in the 25% of responders. However, given the heterogeneous nature of the study population the evidence from this trial is rather weak. (5) An unblinded comparative trial including 54 patients failed to show whether bortezomib 1.3 mg/m2 was more effective than bortezomib 1 mg/m2 in terms of clinical outcome. Another comparative trial including 669 patients indicated that bortezomib was more effective than dexamethasone in terms of the median time to disease progression (5.7 months versus 3.6 months). (6) Animal studies indicate that bortezomib is cardiotoxic and neurotoxic, and that the interval between the maximal tolerated dose and the fatal dose is very small. Experience with bortezomib use is too limited to know the possible clinical repercussions of these experimental findings. (7) Adverse effects were frequent and varied in clinical trials. They included fatigue, nausea and vomiting, diarrhea, anemia, thrombocytopenia and peripheral neuropathies. They affected 30% to 60% of patients overall, and were severe in about 10% to 20% of patients. Other adverse effects included hypotension, fever, headache, pain and dehydration. (8) Bortezomib is metabolised by cytochrome P 450 isoenzyme 3A4, and this implies a high risk of drug-drug interactions. (9) Each vial of bortezomib contains more of the drug than is needed for one injection. This is not only wasteful, but also carries a risk of overdosing, with potentially serious consequences, should the entire contents be injected by mistake. (10) Bortezomib may be used as a last resort in some patients with multiple myeloma, but the individual risk-benefit balance must be carefully weighed in each case.
 ...
PMID:Bortezomib: new drug. A last resort in myeloma: modest efficacy, major risks. 1598 89

In secretory epithelia, activation of PKC by phorbol ester and carbachol negatively regulates Cl(-) secretion, the transport event of secretory diarrhea. Previous studies have implicated the basolateral Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) as a target of PKC-dependent inhibition of Cl(-) secretion. In the present study, we examined the regulation of surface expression of NKCC1 in response to the activation of PKC. Treatment of confluent T84 intestinal epithelial cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA) reduced the amount of NKCC1 accessible to basolateral surface biotinylation. Loss of cell surface NKCC1 was due to internalization as shown by 1) the resistance of biotinylated NKCC1 to surface biotin stripping after incubation with PMA and 2) indirect immunofluorescent labeling. PMA-induced internalization of NKCC1 is dependent on the epsilon-isoform of PKC as determined on the basis of sensitivity to a panel of PKC inhibitors. The effect of PMA on surface expression of NKCC1 was specific because PMA did not significantly alter the amount of Na(+)-K(+)-ATPase or E-cadherin available for surface biotinylation. After extended PMA exposure (>2 h), NKCC1 became degraded in a proteasome-dependent fashion. Like PMA, carbachol reduced the amount of NKCC1 accessible to basolateral surface biotinylation in a PKC-epsilon-dependent manner. However, long-term exposure to carbachol did not result in degradation of NKCC1; rather, NKCC1 that was internalized after exposure to carbachol was recycled back to the cell membrane. PKC-epsilon-dependent alteration of NKCC1 surface expression represents a novel mechanism for regulating Cl(-) secretion.
 ...
PMID:Dynamic regulation of Na(+)-K(+)-2Cl(-) cotransporter surface expression by PKC-{epsilon} in Cl(-)--secretory epithelia. 1600 Jun 38

HEMOLYTIC UREMIC SYNDROME POST-PARTUM: We describe a case of a 37-year-old woman admitted for severe renal failure to our hospital immediately after the delivery by caesarean section of twins. She had anuria, anemia, and moderate thrombocytopenia. A diagnosis of hemolytic-uremic syndrome was made. Plasma exchange was started, substitution was performed with fresh frozen plasma and eight consecutive plasmapheresis sessions were given. She received hydrocortisone and ACE inhibitors. After about fifteen days from the beginning of the illness, signs of active haemolysis disappeared and renal function was partially recovered. A genetic study demonstrated the absence of HF1 and MCP mutations but a polymorphic variant of the HF1 gene (C-257T promoter region). This polymorphism is strongly associated with non-diarrhoea-HUS (D-HUS). Post-partum HUS is quite a rare syndrome and has a poor outcome; however prompt diagnosis and efficacious therapy could save lives without clinical consequences. The excellent outcome of this patient seems to corroborate this concept.
 ...
PMID:A post-partum hemolytic-uremic-like-syndrome in a patient with pre-eclampsia: description of a clinical case. 1642 9

(1) When multiple myeloma relapses more than one year after initial treatment, the median survival time is only 12 to 15 months. (2) Bortezomib is a cytotoxic agent that inhibits the 26S proteasome, a complex involved in intracellular protein breakdown in mammals. Bortezomib was initially licensed for the treatment of myeloma after multiple treatment failure; its indications were subsequently modified to include second-line treatment. (3) Second-line bortezomib therapy has not been compared with haematopoietic stem cell grafting, a treatment with documented efficacy. (4) An unblinded comparative trial involving 54 patients requiring second-line treatment showed that bortezomib at a dose of 1.3 mg/m to the 2nd power (twice a week for two weeks, followed by a 10 day rest period) was significantly more effective than a dose of 1 mg/m to the 2nd power in terms of the median survival time (not determined in the 1.3 mg group, versus 26.7 months in the 1 mg group) and the median time to disease progression (11.7 versus 4.2 months). (5) Among 251 patients in whom first-line treatment had failed, bortezomib was significantly more effective than dexamethasone: the one-year survival rate was 80% versus 66% on dexamethasone, and the progression-free survival time was 6.2 months versus 3.5 months. (6) Adverse effects occurred in 30% to 60% of patients enrolled in clinical trials, and were severe in about 10% to 20% of patients. They mainly included fatigue, nausea and vomiting, diarrhoea, anaemia, thrombocytopenia, and peripheral neuropathy. Animal studies indicated a possible risk of cardiotoxicity, and cases of cardiac arrhythmias and conduction disorders were observed in clinical trials. (7) Bortezomib is metabolised by the cytochrome P450 isoenzyme CYP3A4, with a high risk of interactions. (8) The vials contain an excessive amount of this costly drug, creating a risk of inadvertent overdose and leading to unnecessary waste. (9) In practice, bortezomib is an alternative to steroid therapy for patients with multiple myeloma in whom first-line treatment has failed and who do not qualify for stem cell grafting. The choice of treatment must be discussed with the patient, after providing thorough information on the likely benefits and risks
 ...
PMID:Bortezomib: new indication. Second-line treatment of myeloma: limited efficacy, major risks. 1676 98

Defective control of the alternative route of the complement system is an important cause of the non-diarrhoea haemolytic uraemic syndrome (HUS). On the endothelial surface, mutations in HF1, MCP and IF predispose to development ofHUS. Uncontrolled complement activation on the surface of endothelial cells will damage these cells extensively. Plasmapheresis can be an effective, although temporary, treatment for mutations in HF1 and IF. HUS frequently recurs after renal transplantation in patients with HF1 or IF mutations but not in patients with a mutation of MCP. These genetic defects can be detected by routine diagnostics.
 ...
PMID:[From gene to disease; the haemolytic uraemic syndrome can be caused by mutations in regulating factors of the alternative route of the complement system]. 1728 44

The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60-100 mg m(-2) on day 1) plus bortezomib (1.0-1.5 mg m(-2) on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n=1) and febrile neutropenia (n=4). The MTD was bortezomib 1.5 mg m(-2) plus docetaxel 75 mg m(-2). All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents.
 ...
PMID:Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study. 1845 59


1 2 3 4 Next >>