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)

Carboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200-550 mg/m2 every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m2 Carboplatin, the median platelet nadir was 65 000/mm3. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50-155) ml/min and dropped to a median lowest creatinine clearance of 69 (23-171) ml/min on day four (p less than 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42-155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m2 every five weeks. A starting dose of 450 mg/m2 seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200-500 mg/m2 induced renal and severe hematological toxicity.
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PMID:A phase I trial of cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin, CBDCA, JM-8) with a single dose every five week-schedule. 639 47

cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients. Doses were given initially every 3 weeks and escalated from 20 to 520 mg/m2. Following this, doses were given every 4 weeks and escalated from 300 to 500 mg/m2. The dose-limiting toxicity, thrombocytopoenia, occurred in four-fifths of patients treated at 520 mg/m2, with the nadir occurring 3 weeks after treatment. Leucopoenia and anaemia also occurred but were less severe. Vomiting occurred in all patients receiving over 120 mg/m2 but seldom persisted beyond 24 h. Serial measurements of 51Cr-EDTA clearances, urinary N-acetylglucosaminidase, urinary leucine aminopeptidase, and beta 2-microglobulin did not reveal significant evidence of nephrotoxicity. Detriment to the audiogram has not been seen in the first 13 patients studied. Pharmacological studies showed that most of the dose of platinum was excreted in the urine, and that impairment of renal function may be associated with drug retention and an increased risk of myelosuppression. The previous therapy and age of the patient also affected the tolerance of the drug. Clinical responses were seen in patients with ovarian carcinoma receiving greater than 120 mg/m2. A further dose escalation was performed on a 4-week schedule in patients under 65 with good renal function. The maximum dose it was possible to administer repeatedly without incurring myelosuppression was in the range 400-500 mg/m2. JM8 is not significantly nephrotoxic and is less emetic than cisplatin. It has antitumour activity in man and deserves wider evaluation, along with the other analogues under study in various centres, as an alternative to cisplatin.
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PMID:Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II. 676 Oct 10

Both chemotherapy and interleukin-2 and/or interferon-alpha produce objective responses in a proportion of advanced malignant melanoma patients. While duration of response to chemotherapy is short, i.e. usually below 4 months, immunotherapy has resulted in a small number of long-lasting remissions in patients with metastatic melanoma. In two consecutive phase II trials in a total of 67 patients, we assessed the potential synergism between both modalities, i.e. chemo- and immunotherapy. Treatment consisted of intravenous (i.v.) carboplatin (CBDCA, 400 mg/m2) and dacarbazine (DTIC, 750 mg/m2) given twice (i.v. bolus over 30 min) at 3-week intervals, or 4 cycles of DTIC (220 mg/m2 i.v. 3 days), cisplatin (DDP, 35 mg/m2 i.v. 3 days), carmustine (BCNU, 150 mg/m2 i.v. cycles 1 and 3) and tamoxifen (TAM, 20 mg oral/daily) at 3-week intervals. Chemotherapy was followed by immunotherapy with combined subcutaneous (s.c.) interleukin-2 (rIL-2) and SC interferon-alpha 2 (rIFN-alpha). Among 40 patients who received a full cycle of chemotherapy with CBDCA/DTIC and sequential immunotherapy, there were 3 (7.5%) complete remissions (CRs) with a median duration of 19 months (range 13-26+). Partial remissions (PRs) were noted in 11 (27.5%) patients with a median response duration of 8 (range 5-14) months. Among 27 patients who received DTIC/DDP/BCNU/TAM and rIL-2/rIFN-alpha, there were 3 (11%) complete remissions and 12 (44.5%) partial remissions. Duration of complete and partial remissions ranged from 9+ to 13+ (median, 11+), and 5 to 15+ (median, 7+) months, respectively. Chemotherapy produced mostly moderate toxicity. Thrombocytopenia was common with the nadir after a median time of 18 days following start of CBDCA/DTIC and DTIC/DDP/BCNU, respectively. 10 patients required transfusion of thrombocytes. Nausea and vomiting due to chemotherapy were well tolerated using concomitant ondansetrone (8 mg i.v.). Immunotherapy was self-administered at home with mild to moderate side effects; malaise, fever, chills, nausea/vomiting, diarrhoea, anorexia and arthralgias were most frequent, but were spontaneously reversible after ending rIL-2/IFN-alpha. A mean 87 and 88% of the projected doses of rIL-2 and rIFN-alpha were administered on either protocol. There were no life-threatening complications and no treatment-related deaths. The sequential combination of chemotherapy and rIL-2 plus rIFN-alpha had at least additive therapeutic activity against metastatic malignant melanoma. The schedules produced long-lasting remissions and were tolerated well overall. These trials substantiate a potential role for low to intermediate dose immunotherapy in maintaining and consolidating therapeutic effects of chemotherapy in metastatic melanoma.
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PMID:Chemoimmunotherapy of advanced malignant melanoma: sequential administration of subcutaneous interleukin-2 and interferon-alpha after intravenous dacarbazine and carboplatin or intravenous dacarbazine, cisplatin, carmustine and tamoxifen. 764 14

