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Biomedical subjects

D J Kerr

Publications and source records attributed to D J Kerr.

At least 163 records · Page 9Linked to original sources
PubMed1990

Phase I and pharmacokinetic study of intraperitoneal thioTEPA in patients with ovarian cancer.

A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy.

Adult↗
PubMed1990

The pharmacokinetics of 5-fluorouracil administered by arterial infusion in advanced colorectal hepatic metastases.

The pharmacokinetics of 5-fluorouracil (5FU) following its administration via the hepatic artery in conjunction with biodegradable albumin microspheres and angiotensin II have been studied. Peripheral venous concentrations of 5FU are lower and plasma clearance values higher following intrahepatic arterial administration compared with a similar dose administered by intravenous infusion over both 2 h and 24 h. For the 2 h drug infusions, plasma 5FU concentrations following co-treatment with angiotensin II and microspheres via the hepatic artery were intermediate between those of arterial and venous infusions of 5FU alone. There was a trend towards the peak plasma drug concentrations and the area under the plasma concentration-time curve (AUC) being significantly lower following co-treatment with angiotensin II and microspheres compared with intra-arterial and intravenous infusions of 5FU over 24 h. Co-administration of 5FU, angiotensin II and microspheres via the hepatic artery may reduce drug exposure in the systemic compartment and therefore may increase the therapeutic ratio of 5FU administration via the hepatic artery.

Colorectal Neoplasms↗
PubMed1990

A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer.

Thirty-one patients were entered into a pilot study combining oral quinidine with epirubicin 100 mg m-2 as first line chemotherapy in advanced breast cancer. Three patients were treated with quinidine 1 g b.d., and developed symptoms of toxicity. Of eight subsequent patients treated with quinidine 500 mg b.d., two experienced tiredness and nausea and one severe oral toxicity with epirubicin. The remaining 20 patients received quinidine 250 mg b.d.; one developed cinchonism and one malaise, the remainder showing no excess toxicity compared with epirubicin alone. The median nadir WBC was similar with or without quinidine (2.3 vs 1.6 x 10(9) l-1) as was median nadir platelet count (175 vs 157 x 10(9) l-1). There was no evidence of significant cardiac toxicity. The median plasma quinidine level achieved was 5.6 mumol l-1 (range 2.1-22.1), which is within the range of concentrations which is effective in vitro at reversing experimental anthracycline resistance. A randomised controlled study is proposed to assess the impact of this potential modulation on the efficacy of epirubicin in advanced breast cancer.

Adult↗
PubMed1990

Long-term sequelae of treatment for testicular germ cell tumours.

Seventy-four patients previously treated in our department for germ cell tumour of the testis underwent a series of tests to determine the frequency of long-term therapeutic complications. All had received cisplatin-based chemotherapy as part of their treatment. There was a significant deterioration in renal function throughout the group. Eighteen (24%) had supine blood pressure greater than systolic 140 mmHg or diastolic 90 mmHg after treatment but hypertension did not correlate with renal impairment. Raynaud's phenomenon was common after chemotherapy (26/74) as was persistent sensory neuropathy (23/74). Although 34% had testosterone levels below the normal range, only six patients had a low free testosterone index with one testis still in situ; 18 patients have fathered children after chemotherapy. Approximately half of the patients completed a psychosexual questionnaire and some 30% of them admitted to sexual problems which they attributed to their treatment. Long-term sequelae of cisplatin-based chemotherapy for testicular malignancy are frequent and persistent, and follow-up of these patients should include prospective measurement of changes in blood pressure.

Adolescent↗
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

A comparison of regional and systemic chemotherapy for hepatic metastases.

A 48-year-old man with colorectal liver metastases underwent insertion of an hepatic arterial infusion catheter for regional chemotherapy. Postoperative hepatic arterial perfusion scintigraphy showed that only part of the liver was being perfused by this route. Chemotherapy was administered weekly via the catheter. In effect, part of the liver received regional chemotherapy, whereas the remainder of the organ was exposed to systemic chemotherapy. Ultrasonography demonstrated shrinkage of the metastases in the area of liver receiving regional therapy, whereas disease progression occurred in the region of liver receiving 'systemic' treatment. This patient demonstrates that tumour may respond to regional chemotherapy despite disease progression on systemic therapy and suggests that a controlled trial would yield valuable data.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1989

Characterization of the major metabolites of flavone acetic acid and comparison of their disposition in humans and mice.

