Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
 6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The feasibility to deliver chemotherapeutic agents by protracted i.v. infusion has greatly increased in the recent past. Indwelling ports, longer lasting central venous catheters requiring less than daily maintenance 'flushing', surgical expertise in placement, use in analgesia and nutrition, and 'smart' pump technology have all contributed to their increasing popularity. Justification for use of infusions in cancer chemotherapy has been slow in appearing with few studies proceeding to the comparative stage. This review will focus on three drugs in common use in cancer treatment, with the purpose of appraising the role of such infusions in cancer therapeutics and of deriving some lessons that might be applicable to other drugs or to drug development in general. For fluorouracil and doxorubicin the rationale and clinical findings favoring further development of infusion regimens is particularly strong. In the case of platinum compounds, some toxicologic advantages have emerged, but other measures designed to protect against the toxicities of cisplatin compete with infusion regimens in this regard. The therapeutic potential for this form of drug delivery, therefore, appears still confined to a subset of patients. Stronger rationales for the use of protracted infusions may be forthcoming from pharmacodynamic findings as in the case of etoposide, combined modality therapy with radiation for FU and cisplatin, biochemical modulation for FU, and reversal of multidrug resistance and its modulation for doxorubicin. While awaiting research into these areas of clinical and pre-clinical investigations, the role of infusion appears most evident in the cardiotoxicity protection of anthracyclines, and in further efficacy exploration (through dose or modulation) of FU. Both mechanistic and pharmacologic considerations could also provide additional stimulus for development of new formulations such as long circulating liposomes, and drugs more suitable for oral administration.
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PMID:Protracted drug infusions in cancer treatment: an appraisal of 5-fluorouracil, doxorubicin, and platinums. 828 Jun 52

A 24-year-old man had a mediastinal embryonal carcinoma containing yolk sac foci. Combination chemotherapy with cisplatin, bleomycin, etoposide, and vinblastine was given, and the residual mass was then resected. Histology showed only necrotic cells. No other treatment was given. Two years later the patient presented with episodes of flushing and syncopes related to a systemicmastocytosis. Bone marrow examination showed a diffuse infiltration with large, atypical mast cells often with multilobulated nuclei. The patient suffered several episodes of cardiovascular collapse and died during one of these episodes, 8 months after the diagnosis of systemic mastocytosis and 40 months after the diagnosis of mediastinal tumor. Autopsy findings included the absence of mediastinal tumor and a diffuse liver and spleen mast cell infiltration. This was the second case with the similar clinicopathologic picture of two rare diseases being associated. This fact supports the hypothesis of a distinct entity, part of the mediastinal germ cell tumor/hematologic malignancy syndrome. The hypothesis of a cytokine secretion induced by mediastinal germ cell tumor supporting mast cell proliferation may be considered.
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PMID:Systemic mastocytosis following mediastinal germ cell tumor: an association confirmed. 838 Feb 74

Decarbazine is an imidazole dimethyltriazene with reproducible activity in patients with metastatic melanoma. CB10-277 is a phenyl dimethyltriazene which, like dacarbazine, requires metabolic activation to its corresponding monomethyl species for antitumour activity. In preclinical models (human melanoma xenografts and transplantable rodent tumours) CB10-277 showed a similar spectrum and level of activity when compared to dacarbazine. Pharmacokinetic studies were performed with CB10-277 in mice treated i.v. at the LD10 (750 mg m-2) and plasma analysed by HPLC. The parent drug area under the plasma concentration vs time curve (AUC) was 142 mM x minutes. Drug metabolism occurred as evidenced by the HPLC identification of the monomethyl species (AUC = 8 mM x minutes) as well as other metabolites. A Phase I trial using a short infusion with doses repeated every 21 days has been performed. Thirty-six patients received 80 courses over a dose range of 80-6,000 mg m-2. The dose limiting toxicity was nausea and vomiting which occurred in 80% of the evaluable courses > or = 900 mg m-2. The only other common side effect was a flushing or warm sensation, which occurred in over 75% of courses at > or = 1,350 mg m-2. There were no hemodynamic consequences. Responses occurred in patients with melanoma (one complete, two partial, one mixed/11), sarcoma (one mixed/6) and carcinoid (one partial/l). Pharmacokinetics were performed in 46 courses. The CB10-277 AUC increased linearly with dose (r = 0.9203, P < 0.001) up to 700 mM x minutes at 6,000 mg m-2). Evidence of CB10-277 metabolism was observed, as in mice, by detection of the monomethyl species and other metabolites. However, the plasma levels of the monomethyl species in patients (1.8 and 3.7 mM x minutes at 6,000 mg m-2) were less than those predicted from studies in mice. Despite this, antitumour activity in dacarbazine sensitive histologies was observed and additional studies with CB10-277 are recommended.
Br J Cancer 1993 Feb
PMID:Preclinical, phase I and pharmacokinetic studies with the dimethyl phenyltriazene CB10-277. 843 67