Induction chemotherapy of low-dose CBDCA, 120-hour continuous infusion 5-FU and UFT was applied to 22 patients with untreated head and neck cancer. CBDCA 75 mg/m2 was given on day 1 and, subsequently, 5-FU 1,500 mg/m2/day for 120-hour continuous infusion was started. UFT was administered every day orally at 400-600 mg/day as biochemical modulation. If tumors were reduced and side effects were mild, these schedules were repeated after two weeks. Three patients (14%) achieved a CR and 11 (50%) a PR, for an overall response rate of 64%. Anorexia, nausea, vomiting and stomatitis were the predominant toxicities. They were mild and well tolerable, although severe diarrhea was observed in one case. Good general conditions of patients were kept because of low grade of toxicities. They were important factors for the tolerance of subsequent radiotherapy and surgery. Based on these results, we conclude that the combination of low-dose CBDCA, 5-FU and UFT as biochemical modulation is effective in head and neck cancer.
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PMID:[The effect of induction chemotherapy with CBDCA, 5-FU and UFT in head and neck cancer]. 815 88

Carboplatin, a platinum analog with single-agent activity in previously untreated breast cancer, is characterized by comparatively less renal toxicity and emesis than cisplatin. We combined carboplatin at different dose levels [from 200 to 350 mg/m2 by intravenous (IV) infusion on day 1] with 5-fluorouracil (500 mg/m2 IV on days 1 and 8) and cyclophosphamide (500 mg/m2 IV on day 1), with all three drugs recycled every 28 days, to evaluate anti-tumor activity and toxicity of this novel combination [5-fluorouracil/carboplatin/cyclophosphamide (FCC)] in untreated locally advanced (LABC) or metastatic breast cancer (M+). Of 37 patients treated between March 1990 and August 1991 [LABC 25, M+ 8; World Health Organization (WHO) performance status, 0-1; median number of treatment cycles, 5; median follow-up, 20 months], 33 are evaluable for response and toxicity. The overall complete plus partial remission rate was 57% (LABC 68%, M+ 25%). The median duration of response was 19+ months. The cumulative carboplatin dose ranged from 800 to 2350 mg/m2 (median, 1450 mg/m2). In this series, no correlation was observed between the carboplatin dose level and response rate or toxicity. Leukopenia and thrombocytopenia represented the most frequent toxicities. WHO grades 3 and 4 neutropenia were documented in 34% and 8% of patients, respectively. Thrombocytopenia below 50 x 10(9)/l was observed in 8%. No renal toxicity was observed, and moderate emesis occurred in 67% of patients. These results indicate that FCC is an active and relatively safe combination for the treatment of advanced breast cancer in patients not previously treated with chemotherapy.
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PMID:Carboplatin in combination as first-line therapy in advanced breast cancer. 822 14

