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Biomedical subjects

J Carmichael

Publications and source records attributed to J Carmichael.

At least 109 records · Page 6Linked to original sources
PubMed1992

A phase I study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide.

Multidrug resistance (MDR) is one of the mechanisms of resistance to multiple cytotoxic drugs and is mediated by the expression of a membrane pump called the P-glycoprotein. Nifedipine is one of the calcium channel blocking agents which reverses MDR in vitro. Fifteen patients with various malignancies received nifedipine at three dose levels: 40 mg, 60 mg and 80 mg orally twice daily for 6 days. Etoposide was administered intravenously on day 2 in a dose of 150-250 mg m-2 and orally 150-300 mg twice daily on days 3 and 4. Cardiovascular effects of nifedipine were dose limiting and the maximum tolerated dose was 60 mg bid. Mean area under the plasma concentration curve (AUC0-00) and plasma half-life (beta) of nifedipine and its major metabolite MI at the highest dose level were 7.87 microM.h, 7.97 h and 4.97 microM.h, 14.0 h respectively. Nifedipine did not interfere with the pharmacokinetics of etoposide.

Administration, Oral↗
PubMed1992

Relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility.

There have been a series of reports on the association of a genetic polymorphism at the cytochrome P450 CYP2D6 gene locus with cancer susceptibility. Many of these reports have remained contradictory either because of small numbers of patients studied or because of the limitations and controversy surrounding the pharmacokinetic assay used to identify affected individuals (poor metabolizers; PMs). We have recently developed a DNA-based assay that will allow the unequivocal identification of poor metabolizers and have applied this to the study of 1635 patients with different forms of cancer. Out of 361 lung cancer patients studied no statistically significant change in the proportion of PMs relative to controls was found. However, a significant increase in the proportion of poor metabolizers or heterozygotes was seen in leukaemia, bladder cancer and melanoma patients. This could be explained by a role for CYP2D6 in carcinogen detoxification or by linkage to another cancer-causing gene.

Amino Acid Sequence↗
PubMed1992

Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Given the potential for improved tolerance, a trial was initiated to compare the toxicity and efficacy of a standard regimen of cisplatin-cyclophosphamide (75 mg/m2 and 600 mg/m2, respectively) with an experimental regimen of carboplatin-cyclophosphamide (300 mg/m2 and 600 mg/m2, respectively) in women with postoperative macroscopic residual ovarian cancer. PATIENTS AND METHODS: Between 1985 and 1989, 447 (417 eligible) patients were randomized. Treatment arms were well balanced; most patients had stage III (82%), grade 3 (54%) tumors with bulky residual (greater than 2 cm in 59%), and good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1, 77%). Response was assessed after six 4-week cycles. RESULTS: The treatments were equally deliverable, with 76% of patients completing their allocated regimen. The reported reasons for failure to complete treatment differed; toxicity/refusal predominated on the cisplatin arm, and progressive disease predominated on the carboplatin arm (P = .0092). Cisplatin-treated patients were more likely to develop neuropathy and nephropathy, and carboplatin patients experienced myelosuppression, particularly thrombocytopenia. Efficacy was similar, with no significant differences for the cisplatin and carboplatin arms in clinical response rate (57% v 59% in those with measurable disease), pathologic response rate (52% v 54% in those suitable for relaparotomy), time to progression (median, 56 v 58 weeks), or overall survival (median, 100 weeks v 110 weeks). Time to progression and survival were predicted by residual disease size, performance status, and treatment center (with those treated at centers that accrued more patients doing better). CONCLUSION: Neither regimen is optimal in that relapse remains the norm. It may be inappropriate to expect that any single regimen can be an effective therapy for all patients with advanced ovarian cancer. Both cisplatin and carboplatin are likely to have a role in future treatment strategies.