The dose limiting toxicities of the short infusion trial of the dacarbazine analog, CB10-277, were nausea and vomiting which appeared to be related to the peak plasma level of the parent drug. In addition, based on mouse studies, these dose limiting toxicities occurred at a less than optimal level of the monomethyl metabolite, the presumed species required for antitumour activity. An alternative schedule that would avoid the parent drug peak plasma levels of short infusion, while possibly allowing an increase in the amount of monomethyl metabolite produced was considered. Thus, a 24 h continuous infusion schedule, repeated every 21 days was explored. Twenty-two patients received 42 courses with a dose range of 4,700-15,000 mg m-2. The dose limiting toxicity was myelosuppression (leucopenia and thrombocytopenia). Although nausea and vomiting also occurred, it was manageable with routine antiemetic therapy. Other toxicities included diarrhoea, hallucinations, malaise, muscle ache, headache and flushing and all were < or = WHO grade 2. Pharmacokinetic studies were performed with 13 courses which included all dose levels. The mean t1/2 of the parent drug was 178 min. Area under the concentration x time curve (AUC) at the highest dose for the parent drug and the monomethyl metabolite were 2,350 and 9 mM x minutes, respectively. This monomethyl metabolite AUC and the associated myelosuppression showed a more favourable comparison to the preclinical data determined in mice than the results from the short infusion trial of CB10-277. Therefore, the recommended Phase II dose and schedule of this drug was 12,000 mg m-2 given by 24 h continuous infusion.
Br J Cancer 1993 Feb
PMID:Phase I trial with pharmacokinetics of CB10-277 given by 24 hours continuous infusion. 843 68

Individuals with cancer frequently require long-term central venous access to deliver chemotherapy, blood products, and other fluids. A rare, but potentially lethal complication associated with central venous catheterization is venous air embolism which occurs most commonly after damage or disconnection at the catheter hub. The Groshong (Bard Access Systems, UT) catheter is a device with a unique three-position valve at its distal tip which eliminates the need for routine heparin flushing and minimizes the risk of venous air embolism. This report describes for the first time a near fatal venous air embolism in a patient with an externally accessed Groshong catheter.
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PMID:Venous air embolism through a Groshong catheter. 846 5

Carcinoids, tumors arising from enterochromaffin cells, represent the most common type of gastrointestinal endocrine neoplasm; they are often multiple and may appear anywhere in the gut. Carcinoid tumors may also occur in bronchi and ovaries. Classic symptomatology includes secretory diarrhea, flushing, edema, bronchospasm and cutaneous teleangectasias; however, over 30% of patients with demonstrably elevated serotonin levels may not exhibit any symptoms at all. The diagnosis of carcinoid tumor is typically made by measurement of 24-hour urinary excretion of 5-hydroxyindoloacetic acid. Commonly, tumor localisation is established with CT, US, NMR and arteriography. MIBG scintigraphy is also used to visualize tumors deriving from neuroendocrine cells as carcinoid. These tumors may express somatostatin receptors located on the cell surface. Therefore 111In Octreotide (Octreoscan), a somatostatin analogue, can be employed for tumor localisation. A 32-years-old man with liver metastases secondary to a carcinoid tumor of unknown origin is presented. Classic carcinoid symptoms were absent. Diagnosis was supported by elevated values of urinary 5-hydroxyindolocetic acid and liver fine-needle aspiration. Abdominal US and CT scan detected only liver masses but not the primary tumor. Arteriography was not performed. 131I MIBG and 111I octreotide scans both failed in locating the primary cancer too; only the second tracer showed marked uptake in liver metastases. Beside localization, these two tracers give also informations about the following therapy especially in malignant tumors where local resection isn't an adequate treatment.
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PMID:131I MIBG/111In octreotide mismatch in a patient with liver metastases secondary to a carcinoid of unknown origin. 853 97