Flavone acetic acid represents a novel chemical structure currently undergoing clinical investigation. Broad spectrum activity has been observed in preclinical animal screens, but at doses close to toxic in mice. Phase I clinical trials have established that equivalent plasma drug levels can be achieved in humans, but to date Phase II trials have not demonstrated significant activity in a range of tumor types. Little is known about the drug's biotransformation, although metabolites have been implicated in proposed mechanisms of action. In this paper, we have purified the two major human metabolites present in urine (also the only two metabolites detected in plasma) and characterized their structure, chemical properties, activity, and pharmacokinetics. Metabolite 1 (M1) was a glucuronide conjugated to the 8-acetic acid grouping (Mr 456), was chemically labile, and showed a strong tendency to undergo chemical rearrangement at mildly alkaline pH. Metabolite 2 (M2) was also a glucuronide (Mr 456) but appeared to be an unusual isomer of M1. Both were noncytotoxic. In patients, biotransformation represented the predominant mechanism of drug clearance with as much as 80% of a low dose (0.5 g/m2) recovered in urine as M1 and M2 after only 6 h. At high dose (4.8 to 8.6 g/m2, 1- to 6-h infusion) the appearance of peak concentrations of metabolites in plasma and urine was delayed, apparently due to saturation of glucuronidation pathways. This resulted in an overall reduction in drug clearance by 3- to 4-fold. Mice cleared flavone acetic acid much more slowly than patients (289 ml/h/m2 after 600 mg/m2 i.p. versus 2.3 liters/h/m2 after 4.8 g/m2-1-h i.v. infusion) without producing M1 or M2. A different metabolite, exhibiting characteristics of a conjugate, was detected at low concentrations in plasma, tissues, and tumor. Extensive metabolism to inactive products followed by their rapid clearance may contribute to the lack of activity so far seen in humans.

Animals↗
PubMed1989

Could interspecies differences in the protein binding of flavone acetic acid contribute to the failure to predict lack of efficacy in patients?

We investigated the differences in plasma protein binding of flavone acetic acid (FAA) in mice and men in an attempt to explain the inter-species differences in response. In vitro data indicate both qualitative and quantitative differences in FAA protein binding: approximately 80% is bound in humans, with two different types of binding site identified; in mice, 70% is bound and only one binding site could be described. Protein binding is dose-dependent in both species. Plasma samples from 20 patients receiving FAA showed that most achieved levels that would be active in mice. We conclude that these differences in protein binding are insufficient to explain totally the observed differences in response.

Animals↗
PubMed1989

Clinical evaluation of angiotensin II enhanced perfusion scintigraphy in metastatic liver disease.

The hepatic perfusion index (HPI) may be of value in the diagnosis of liver micro-metastases. However, raised values of HPI also occur in some benign liver conditions (e.g. cirrhosis), thereby weakening the diagnostic power of this test. It has been suggested that infusion of the vaso-active agent angiotensin II might improve the predictive value of dynamic scintigraphy because it has been shown to alter liver perfusion in patients with metastatic liver disease. Basal HPI values were not significantly different in a group of patients with metastases (n = 10) and a group with cirrhosis (n = 9). A significant rise in HPI occurred in the metastatic group using angiotensin II enhancement (p less than 0.01, Wilcoxon test). In the cirrhotic group there was no significant increase in the HPI with angiotensin II enhancement. Within the groups, there was considerable variation in response, with eight of ten metastatic and five of nine cirrhotic patients showing a rise in HPI during an angiotensin II infusion. As a result, there was complete overlap in the angiotensin II enhanced HPI for the two groups. Angiotensin II enhancement of HPI is therefore unlikely to improve the diagnostic power of dynamic scintigraphy in individual patients with established hepatic disease.

Angiotensin II↗
PubMed1989

The cytostatic effects of alpha-interferon may be mediated by transforming growth factor-beta.

There is some evidence to suggest that transforming growth factor-beta (TGF-beta) mediates the cytostatic effects of the anti-oestrogen tamoxifen. In this study we have demonstrated that alpha-interferon has a significant anti-proliferative effect on the oestrogen receptor-positive human breast cancer cell line ZR-75. There is decreased phenotypic expression of the oestrogen receptors (to about 30% of control values) and increased TGF-beta mRNA. Under the growth conditions used here, ZR-75 cells had approximately 5800 TGF-beta binding sites per cell, with an apparent dissociation constant of 70 pm, and we have shown that the anti-proliferative effects of alpha-interferon can be reduced by 60% by co-treating the cells with a TGF-beta polyclonal antibody. The cytostatic effects of alpha-interferon may therefore be mediated by TGF-beta in this human breast cancer cell line.

Antibodies↗
PubMed1988

Comparative cellular uptake and cytotoxicity of a complex of daunomycin-low density lipoprotein in human squamous lung tumour cell monolayers.

