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Biomedical subjects

M J Lind

Publications and source records attributed to M J Lind.

At least 19 recordsLinked to original sources
PubMed1992

Phase I/II study of intraperitoneal iproplatin in patients with minimal residual disease following platinum-based systemic therapy for epithelial ovarian carcinoma.

13 patients with minimal residual disease following platinum-based systemic therapy for epithelial ovarian cancer were treated with intraperitoneal iproplatin. A total of three cycles were given at monthly intervals. All patients had minimal residual disease (defined as less than 2 cm in diameter) or positive cytology documented at second look laparotomy following systemic chemotherapy. Iproplatin was administered via a temporary dialysis catheter (n = 11) or a semi permanent Tenckhoff peritoneal dialysis catheter (n = 2). The dose of iproplatin ranged from 150 to 450 mg/m2. No responses to therapy were documented. In this trial the major toxic side effects of iproplatin were thrombocytopenia, diarrhoea, nausea and vomiting. The maximum tolerated dose was 300 mg/m2.

Adult↗
PubMed1992

A phase II trial of goserelin (Zoladex) in relapsed epithelial ovarian cancer.

Thirty patients with advanced epithelial ovarian cancer were treated with the luteinising hormone releasing agonist, goserelin. There were two partial responses lasting 40 and 105 weeks respectively. In addition five patients had disease stabilisation lasting 25, 35, 40, 66 and 70 weeks respectively and 23 patients had progressive disease. No significant or unexpected toxicities occurred. This minimally toxic therapy halted disease progression for 6 months or more in 23% of patients, the majority of whom were heavily pretreated. There were five early deaths due to disease progression. The use of goserelin in patients with epithelial ovarian cancers resistant to or relapsing soon after first line platinum based chemotherapy needs to be further evaluated.

Adult↗
PubMed1991

Comparative intraperitoneal pharmacokinetics of three platinum analogues.

The pharmakokinetic profiles of intraperitoneally infused platinum analogues were determined in 13 women exhibiting minimal residual disease following surgery and systemic chemotherapy for epithelial ovarian cancer or fallopian tube carcinoma by following the disposition of tracer doses of 195mPt radiolabel. Six patients received iproplatin, four were given cisplatin and three received carboplatin. The present data demonstrate no difference in the disposition of total platinum between these three analogues, but differences in the kinetics of free platinum may exist.

Antineoplastic Agents↗
PubMed1991

A phase II study of ifosfamide and a2b-interferon in advanced non-small-cell lung cancer.

A total of 45 patients with advanced non-small-cell lung cancer were treated with a combination of 1.5 g/m2 ifosfamide given on days 1-5 every 3 weeks for four courses with 3 million IU a2b-interferon (Intron A) given s.c. three times a week for 12 weeks. Nine objective responses were seen, including two complete responses (CRs) and seven partial responses (PRs). Haematological and non-haematological toxicities were generally mild and did not necessitate discontinuation of therapy.

Adult↗
PubMed1991

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.

Ambulatory Care↗
PubMed1990

The effect of route of administration and fractionation of dose on the metabolism of ifosfamide.

The measurement of urinary ifosfamide, isophosphoramide mustard, dechloroethyl ifosfamide and carboxyifosfamide using high-performance thin-layer chromatography with photographic densitometry (TLC-PD) is described. This technique was also used to demonstrate the large inter-individual variation in the ifosfamide metabolic profile of patients receiving the drug as single-agent therapy for non-small-cell lung cancer. In addition, oral administration was shown to result in higher levels of these metabolites in the urine. Fractionation of the ifosfamide dose over several days resulted in increasing levels of metabolites in the urine, consistent with auto-induction of ifosfamide metabolism.

Administration, Oral↗
PubMed1990

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.

Ambulatory Care↗
PubMed1990

Therapy for poor-risk patients with small-cell lung cancer using bolus ifosfamide and oral etoposide.

A total of 47 poor-risk small-cell lung cancer patients (elderly, poor performance status, recent myocardial infarction, or extensive-stage disease with biochemical abnormalities) were treated with a regimen of bolus ifosfamide at 1.5 g/m2 with equidose mesna as a 30-min infusion, followed by 100 mg oral etoposide daily for 8 days. Therapy was repeated every 3 weeks. The overall response rate was 60% (75% for limited-stage and 48% for extensive-stage disease), and the overall median survival was 7 months. Patients' performance status significantly improved with therapy (P less than 0.0001). Despite the poor-risk factors, the Manchester prognostic score was applied and verified. The median survival was 8 months for patients with a good prognosis, 6 months for those with an intermediate prognosis and 2.5 months for poor-prognosis patients (P = 0.0002). Therapy was well tolerated. The median WHO grade of haematological toxicity was 2 (range, 0-4). Only 10/226 (4%) courses were delayed due to leukopenia. Blood transfusions followed 18/226 (8%) courses. Intravenous antibiotics were given following 15/226 (7%) courses. No patient required platelet support. Poor-risk patients who have a good or intermediate Manchester prognostic score may benefit from this low-toxicity regimen.

