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)

Chemotherapeutic regimens containing Cisplatin are the most effective in the treatment of squamous cell carcinoma of the head and neck. Because of the high rate of dose-limiting side effects of Cisplatin, Carboplatin, a second generation Cisplatin analog, was tested in a phase II trial with 5-FU on 55 previously untreated patients with advanced carcinoma of the head and neck. The results of the completed study are: 33% CR, 54% PR, 10% NR and 4% PD. Toxic side effects were tolerable myelotoxicity as with Cisplatin/5FU, mild nausea, vomiting and nephrotoxicity. No ototoxicity was seen. Most patients showed better performance status after chemotherapy with increased body weight. These results indicate that Carboplatin/5-FU is more effective and has milder side effects than Cisplatin/5-FU.
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PMID:[Results of a phase II study with the new cytostatic drug carboplatin in combination with 5-fluorouracil in the primary treatment of advanced squamous cell cancers of the head and neck]. 306 15

Cisplatin combinations are active in patients with epidermoid cancer of the head and neck. Because of the incidence of dose-limiting toxicity and the need for hospitalization for iv hydration and mannitol diuresis, the search for active analog(s) with less of such toxicity has been intensive. In a limited institution study of Wayne State University and the Southwest Oncology Group, a clinical trial of carboplatin (CBDCA) and iproplatin (CHIP) in patients with recurrent head and neck cancer was carried out. Sixty-four patients were entered and 63 were evaluated, 29 receiving CBDCA and 34 receiving CHIP therapy. These patients were stratified according to important prognostic factors. The response rate to CBDCA was 24% (seven responses among 29 patients; three complete responses and four partial responses), and to CHIP was 12% (four responses among 34 patients; one complete response and three partial responses). Both drugs were administered without prior hydration or mannitol diuresis on an outpatient basis. The major side effect was myelosuppression, which was reversible but cumulative and dose-limiting. Less severe vomiting occurred as compared to the incidence of this toxicity with cisplatin and no significant renal or hearing loss occurred. It was concluded that further evaluation of these agents with other active drug(s) in patients with head and neck cancer is warranted.
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PMID:Platinum analogs in recurrent and advanced head and neck cancer: a Southwest Oncology Group and Wayne State University Study. 330 Sep 67

A toxicology study of cis-diamminedichloroplatinum (II) (CDDP), aqua(1,1-bis-(aminomethyl)cyclohexane)sulfatoplatinum(II) (TNO-6), diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA), cis-dichloro-trans-dihydroxo-cis-bis(isopropylamine)platinum-(IV) (CHIP) and ethylenediaminemalonatoplatinum(II) (JM-40) was carried out in dogs. The main purpose of the study was to compare the results with those obtained earlier in mice and rats and with the toxicology data in humans. Each platinum compound was tested in three dogs. Each dog received three intravenous bolus injections at intervals of 3 weeks. The compounds were administered in dosages of 1.2, 1.0, 12, 10 (or 6) and 10 mg/kg, respectively. Toxic death occurred for two dogs (both on day 54) from haematotoxicity (10 mg/kg CHIP) and renal toxicity (TNO-6), respectively. Serum urea nitrogen and creatinine concentrations were variable after TNO-6 and remained within normal values after treatment with the other compounds. Severe proteinuria was observed in all three dogs treated with TNO-6. Values returned to normal within 16 days. JM-40 did not cause significant proteinuria. CDDP, CBDCA and CHIP caused short-lasting and slight proteinuria. CHIP caused a severe reduction in the number of leukocytes and platelets, while the other drugs caused acceptable reductions. Except after the high dose CHIP regimen, haematotoxicity was of a transient nature. Vomiting in order of severity occurred after TNO-6, CHIP, CDDP and JM-40, while CBDCA did not cause any vomiting. The dogs were sacrificed 6 weeks after the last drug dose. Organs were fixed for histopathology to complete and support clinical-toxicological parameters. On the basis of the results from the single-dose study in dogs and those obtained earlier in mice and rats it can be concluded that the gain from the use of the dog as a prognosticator for organ toxicity in man was disappointing and limited to the prediction of vomiting.
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PMID:Preclinical toxicology of platinum analogues in dogs. 330 82

