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Biomedical subjects

D Cunningham

Publications and source records attributed to D Cunningham.

At least 289 records · Page 16Linked to original sources
PubMed1986

Influence of polysorbate 80 (Tween 80) and etoposide (VP-16-213) on the pharmacokinetics and urinary excretion of adriamycin and its metabolites in cancer patients.

Polysorbate 80 (Tween 80) is present in the IV pharmaceutical preparation of VP-16-213 marketed as VePesid (Bristol-Myers) (etoposide 100 mg, benzylalcohol 150 mg, polyethylene glycol 300 3250 mg, citric acid 10 mg, Tween 80 400 mg and absolute alcohol to 5 ml per 100 mg ampule of VP16), to increase its miscibility with blood. We have examined the effects of 400 mg/m2 Tween 80 IV and 100 mg/m2 VP16 on the pharmacokinetics of Adriamycin (ADR, 30 or 40 mg/m2). ADR and metabolite concentrations were measured by HPLC. ADR plasma profiles were best fitted to a bi-exponential decay and a two-compartment open model. Tween 80 did not alter the values of the two ADR half-lives, nor did it affect metabolite kinetics of their urinary excretion. However, in a similar manner and consistently in all patients, both Tween 80 and VP16 increased the volume of distribution of the central compartment for ADR up to 3-fold, decreased the AUC of ADR up to 2-fold and increased its clearance by exactly the same amount. These effects were due to reduced plasma ADR concentrations during the early phase of its kinetics. Urinary excretion of ADR was also increased. In conclusion, VP16 is likely to affect the kinetics of drugs administered with it: early plasma concentrations will fall due to a general physiological effect of Tween 80 on the apparent volume of circulation.

Adult↗
PubMed1986

Small cell lung cancer: results of a phase II study of 1,2,4 triglycidylurazol.

Fourteen patients with small cell lung cancer (SCLC) received treatment with 1,2,4 triglycidylurazol (TGU) 600 mg/m2 or 800 mg/m2 as an IV bolus every 4 weeks. Twelve patients had received previous chemotherapy consisting of a five-drug regimen given for the short duration of only 9 weeks. All had measurable disease. Following TGU 11 patients had progressive disease and 3 patients had stable disease. The most frequent toxicity was nausea and vomiting, which occurred in all patients but was generally mild. Myelosuppression was common with a median white blood count nadir of 2.5 X 10(9)/l (range 0.9-7.4 X 10(9)/l) and median platelet count nadir of 76 X 10(9)/l (range 5-173 X 10(9)/l. Alopecia, thrombophlebitis, and hepatic or renal toxicity were not observed. In this study, TGU had no activity in SCLC, and the dose-limiting toxicity was myelosuppression.

Antineoplastic Agents↗
PubMed1986

Etoposide: a pharmacokinetic profile including an assessment of bioavailability.

The pharmacokinetics of intravenous etoposide (50-150 mg m-2) have been studied in 17 patients. Bioavailability studies on either the capsule or intravenous (i.v.) formulation were performed in 13 patients, 7 of whom received both oral formulations given in the dose range 50-250 mg m-2. After i.v. administration the mean +/- SD half-lives were t1/2 alpha 0.62 +/- 1.01 h and t1/2 beta 6.04 +/- 2.5 h. The bioavailability of etoposide was extremely variable: for the capsule it was 38 +/- 14% (range 10-55) and for the i.v. formulation it was 53 +/- 25% (range 31-88). The i.v. formulation was not significantly better than the capsule. The results confirm the low and variable bioavailability of oral etoposide.

Administration, Oral↗
PubMed1986

TNO-6 has no effect in gastrointestinal cancer: N-acetyl-glucosaminidase shows renal damage.

Twenty-five patients, 16 with gastric cancer and nine with colonic cancer, received TNO-6 30 mg m-2 every four weeks. No objective tumour response was recorded. Nausea and vomiting occurred in 21 patients and was severe in 17. Severe marrow suppression developed in five patients. Renal function was unaffected in all but one patient who developed renal failure, probably as a result of septicaemia. However, the renal tubular enzyme N-acetyl-beta-D-glucosaminidase was measured in six patients and showed a rise in all. In this study TNO-6 had no anti-tumour activity in gastrointestinal malignancy, but produced significant renal tubular damage.

Acetylglucosaminidase↗
PubMed1986

Marked inter-patient variation in adriamycin biotransformation to 7-deoxyaglycones: evidence from metabolites identified in serum.