Aged↗
PubMed1990

Ifosfamide, doxorubicin and etoposide in small cell lung cancer patients with poor prognosis.

61 patients with small cell lung cancer in a poor prognosis group were treated with chemotherapy and with thoracic radiotherapy if they had 'limited stage' disease. No prophylactic cranial irradiation was given. Chemotherapy comprised doxorubicin 50 mg/m2 and ifosfamide 5 g/m2 with mesna on day 1, and etoposide 120 mg/m2 intravenously on days 1 and 2 and 240 mg/m2 orally on day 3. Treatment was repeated every 3 weeks for a maximum of six courses and no dosage reductions were allowed. Complete response rate in limited stage patients was 55% and 16% in extensive stage patients. The partial responses were 38% and 66% respectively. Overall median survival was 10.5 months with 2-year survival of 14%. The corresponding values for limited stage disease were 13 months and 16% and for extensive stage disease 8 months and 13%. Despite the addition of doxorubicin at a somewhat higher dosage than usual in this type of regimen and a policy of no dose reduction, toxicity was generally mild. There was, however, a 19% relapse rate in complete responders in the brain, apparently as the sole site of disease.

Adult↗
PubMed1990

The effect of age on the pharmacokinetics of ifosfamide.

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.

Adult↗
PubMed1989

The effect of ifosfamide and its metabolites on intracellular glutathione levels in vitro and in vivo.

The effect of ifosfamide and its metabolites on intracellular levels of glutathione in P388 cells in vitro has been studied. It is demonstrated that glutathione depletion occurs only in the presence of 4-hydroperoxyifosfamide and chloroacetaldehyde. In contrast isophosphoramide mustard had no effect on glutathione levels in intact cells. The concentration of 4-hydroperoxyifosfamide required to reduce glutathione levels by 50% was approximately 1 mM and this represents a concentration far in excess of that achievable in patients receiving the drug. However the concentration of chloroacetaldehyde (approximately 100 microM) required to reduce intracellular levels of glutathione to a similar extent is attained in patients receiving ifosfamide. The glutathione levels in lymphocytes isolated from a patient undergoing an eight hour infusion of ifosfamide showed a marked decrease to about 30% of their original value. We conclude that ifosfamide causes glutathione depletion in vivo and the majority of this can be accounted for by the production of chloroacetaldehyde.

Acetaldehyde↗
PubMed1989

Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma.

20 patients with advanced non-small cell lung cancer were treated with ifosfamide and mesna 1.5 g/m2 daily for 5 days; 10 received the drug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5-day period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the i.v. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients' waking hours. Nadir blood counts and response rates were similar in both arms. The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. In addition it was shown that the total and nonrenal clearance of the drug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed i.v. doses.

Administration, Oral↗
PubMed1989

Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution.

The pharmacokinetics of intravenous ifosfamide were determined in 16 patients with carcinoma of the bronchus. In all 25% (4) of these patients were obese (i.e. greater than 20% over their ideal body weight). The terminal elimination half-life (t1/2 beta) was found to be higher in the obese group than in the control group (6.36 h, range 5.77-7.45 h) vs 4.95 h, range 1.82-6.48 h) (P less than 0.05). This prolongation of the elimination half-life was due to an increased volume of distribution (Vd beta) in the obese group (42.81 1, range 35.49-51.90 l) vs 33.70 l range (17.76-50.62 l) (P less than 0.05). There was therefore no significant difference in total plasma clearance between the obese and normal groups. No correlation of ifosfamide plasma half-life was observed with total body weight (TBW) or ideal body weight (IBW). However, a significant positive correlation was observed between the percentage of IBW and plasma half-life. A strong positive correlation was observed between IBW and the plasma clearance of ifosfamide. The Vd beta correlated with both TBW and the percentage of IBW, but not with IBW itself. When Vd beta was normalised for IBW, there was a strong positive correlation with the percentage of IBW, suggesting that ifosfamide distribution into the TBW is higher than that into the IBW.

Adult↗
PubMed1989

The role of postoperative alkylating agent therapy in early-stage epithelial ovarian cancer.

Forty-six patients with early (Stage I and II) ovarian cancer referred as free of residual disease after primary surgery, selected for high-risk features, were treated with adjuvant single-agent alkylating therapy comprising either intravenous cyclophosphamide (1 g/m2) in 36 patients, or oral melphalan (0.2 mg/kg daily for 5 days) in eight. Cyclophosphamide was repeated every 3 weeks for 10 cycles and melphalan every 6 weeks for 12 cycles. With a median follow-up of 36+ months, 18 patients have relapsed. The actuarial 5-year relapse-free survival was 48% and the overall 5-year survival was 54%; median survival was 84 months. Pretreatment FIGO stage was the single most important predictor of relapse-free and overall survival duration. For patients with Stage IA and IB tumours the 5-year actuarial relapse-free survival was 89%; for patients with stage IC and II (all substages), the 5-year relapse-free survival was 24% (P = 0.001). For this latter group adjuvant single alkylating agent therapy was not adequate and alternative therapeutic regimens are required. The problem of suboptimal primary surgical staging is also addressed.

Administration, Oral↗