Cis-platinum causes profound gastrointestinal symptoms in patients and these may persist for many days after drug administration. Gut mucosal toxicity may be a factor in the pathogenesis of such prolonged nausea, vomiting and anorexia. The effects of cis-platinum on mouse ileal mucosal architecture, villus epithelial cell influx and disaccharidase activity are described in comparison with dhe effects of two platinum analogues, CBDCA and CHIP. In addition the effect of dexamethasone, a useful drug in the palliation of cis-platinum-induced emesis, in combination with cis-platinum is described. Cis-platinum, CBDCA and CHIP cause profound reduction in crypt cell production rate (CCPR) and thus villus epithelial cell influx within hours of administration leading to villus stunting and diminished function. CBDCA showed the least profound effect with early rebound in CCPR by day 3. Cis-platinum and CHIP were roughly equitoxic to ileal crypts with rebound in CCPR being delayed until day 7. Similarly, CBDCA caused least reduction in disaccharidase activity with cis-platinum and CHIP being equitoxic. The addition of dexamethasone had no protective effect on the effects of cis-platinum on murine ileal mucosa and mice given the combination chronically had no weight gain over 18 weeks, their weight paralleling those receiving cis-platinum alone. The platinate compounds have differing degrees of intestinal mucosal toxicity but no direct inference can be drawn in respect to the clinical situation where CBDCA causes less gastrointestinal symptomatology than CHIP but where both cause less than cis-platinum. Dexamethasone does not act by mucosal protection to provide its useful effects in prolonged cis-platinum-induced gastrointestinal symptoms.
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PMID:Small intestinal mucosal toxicity of cis-platinum--comparison of toxicity with platinum analogues and dexamethasone. 351 92

Because of the clinical activity of carboplatin in several types of tumors, this drug was studied in a phase II trial of 25 patients with advanced head and neck cancer [stage IV (M0)] without prior treatment. Six patients (24%) achieved objective response, including two patients with complete response. Carboplatin toxicity was mild in most patients, with nausea, vomiting, and myelosuppression being the most frequent side effects. No renal or neurologic toxicity was observed. Further trials of carboplatin in advanced head and neck cancer are warranted.
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PMID:Carboplatin, an active drug in advanced head and neck cancer. 353 Apr 43

Since the introduction into clinical practice in 1972, cisplatin (CDDP) has assumed an important role in the treatment of various tumors such as testicular, ovarian or pulmonary cancer. Its toxicities include emesis, renal impairment, neuropathy, hearing loss and anemia. In clinical trials renal toxicity has been proved to be dose limiting factor. Thus the total number of courses which may be given is limited. For this reason second-generation CDDP analogues with reduced toxicity have been tried to develop and are reaching clinical testing. A number of studies have now been published relating the results of these trials. The best studied of these analogues is carboplatin (CBDCA, JM-8) which was noted to be less nephrotoxic, but more myelosuppressive than CDDP in preclinical study. Phase I trials have shown that CBDCA is relatively free of renal toxicity and that its dose limiting factor is myelosuppression, especially thrombocytopenia. In phase II trials CBDCA has been shown to be an active agent in advanced carcinomas of the ovary, head and neck, lung and urogenital organs. Similar results have been obtained in clinical trials of iproplatin (CHIP, JM-9) which is synthesized as an analogue of CDDP. Two other analogues developed in Japan have been evaluated to be active for various mouse tumors in preclinical studies. Phase I trials of these agents is now ongoing.
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PMID:[Second-generation cisplatin analogs]. 355 46

We undertook a phase 1 study of Carboplatin (CBDCA) on an intermittent single intravenous (IV) bolus (schedule A) and a 24-hour continuous infusion schedule (schedule B). Hydration and forced diuresis were not performed. Patients were not premedicated for anticipated vomiting. Thirty-eight adult patients with solid tumors received a total of 71 courses. In schedule A, doses were escalated from 20 to 600 mg/m2. The dose-limiting toxicity was myelosuppression. At doses of 270 mg/m2 and higher, leukopenia and thrombocytopenia were reproducibly seen. The dose of 600 mg/m2 was the maximally tolerated dose, producing severe thrombocytopenia (platelet counts less than 30,000/microL). Other toxicities included a fall in hemoglobin levels and tolerable nausea and vomiting. Schedule B produced comparable hematologic and emetogenic toxicities to those in schedule A. In three patients audiograms became abnormal with high-frequency hearing loss without overt deafness. Two patients developed hypomagnesemia without irreversible renal dysfunction. Patients with poor performance status, preexisting renal dysfunction, a third fluid space, or bone metastases seemed to develop increased hematologic toxicity. The recommended phase 2 dose for good risk patients is 400 mg/m2 IV bolus and for poor risk patients 270 mg/m2 IV bolus. Responses were seen in one patient each with head and neck carcinoma (partial response), small cell lung cancer (minor response), and breast cancer (minor response).
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PMID:Phase 1 study of carboplatin in patients with advanced cancer, intermittent intravenous bolus, and 24-hour infusion. 390 Mar 2