Cisplatin combined with cyclophosphamide has been considered a very active treatment for advanced ovarian cancer. Unfortunately, cisplatin is associated with dose-limiting neurotoxicity, as well as possible neuropathy, ototoxicity, and occasional renal dysfunction. Carboplatin, a cisplatin analogue, is active against advanced ovarian cancer, with a presumed lower incidence of emesis, ototoxicity, neuropathy, and renal dysfunction. The Southwest Oncology Group initiated a phase III randomized trial, in which 342 patients with stage III (suboptimal disease) and stage IV ovarian cancer were randomly assigned to treatment with six courses of intravenous cisplatin 100 mg/m2 plus cyclophosphamide 600 mg/m2 or carboplatin 300 mg/m2 plus cyclophosphamide 600 mg/m2. The median survival for the cisplatin arm was 17.4 months; for the carboplatin arm, median survival was 20.0 months. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the p = 0.02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. There was less thrombocytopenia in the cisplatin arm (p < 0.001); however, there was less nausea and emesis (p < 0.001 for courses one to five), renal toxicity (p < 0.001), anemia (p < 0.001), hearing loss (p < 0.001), and neuromuscular toxicity (p < 0.001) in the carboplatin arm. Carboplatin/cyclophosphamide proved to have a significantly better therapeutic index than cisplatin/cyclophosphamide in these patients with advanced ovarian cancer.
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PMID:Results of a Southwest Oncology Group phase III trial of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide in advanced ovarian cancer. 823 97

Cisplatin is an active cytostatic that became successful in the treatment of several types of solid tumours after its nephrotoxic potential was controlled by hydration and diuresis. Thiol compounds were tested to reduce further cisplatin-induced nephrotoxicity. Thiosulphate is rapidly excreted by the kidneys and protects against cisplatin-induced nephrotoxicity by inactivating reactive platinum species in the kidney. Due to inactivation of cisplatin in the circulation, thiosulphate also interferes with its antitumour activity. Therefore, it is mainly used in two-route schedules, whereby cisplatin is delivered locally to the tumour (i.p. or i.a.) while systemic (i.v.) thiosulphate protects the kidneys. Diethyldithiocarbamate was shown to protect against cisplatin-induced nephrotoxicity in several animal models by reversing cellular damage. However, in the clinic it has been less successful, partly due to its central nervous system toxicity. The endogenous thiol compounds glutathione and metallothionein have been shown to reduce cisplatin-induced toxicity both in animal models and in clinical trials. However, the results are rather preliminary and a reduction in therapeutic efficacy may be expected, for both glutathione and metallothionein have been reported to be involved in platinum resistance. The thioether methionine has been shown to reduce cisplatin-induced nephrotoxicity in animal models but it has not yet been tested in the clinic. Cisplatin-induced acute emesis can be sufficiently controlled with a new class of 5-hydroxytryptamine-3 (5HT3)-receptor blockers, but delayed emesis remains a problem. High-dose cisplatin regimens with protection of the kidneys induces ototoxicity, peripheral neuropathy and myelotoxicity, which become dose-limiting. Neurotoxicity was partly reversed by the neurogenerative agent ORG2766, but this agent does not reduce other cisplatin-induced toxicities. Therefore, an agent capable of protecting multiple non-tumour tissues is needed. Carboplatin is a second-generation analogue of cisplatin with less nephro-, neuro- and ototoxicity. Carboplatin is at least as active as cisplatin at its maximum tolerated dose, which is defined by its myelotoxicity. Protection from carboplatin-induced myelotoxicity may be controlled by autologous bone marrow transplantation and/or hematopoietic growth factor infusions. High-dose carboplatin schedules may cause nephrotoxicity, neurotoxicity and ototoxicity. Again, the protection of multiple non-tumour tissues is needed. WR2721 appears to be such a modulating agent capable of protecting multiple non-tumour tissues. It was shown to be preferentially metabolized and taken up as the thiol metabolite WR1065 by non-tumour tissues as compared with (hypoxic) solid tumours. It was shown to protect mice from cisplatin-induced nephrotoxicity and from cisplatin- and carboplatin-induced myelotoxicity without interfering with the antitumour activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:WR2721 as a modulator of cisplatin- and carboplatin-induced side effects in comparison with other chemoprotective agents: a molecular approach. 826 81