Adult↗
PubMed1991

Two phase I studies of carboplatin dose escalation in chemotherapy-naive ovarian cancer patients supported with granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) may reduce myelosuppression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the first trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m2) and fixed doses and schedules of cyclophosphamide (600 mg/m2) and rHuGM-CSF (10 micrograms/kg given subcutaneously once daily on days 2-11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the first dose level tolerated five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m2 dose level. When 500 mg/m2 carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the first dose level (600 mg/m2) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or nonsteroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, (b) early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m2, and (c) 500 mg/m2 carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Keynote address: mechanisms of cellular resistance to cytotoxic drugs and X-irradiation.

Lack of response to X-irradiation and cytotoxic chemotherapy is the major cause of treatment failure in patients with cancer. However, "resistance" to these modalities may be considered a normal cellular response. The ability to cure patients with particular tumor types may be related to hypersensitivity to these modalities caused by loss or abnormality of certain normal cellular constituents such as enzymes involved in DNA repair. It is likely that the initial chemo or radiosensitivity of a tumor will broadly reflect the intrinsic resistance of the tissue type from which the tumor arose. There are many cellular biochemical mechanisms responsible for this relative resistance to drugs and radiation. Many of these mechanisms, although present in normal tissues, may be inducible and can result in enhanced resistance to DNA damaging agents. Although certain resistance mechanisms would appear to be specific for drug resistance or for radiation resistance, there are other resistance mechanisms that potentially affect both modalities. In particular, the study of DNA repair genes in mammalian cells may give us greater insight into common mechanisms of resistance to these modalities.

Animals↗
PubMed1990

Comparison of short-term and continuous chemotherapy (mitozantrone) for advanced breast cancer.

132 patients with advanced recurrent breast cancer were treated with four courses of mitozantrone 14 mg/m2 intravenously every 3 weeks (9 weeks). Patients showing disease stabilisation or objective response were randomised to stop chemotherapy or to continue until disease progression. At that stage 27% showed partial responses, 3% complete responses, and 10% disease stabilisation. 22 patients were randomised to continue chemotherapy and 21 to stop. There was no difference in time to disease progression, response duration, or survival between the two groups. Toxicity was mild during the first four courses of therapy. Thus, short courses of single-agent chemotherapy can produce similar therapeutic results to long-term chemotherapy, which has major implications for cost, resource allocation, and toxicity of therapy. Stopping chemotherapy early in responders did not cause rapid relapse. Since drug resistance apparently develops early during therapy, new approaches to modify resistance should be more useful than continuous chemotherapy.

Adult↗
PubMed1990

Assessment of renal toxicity by urinary enzymes in patients receiving chemotherapy with 8-methyl-8-acetylenic-putrescine.

Renal toxicity was assessed in 19 patients receiving methyl acetylenic putrescine (MAP), an irreversible inhibitor of ornithine decarboxylase. Patients received 250 mg t.d.s. for up to 13 weeks. This dose effectively inhibited the target enzyme, as shown by elevations in decarboxylated S-adenosyl methionine levels. No significant nephrotoxicity was observed in these patients as determined by plasma urea, creatinine and creatinine clearance measurements, although minor elevations of the urinary enzymes lactate dehydrogenase, N-acetyl-beta-glucosaminidase, alkaline phosphatase and alanine aminopeptidase were observed. As this could represent sub-clinical renal damage, caution should be exercised when using MAP in combination with other cytotoxic drugs.

Acetylglucosaminidase↗
PubMed1990

A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.

Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6 g m-2, above which dose-limiting hepatic toxicity was observed. Patient tolerance was significantly better using the 36 h infusion compared to patients receiving the drug by a 30 min infusion; in particular, there were no reports of nausea or vomiting. No responses were seen in these patients. Detailed pharmacokinetics were performed at 6 g m-2 comparing the 36 h and 30 min infusions in four patients. Parent drug AUC values were lower for the 36 h infusion, 67.8 micrograms ml-1 h-1 compared to 232 micrograms ml-1 h-1 for the 30 min infusion. AUC values for the 3-hydroxy metabolite were much higher following the 36 h infusion: 55.4 compared to 18.6 micrograms ml-1 h-1. In contrast, the amide metabolite was not detected following the 36 h infusion, but AUC values of 23 micrograms ml-1 h-1 were seen after the 30 min infusion. The mean peak plasma level was 72 micrograms ml-1 following 6 g m-2 given by a 30 min infusion compared to 2.8 micrograms ml-1 following the prolonged infusion. Clearance was higher following the 36 h infusion: 97.6 versus 24.4 l h-1.