Carboplatin has been developed for clinical trials as a less nephrotoxic, less emetogenic analog of cisplatin. In preclinical tumor models it was less potent than the parent compound on a molar basis, but reduced toxicity allowed comparable antitumor doses to be given. In phase I studies its dose-limiting toxicities were reversible myelosuppression, especially thrombocytopenia. Leucopenia and anemia occurred to a lesser degree. Other reported toxicities included nausea, vomiting, malaise, myalgia, arthralgia, ototoxicity, hypomagnesemia, and proteinuria. Nausea and vomiting occurred frequently, but was much less severe than that observed with cisplatin. The incidence of serum creatinine elevations was low. The increase was usually reversible and occurred only in association with administration of aminoglycosides, or abnormal pretreatment renal function. Recommended phase II doses by schedule are: bolus every 4 weeks, 400-500 mg/m2 (560 mg/m2 in children); 24 hour continuous infusion every 4 weeks, 320-400 mg/m2; weekly bolus for 4 consecutive weeks with 2 weeks rest, 100-125 mg/m2 (175 mg/m2 in children); bolus for 5 consecutive days every 4 weeks, 77-95 mg/m2. Objective responses were observed during these phase I studies in adult patients (head and neck, breast, renal carcinomas) and children (osteosarcoma, brain stem lesions). In addition to phase II evaluations in all major tumor types, plans for phase III studies in selected tumors are underway.
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PMID:Results of NCI-sponsored phase I trials with carboplatin. 391 Feb 21

Thirty-one patients with advanced epidermoid carcinoma of the esophagus were treated with carboplatin (CBDCA), a second-generation cisplatin analog. Thirty patients were evaluable for response. Major responses (complete response) were seen in two patients (7%; 95% confidence limits, 1%-20%). The median survival from initiation of the protocol was 3 months (range, 0.1-16). Neither renal dysfunction nor emesis was a significant problem with CBDCA; hematologic toxicity was dose-limiting. Thrombocytopenia was more marked than leukopenia. CBDCA is a well-tolerated cisplatin analog that produced two complete responses in patients with advanced epidermoid carcinoma of the esophagus, where such responses are rarely observed. Although the observed response rate was only 7%, the 95% confidence limits overlap those previously reported for cisplatin (12%-31%).
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PMID:Carboplatin: a new platinum analog in the treatment of epidermoid carcinoma of the esophagus. 391 41

Since the discovery of the antitumor activity of cis-dichlorodiammine platinum (II) in various tumor systems by B. Rosenberg in 1969, many Pt complexes have been prepared to ameliolate DDP. It has been known to have severe nephrotoxicity, nausea and vomiting, as well as ototoxicity. However, DDP has a wide spectrum of antitumor activity, and it is specifically active against cancers in bladder, testis, ovary and, head and neck. To attenuate such toxicities, hydration prior to DDP administration and/or application of diuretics, as well as combination therapy with other antitumor agents have been developed. Various studies indicated that the nephrotoxicity was attenuated by changing carrier ligands and leaving groups. Toxicity to be removed so far is myelosuppression and vomiting. Another problem is the cross-resistance of DDP. Against L1210/DDP, amine, ethylenediamine, o-phenylenediamine and 1,2-cyclopentanediamine Pt complexes showed cross-resistance, while dach and 1,2-cycloheptanediamine Pt complexes showed no cross-resistance. In this review, the author discusses mainly preparation of the Pt complex of the 2nd generation, being now in the clinical trials and my approach to the development of the antitumor Pt complexes in my laboratory. Pt complexes being now in the advanced studies are: CBDCA, CHIP, DACCP, PYPl PHIC, TNO-6 and l-OHP. New Pt complexes are still deviced continuously. The capability of synthesizing Pt complexes which are characteristically effective against the slow-growing solid tumors, from the standpoint of the coordination chemist.
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PMID:[Development of antitumor platinum complexes]. 636 50


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