Several factors are known to modulate the clinical pharmacokinetics of adriamycin (ADR). Biotransformation has not been studied in this context because of problems identifying serum metabolites. We have studied patterns of ADR biotransformation in 25 patients with normal liver and kidney function and in most cases receiving ADR for the first time. Three major serum metabolites were identified by HPLC, TLC and mass spectrometry and their pharmacokinetics were followed over a 24-hr period. The relative amount of each metabolite present in a patient was quantitated by calculating its AUC. Adriamycinol was the major metabolite detected in the majority of patients. Adriamycin 7-deoxyaglycone was detected in the serum of 15 patients where it accounted for a small percentage of the total ADR concentration (1-5%). Its apparent half-life was normally less than 30 min. Adriamycinol 7-deoxyaglycone was detected in the serum of only 13 patients where it accounted for a greater percentage of the total ADR concentration (10-20%). Its pharmacokinetics exhibited marked inter-patient variations, with apparent half-lives ranging from 0.1 to 24 hr. There was a correlation between the AUC of ADR and the relative amount of metabolites present in each patient (r = 0.73). Thus, biotransformation may explain, partly, inter-patient variations in ADR pharmacokinetics. In turn, variations in biotransformation are dictated by whether or not ADR is converted to 7-deoxyaglycones.

Biotransformation↗
PubMed1986

A clinical and pharmacokinetic phase I study of 1,2,4-triglycidylurazol (TGU, NSC 332488).

Twenty-six patients with advanced malignancies received TGU given as an intravenous (i.v.) bolus in physiological saline at 3 weekly intervals. The starting dose was 30 mg/m2 with standard graded escalations to 900 mg/m2. Myelosuppression occurred at 800 mg/m2, with a mean nadir of 2.0 +/- 0.8 X 10(9)/l and a mean nadir platelet count of 41 +/- 31 X 10(9)/l. At 800 or 900 mg/m2 nausea and vomiting was WHO grade 0 in 5, grade I in 6, grade II in 11 and grade III in 10 courses of therapy. Alopecia did not occur. TGU was given by i.v. infusion at 800 mg/m2 in 2 patients, both of whom developed severe thrombophlebitis. Five patients given TGU by i.v. bolus developed mild phlebitis. No renal, hepatic or cardiac toxicity was noted. Two patients had partial responses; both had adenocarcinoma of unknown primary origin, one of whom had been resistant to prior therapy with FAM. An HPLC analytical method was developed with a sensitivity of 250 ng/ml. The data from 7 patients studied best fit a one compartment pharmacokinetic model with an exponential decay and a t1/2 of only 2.1 min. In conclusion, the dose limiting toxicity of TGU appears to be myelosuppression and we would recommend a dose of 800 mg/m2 given as an intravenous bolus every 4 weeks for future phase II trials.

Adult↗
PubMed1986

Adult respiratory distress syndrome in a child with acute epiglottitis.

Intubation of a 23-month-old child suffering epiglottitis was complicated by pulmonary edema progressing to the adult respiratory distress syndrome. Increased pulmonary shunt and pulmonary hypertension required high levels of positive end-expiratory pressure and prolonged mechanical ventilation to correct hypoxemia. A possible role for a cuffed endotracheal tube in epiglottitis is discussed.

Acute Disease↗
PubMed1986

A new low energy power source for catheter ablation.

The current technology in the area of catheter ablation for cardiac arrhythmia is limited by the amount of damage sustained by the ablated area in relationship to the energy used. Thus, a newly designed power source is described in this report in three patients, two with resistant atrial flutter/fibrillation and one with a reentrant AV tachycardia. The delivered energy in all patients was 5.1 joules or less with the exception of a single shock of 37.5 joules, which was required in one patient. We conclude that this effort of low energy ablation using a unique power source represents an advance in the field of ablation that merits further evaluation.

Aged↗
PubMed1986

Continuous ambulatory pulmonary artery pressure monitoring. A new method using a transducer tipped catheter and a simple recording system.

A transducer tipped catheter and simple recording system were used for the continuous measurement of ambulatory pulmonary artery pressure. The pulmonary artery pressure was recorded on a miniaturised tape recorder and replayed via an optical writer. Pulmonary arterial systolic and diastolic pressures can be analysed on a beat to beat basis. Continuous ambulatory monitoring was performed for a total 288 hours in 13 patients who were undergoing routine investigation for coronary artery disease. There was less than 1% zero drift and 0.25% linearity error per full scale pressure. The frequency response of the entire system was flat to 8 Hz with a linear phase delay. The transducer tipped catheter and a conventional fluid-filled system were used to measure left ventricular and pulmonary artery end diastolic pressures in eight patients. The correlation between the results obtained by the two methods was excellent. This method could be used at any centre equipped for ambulatory electrocardiographic monitoring.