The traditional adjuvant therapy for seminoma stage I is abdominal radiotherapy. Although the relapse rate ranges below 5% this treatment is challenged because concerns about adverse late effects are accumulating. Carboplatin is effective in metastatic seminoma and two pilot studies have indicated effectivity in the adjuvant setting also. As this drug is almost non-toxic in moderate doses it could be an ideal adjuvant treatment for seminoma stage I. A group of 82 patients, mean age 37.5 years (range 22-73 years), with histologically pure seminoma stage I, were given carboplatin 400 mg/m2 after orchiectomy; 60 patients received only one course of carboplatin, and 22 patients received two courses. The median time of observation is 24 months, ranging from 2 to 48 months, and 66 patients have a minimum follow-up of 1 year. There is one relapse so far. Toxicity is rather mild with no severe nausea/emesis. Mean platelet counts were 164/nl after 3 weeks and 208/nl after 4 weeks; thus, myelotoxicity was negligible. Gonadal toxicity was measured by serial follicle-stimulating hormone levels. The mean level was 11.4 U/l before treatment, and 16.2 U/l after 5 weeks, 17.3 U/l after 4 months, 14.5 U/l after 8 months and 13.5 U/l after 12 months. Thus, gonadal toxicity also appeared to be mild. In summary, the efficacies of adjuvant carboplatin and of abdominal radiotherapy seem to be identical. As carboplatin, in the dosage used, involves no severe acute side-effects and probably few late adverse effects, this regimen constitutes a promising new treatment option in seminoma patients stage I that deserves to be studied in randomized trials.
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PMID:Adjuvant carboplatin treatment for seminoma clinical stage I. 854 95

Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.
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PMID:Comparative adverse effect profiles of platinum drugs. 857 96

Carboplatin has proven efficacy in the treatment of ovarian cancer and has been proven to be less toxic compared to the parent compound cisplatin. Nevertheless, emesis is still a major problem associated with carboplatin-containing chemotherapy. Several investigators have focussed on the understanding of the pathophysiology and pattern of cisplatin-induced emesis. Data describing both the pathomechanisms and pattern of carboplatin-induced emesis are still lacking. This paper combines data from the literature with our own experience with the pattern and control of carboplatin-induced emesis, and presents data contributing to the understanding of the underlying pathomechanisms. Carboplatin induces a significant increase in urinary 5-HIAA excretion, the main metabolite of serotonin. 5-HIAA excretion levels remain elevated over 3 days following chemotherapy. Carboplatin-induced emesis is observed in about 40% of patients despite anti-emetic prophylaxis with 5-HT3 antagonists. Vomiting after carboplatin extends over days 1-3 with an equal distribution regarding the severity on each day. Analysis of the pattern of emesis revealed that delayed emesis (> 24 h after chemotherapy) is a major problem associated with carboplatin therapy. Description of the pattern of emesis as 'prolonged emesis' seems to be appropriate. 5-HT3 receptor antagonists such as ondansetron seem to be efficacious both in the control of acute and prolonged emesis following carboplatin chemotherapy, but randomly controlled data comparing ondansetron with other anti-emetic regimens have not yet been published. Univariate analysis reveals gender and combination therapy containing carboplatin and cyclophosphamide and/or anthracyclines as risk factors for emesis.
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PMID:Pathophysiology, severity, pattern, and risk factors for carboplatin-induced emesis. 869 51


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