Adult↗
PubMed1990

Indications for placement of drains in the splenic fossa.

Drainage of the splenic fossa has for years remained a controversial issue. A large potential space exists in the left hypochondrium following splenectomy. Proponents of the use of drainage maintain that drainage is safe, efficacious in removal of blood, serum, and pancreatic enzymes, and carries little, if any, risk of subsequent infectious morbidity. Critics of the use of drainage cite the heretofore reported high incidence of subphrenic abscess formation in those patients in whom drains are placed as the reason for abandoning routine or therapeutic drainage of the splenic fossa.

Drainage↗
PubMed1989

Single high-dose (45 mg) infusions of aminohydroxypropylidene diphosphonate for severe malignant hypercalcemia.

A 3-hour single intravenous infusion of aminohydroxypropylidene diphosphonate (APD) 45 mg was given to 25 patients with malignant hypercalcemia. There were seven patients with breast cancer, eight with lung cancer, and ten with a variety of other cancers. Twenty-four patients responded to a single APD 45 mg infusion, 18 of whom (75%) had falls in plasma calcium to below the upper limit of normal (less than or equal to 2.75 mmol/l). Of 15 patients who had severe hypercalcemia, i.e., plasma calcium levels greater than 3.5 mmol/l, 14 responded and 9 (60%) achieved normocalcemia. Five patients developed hypocalcemia. One patient with lung cancer developed spontaneously reversible acute dyspnea after APD which was considered to be an idiosyncratic drug reaction. Single short-duration infusions of APD 45 mg are very effective in correcting malignant hypercalcemia in the majority of patients and are particularly suitable for patients with pre-APD plasma calcium levels greater than 3.5 mmol/l, who are less likely to develop hypocalcemia.

Adult↗
PubMed1989

A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response.

As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.

Adult↗
PubMed1989

Radiation sensitivity of human lung cancer cell lines.

X-Ray survival curves were determined using a panel of 17 human lung cancer cell lines, with emphasis on non-small cell lung cancer (NSCLC). In contrast to classic small cell lung cancer (SCLC) cell lines, NSCLC cell lines were generally less sensitive to radiation as evidenced by higher radiation survival curve extrapolation numbers, surviving fraction values following a 2 Gy dose (SF2) and the mean inactivation dose values (D) values. The spectrum of in vitro radiation responses observed was similar to that expected in clinical practice, although mesothelioma was unexpectedly sensitive in vitro. Differences in radiosensitivity were best distinguished by comparison of SF2 values. Some NSCLC lines were relatively sensitive, and in view of this demonstrable variability in radiation sensitivity, the SF2 value may be useful for in vitro predictive assay testing of clinical specimens.

Adenocarcinoma↗
PubMed1989

Phase II study of low dose aminoglutethimide 250 mg/day plus hydrocortisone in advanced postmenopausal breast cancer.

Low dose aminoglutethimide 125 mg twice daily plus hydrocortisone 20 mg twice daily was shown to produce oestrogen and androgen suppression in postmenopausal women. A phase II study was carried out in 101 patients with advanced postmenopausal breast cancer. Objective response rates were 4% CR and 21% PR. Fourteen per cent had disease stabilization for more than 6 months (SD). Soft tissue sites showed the best response. Responses occurred in previous tamoxifen failures (28%) including SD. Toxicity was less than reported for higher dose regimens or low dose aminoglutethimide without hydrocortisone, particularly nausea and drowsiness. Survival from first relapse and start of therapy was not significantly different between PR and SD. This dosage regimen appears of comparable efficacy to previously reported higher dosage regimens with reduced toxicity compared to low dose regimens without hydrocortisone.

Aged↗