Adult↗
PubMed1986

Use of Leu M1 and antiepithelial membrane antigen monoclonal antibodies for diagnosing Hodgkin's disease.

Biopsies of 82 patients diagnosed as having Hodgkin's disease were reviewed. Seventeen were reclassified histologically as non-Hodgkin's lymphoma or reactive lymphoid hyperplasia. A substantial number of cases of Hodgkin's disease were negative when stained with Leu M1. Staining for Leu M1 was not found in the cases of non-Hodgkin's lymphoma or reactive lymphoid hyperplasia. With the exception of the lymphocyte predominant nodular subtype of Hodgkin's disease, epithelial membrane antigen staining was seen in a few cases of Hodgkin's disease and non-Hodgkin's lymphomas. This was not a useful discriminating feature.

Antibodies, Monoclonal↗
PubMed1986

T-cell lymphoblastic lymphoma of the uterus complicated by Chlamydia trachomatis pneumonia.

This is the first documented case of a T-cell lymphoblastic lymphoma arising in the uterus. At presentation, the patient also had a life-threatening pneumonia due to Chlamydia trachomatis which responded to erythromycin and tetracycline. Cytotoxic therapy produced partial tumour regression, but the patient died 14 weeks after diagnosis, probably as a result of intercurrent infection.

Adult↗
PubMed1986

Short duration combination chemotherapy in the treatment of small cell lung cancer.

Ninety five patients (57 with limited disease and 38 with extensive disease) with previously untreated small cell lung cancer were entered into a study of short duration combination chemotherapy with intravenous cyclophosphamide (750 mg/m2) on day 1, adriamycin (40 mg/m2) on day 1, and etoposide VP-16 (100 mg/m2) on days 1, 2, and 3, with the addition on day 10 of methotrexate 50 mg/m2 with folinic acid rescue and vincristine 2 mg. The treatment was repeated on day 22 and only three courses were given. No maintenance chemotherapy was given, though patients with a complete response received radiotherapy (30-40 Gy (3000-4000 rads] to the primary site in most cases. Forty nine patients (86%) with limited disease achieved a response, with 26 (46%) complete remissions. Twenty five patients (66%) with extensive disease had a response, but only eight (21%) had a complete response. Actuarial survival analysis for the whole patient population showed a median survival of 13 months for patients with limited disease and seven months for those with extensive disease. The median survival was 14 months for those patients with limited disease who achieved a complete response, but only 10 months for non-responders. Myelosuppression was the major expression of toxicity. There were three deaths related to treatment and seven patients had febrile episodes during neutropenia that required antibiotics. Mucositis, which was usually mild, occurred in 49% of patients. The primary site was the main site of initial relapse in 56% of the patients who relapsed. Among patients with limited disease who achieved a complete response, relapses at the primary site were less common in those who received radiotherapy (five out of 12) than in those who did not (all eight). The results indicate that this short duration chemotherapy in small cell lung cancer gives response rates and the potential for long term survival similar to those obtained in other series while allowing patients the maximum time free from treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Phase I and pharmacokinetic study of LM985 (flavone acetic acid ester).

We have conducted a Phase I and initial clinical pharmacological evaluation of LM985, the first of a series of compounds based on the flavone ring structure to be considered for clinical trial in malignant disease. The drug was administered i.v. to 26 patients with advanced cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible hypotension occurring during drug infusion; no leukopenia, alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with colorectal carcinoma had stable disease after three courses of LM985; however, no other responses were seen. Pharmacokinetic and in vitro drug degradation studies imply that the ester LM985 is hydrolyzed to LM975 (flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal tumor models, but it does not have the cardiovascular side effects seen with LM985 (hypotension and bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of LM985 can be given without dose limiting cardiovascular toxicity.

Adult↗
PubMed1985

Alfacalcidol as a modulator of growth of low grade non-Hodgkin's lymphomas.

Ten patients with low grade non-Hodgkin's lymphoma (seven follicular small cleaved and three small lymphocytic) were treated with 1 microgram oral alfacalcidol (1 alpha-hydroxycholecalciferol) daily. Of the seven patients with lymphomas of follicular small cleaved subtype, one achieved complete and three partial remission, whereas none of three patients with small lymphocytic lymphomas responded. In seven of the 10 patients, 1,25(OH)2D3 receptors were measured in tissue from lymph nodes, and a positive correlation between the presence and amount of receptor and response to alfacalcidol was found. These preliminary data suggest that alfacalcidol has appreciable antitumour activity in low grade non-Hodgkin's lymphomas.

Adult↗