In an attempt to target cytotoxic drugs to tumour cells daunomycin-low density lipoprotein (LDL) complexes were synthesised. Human squamous lung tumour cells in vitro have large numbers of high affinity cell surface LDL receptors (Vmax = 19 ng LDL/micrograms cell protein per 24 hr; Km = 23 micrograms/ml). Cellular uptake of daunomycin and LDL-daunomycin was rapid and approached equilibrium by approximately 3 hr. Intracellular daunomycin concentrations were similar at each time point regardless of whether free drug or the complex was used. The degree of intracellular drug metabolism differed markedly with significantly higher production of daunomycinol following exposure to free daunomycin for 90 min. Daunomycin and LDL-daunomycin were equally cytotoxic in vitro (respective clonogenic ID90s of 1 microgram/ml and 0.7 microgram/ml). Fluorescence microscopy indicated that both free daunomycin and LDL-daunomycin have a punctate, granular distribution within the cytoplasm.

Carcinoma, Squamous Cell↗
PubMed1988

Optimisation of a reversed-phase high-performance liquid chromatographic method for the determination of flavone acetic acid and its major human metabolites in plasma and urine.

A high-performance liquid chromatographic method for the determination of flavone acetic acid (FAA) and its major human metabolites in plasma and urine is described. Two factors were identified as being the key to resolving the metabolites; pH and buffer ionic strength. Run at optimal conditions of 10 mM ammonium acetate, pH 5.5-propan-2-ol (80:20) and a column temperature of 40 degrees C on a muBondapak C18 10 microns particle column (30 cm X 3.8 mm I.D.), two major metabolites were identified [FAA, retention time (tR) 6.02 min +/- 0.5% coefficient of variation (C.V.); metabolite 1, tR 4.13 min +/- 1.1% C.V.; metabolite 2, tR 5.10 min +/- 0.5% C.V. and hesperidin, internal standard, tR 4.69 min +/- 1.6% C.V.]. A solid-phase technique using Bond Elut C2 40-microns particles is described which extracts FAA, metabolites and internal standard with efficiencies in excess of 90%. Considerable attention has to be paid to sample preparation: FAA has poor aqueous solubility at acidic pH and the metabolites degrade back to FAA via intermediates at alkaline pH. Both problems can be avoided by buffering and diluting samples with 10 mM ammonium acetate, pH 5.5.

Antineoplastic Agents↗
PubMed1988

Target organ disposition and plasma pharmacokinetics of doxorubicin incorporated into albumin microspheres after intrarenal arterial administration.

We synthesized doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-loaded human albumin microspheres (containing approximately 1% doxorubicin w/w) between 15 and 20 micron in diameter. Intrarenal arterial administration of 99mTC-labeled microspheres demonstrated a high renal entrapment ratio (97% of recovered radioactivity). The pharmacokinetics and metabolism of doxorubicin are different when it is administered in microspherical form. Peak plasma levels are lower (16 ng/ml versus 135 ng/ml) compared with treatment by a doxorubicin solution. Histologic studies showed that the microspheres were trapped within capillaries and small arterioles in the renal vascular arcade. It is apparent that chemoembolization with doxorubicin-loaded microspheres significantly reduces systemic exposure to the antineoplastic agent, and maintains intrarenal drug levels.

Albumins↗
PubMed1988

Cytotoxic-loaded albumin microspheres: a novel approach to regional chemotherapy.

Adriamycin-loaded albumin microspheres (15-40 micron diameter) incorporating 1 per cent by weight of Adriamycin were prepared by cross linking albumin with glutaraldehyde. After systemic administration in rats, the microspheres were trapped in the pulmonary capillary bed, biodegradation occurring over 48 h. After selective intrarenal arterial injection of 99mTc-labelled albumin microspheres in rabbits, 97 per cent of the injected microspheres were trapped within the kidney; less than 1 per cent were found in the contralateral kidney, lungs and liver. Similar results were obtained after selective intrahepatic arterial injection. The selective injection of cytotoxic-loaded microspheres may provide a reliable method of administering high concentrations of cytotoxic drug to a target organ without producing high serum levels; this technique may have a role in the management of solid tumours.

Animals↗
PubMed1988

Flavone acetic acid: a nonlinear pharmacokinetic model.

Flavone acetic acid pharmacokinetics were studied in 31 patients in a phase I clinical trial. The drug was given by i.v. infusions over 1, 1.5, 3, and 6 h at doses ranging from 0.5 to 6.4 g/m2. The pharmacokinetic parameters were determined according to a nonlinear model including Michaelis-Menten-type kinetics. The mean elimination half-life is 4.8 h and the mean volume of distribution of the central compartment, 7.61. Our model predicted a maximal tolerated dose (MTD) of 11.1 g/m2 on the basis of the "therapeutic window" concept, very close to the clinically observed MTD of 10 g/m2. This model is also operational when different protocols of inoculation are considered, such as a divided-dose schedule vs a unique infusion, and indicates that, at the MTD, injections should be made every 72 h to avoid drug accumulation.

Algorithms↗