A large study of tumors of low malignant potential confirmed the favorable survival in this group of patients compared to invasive epithelial ovarian tumors. Only 8% of patients died with recurrent disease after surgery. Patients with stage IA borderline tumors with mucinous histology tended to recur later and carried a poorer prognosis than patients with serous histology and similar stage. The group at highest risk for relapse were age greater than 70, stage II or III tumors, and histology other than serous. Long-term survival in this group was less than 75%. This high-risk group of patients should be targeted for innovative adjuvant treatment strategies. This year several well-designed studies with large sample sizes showed DNA ploidy to be an important new independent prognostic factor in stage I ovarian carcinoma. In patients with well-differentiated early stage ovarian cancer, DNA flow cytometric analysis may indicate subgroups with less favorable prognostic characteristics. This method of analysis may be beneficial in determining the need for additional treatments after surgery for early stage ovarian carcinoma. Recommendations for the definitive management of early stage ovarian cancer awaits completion of current GOG and European randomized prospective studies. Paclitaxel given in combination with platinum-containing agents is an intense area of research for treatment of advanced stage disease. Early data from a prospective randomized trial of patients with advanced ovarian cancer showed a higher response rate and longer disease-free survival in patients treated with paclitaxel and cisplatin compared to a standard regimen of cyclophosphamide and cisplatin. The impact of this treatment on long-term survival awaits maturation of data. Preliminary results evaluating G-CSF in combination with paclitaxel and cisplatin for dose escalation was reported. Paclitaxel, 250 mg/m2, and cisplatin, 75 mg/m2, were the maximally tolerated doses, with peripheral neuropathy or myalgias the dose limiting toxicities. Further studies are now underway to test the effect of dose-response with escalation therapies and to determine the optimal dose and schedule for the management of patients with advanced ovarian cancer. IL-3 significantly ameliorated neutropenia but did not prevent cumulative platelet toxicity in a regimen utilizing high-dose carboplatin. This mild improvement in myelosuppression was obtained at the cost of significant toxicity. Nausea, vomiting, malaise, bone pain, headache, fever, chills and facial flushing were frequent. Intraperitoneal chemotherapy was tested as a means of consolidation treatment for patients after having a negative second-look laparotomy. These treatments were shown to be feasible; however, prospective randomized trials will be necessary to determine a benefit over operative therapy alone. Several studies addressed to problem of residual disease after primary surgery and adjuvant chemotherapy. A large phase II study conducted by the GOG confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer with favorable pretreatment characteristics. Whether intraperitoneal platinum-based therapy represents an advantage over systemic platinum therapy is being addressed in a prospective SWOG study. The use of six additional cycles of CAP for treatment of residual disease after primary treatment of surgery and adjuvant chemotherapy did not significantly improve complete pathological response and survival. Prolonged duration of chemotherapy above six cycles is not likely to impact treatment for residual disease. A regimen of high dose carboplatin was compared to whole abdominal radiotherapy for treatment of residual disease after initial chemotherapy. There was no difference in survival or disease-free survival between treatments.(ABSTRACT TRUNCATED)
Cancer Chemother Biol Response Modif 1996
PMID:Gynecological malignancies. 863 1

The classical carcinoid tumour (WHO) of the pancreas is extremely rare and its diagnosis may puzzle physicians and pathologists. Here, 29 previously published cases of pancreatic carcinoid tumours, including one new case, are reviewed. Literature research was done using MedLine from 1966 to 1995. Pancreatic carcinoids produce an atypical carcinoid syndrome. Skin flushing was reported in only 34%. The main symptom was pain, followed by diarrhoea and weight loss. Elevated urinary 5-HIAA levels were found in 85% (17/20). The immunocytochemical sensitivity for serotonin was 100% (11/11). The diagnosis of pancreatic carcinoid tumour is based on the typical endocrine histological features together with increased serotonin metabolism. Generally, the slow growth rate and late invasion of adjacent organs render local resection possible, but the high incidence of distant metastases (69%) prevents long-term survival in the majority of patients. The possible role of the Octreoscan, a new radionuclide imaging technique, is discussed with regard to this tumour entity.
Eur J Cancer 1996 Jun
PMID:Carcinoid of the pancreas: clinical characteristics and morphological features. 875 39

Carcinoid tumours derived from the neural crest are usually associated with the symptoms of flushing and diarrhoea in the presence of liver metastases. Scintigraphs with 131I-metaiodobenzylguanidine (131I-MIBG) which is accumulated in the argentaffin granules of the cell, as well as with 111In-pentetreotide for the imaging of somatostatin receptors on the cell surface, are positive in a large proportion of carcinoid patients. To evaluate the complementary role of both radionuclide tests, we studied 20 consecutive carcinoid patients: 14 with the characteristic carcinoid syndrome and 6 with tumour symptoms, such as pain or obstruction. A positive test was found in 84% with either 131I-MIBG or 111In-pentetreotide; the combination yielded a sensitivity of 95%. A positive correlation was found with the presence of the carcinoid syndrome, but not with 5-HIAA excretion. A positive test may help in adjusting treatment: either to predict the response to octreotide or to select patients for 131I-labelled MIBG treatment. Application of a therapeutic dose of 111In-pentetreotide may be limited by the high normal uptake in the kidneys.
Eur J Cancer 1996 Oct
PMID:Combined diagnostic imaging with 131I-metaiodobenzylguanidine and 111In-pentetreotide in carcinoid tumours. 894 76

A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1).
Br J Cancer 1996 Dec
PMID:Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution. 898 Apr 9


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