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Biomedical subjects

W E Lindup

Publications and source records attributed to W E Lindup.

At least 19 recordsLinked to original sources
PubMed1992

Cisplatin-albumin complex for treatment of cancer of the head and neck.

Many patients with cancer of the head and neck are unable to receive or continue treatment with cisplatin, which is nephrotoxic, because of poor renal function. We present here, however, the case of a patient who underwent conventional cisplatin therapy but who then had to be withdrawn from treatment because of renal toxicity despite having undergone partial remission. Treatment was then changed to cisplatin in the form of a cisplatin-albumin complex which is not nephrotoxic. The patient went on to a histologically confirmed complete response and we suggest that although the cisplatin-albumin complex may not be as effective as the conventional form of the drug it offers a possible form of treatment of patients with compromised renal function who could not otherwise be treated.

Aged↗
PubMed1992

Phase I trial of a cisplatin-albumin complex for the treatment of cancer of the head and neck.

1. A phase I trial of a cisplatin-albumin complex for the treatment of end-stage squamous cell carcinoma of the head and neck is reported. The complex was prepared by overnight incubation of cisplatin with human albumin at 37 degrees C. This resulted in more than 98% of the drug being bound to protein at the start of treatment. The patients were either unable to continue with or had refused conventional therapy with cisplatin. 2. The trial began at a dose of 100 mg cisplatin m-2 and was increased in 25 mg m-2 increments to 650 mg m-2. Despite the absence of the customary protective measures of pre-hydration and anti-emetic treatment no serious toxicity was encountered. 3. Unbound plasma platinum concentrations were lower than after conventional cisplatin treatment but total plasma platinum and tumour platinum concentrations were much higher. Urinary excretion of platinum was low and the incidence of nephrotoxicity was greatly diminished. Two responses were seen (one complete and one partial) in 38 patients treated and the median survival time was 109 days, compared with 151 days for patients treated conventionally with cisplatin and 56 days for untreated patients. 4. The complex is not as effective as conventional cisplatin therapy but is much less toxic, offers improved quality of life during treatment and may prove to be of benefit in patients who could not otherwise be treated.

Carcinoma, Squamous Cell↗
PubMed1992

Renal organic acid transport: uptake by rat kidney slices of a furan dicarboxylic acid which inhibits plasma protein binding of acidic ligands in uremia.

The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA), accumulates in uremic plasma and inhibits the binding of various drugs and marker ligands that are organic acids. 5-Propyl FPA is excreted unchanged in human urine and active tubular secretion is likely to be involved because of its high affinity for albumin. The uptake of 5-propyl FPA by rat kidney slices has been measured and compared with that of p-aminohippurate (PAH). The mean (+/- S.D.) slice/medium ratio for uptake of 5-propyl FPA (76 microM) was 22.7 +/- 2.6 (n = 11) and for PAH (75 microM) was 15.9 +/- 3.2 (n = 9) after incubation for 90 min at 25 degrees C. 5-Propyl FPA (149-829 microM) inhibited the uptake of PAH (77 microM) in a concentration-dependent manner, and likewise, PAH (150-830 microM) inhibited the uptake of 5-propyl FPA (77 microM). The mean apparent Km and Vmax values for the uptake of 5-propyl FPA were 194 +/- 125 microM and 55 +/- 28 nmol/g kidney/min, respectively, and 487 +/- 179 and 99 +/- 46 nmol/g kidney/min, respectively, for PAH. The kinetics of inhibition of uptake of PAH by 5-propyl FPA were mainly competitive. 5-Propyl FPA is thus likely to undergo active tubular secretion in a similar way to PAH, and this furan dicarboxylic acid, therefore, has the potential to inhibit the renal excretion of various drugs, drug conjugates and other endogenous organic acids.

Animals↗
PubMed1991

Effect of beta-carboline derivatives on the binding of L-tryptophan and diazepam to bovine and human albumin.

The effects of 12 beta-carboline derivatives on the binding of L-tryptophan and diazepam to bovine and human albumin have been investigated to seek similarities between the indole binding site on albumin and the benzodiazepine receptor in the brain. The binding of L-tryptophan and diazepam was measured at 37 degrees and pH 7.4 by equilibrium dialysis. Norharmane was the most potent inhibitor of the binding of L-tryptophan and diazepam to both bovine and human albumin. The kinetics of the inhibitory effects of several of the beta-carbolines were studied. Norharmane decreased the value (n) for the number of binding sites for the binding of L-tryptophan to both bovine and human albumin. Norharmane and harmane decreased the apparent association (Ka) but increased n for the interaction of diazepam with bovine albumin. Norharmane also had a similar effect on the binding of diazepam to human albumin. The similarities between the inhibitory effects of the beta-carbolines on the binding of L-tryptophan and diazepam to albumin and the affinity of the beta-carbolines for the central benzodiazepine receptor point to some common structural requirements for binding to the receptor and to albumin.

Albumins↗
PubMed1991

Failure of a 21-aminosteroid antioxidant to ameliorate cisplatin-induced nephrotoxicity.

1 Lazaroid (U74500A), a 21-aminosteroid antioxidant, was administered to rats at a dose of 10 mg kg-1 in an attempt to reduce the toxicity of cisplatin (5 mg kg-1). 2 No protective effect was apparent under the schedule used and, in contrast to other antioxidants and free-radical scavengers, U74500A offers no potential benefit in cisplatin treatment.

Animals↗
PubMed1979

Decreased binding of drugs and dyes to plasma proteins from rats with acute renal failure: effects of ureter ligation and intramuscular injection of glycerol.

1 The decreased binding of drugs and dyes to plasma proteins from male and female rats with acute renal failure has been investigated using equilibrium dialysis at 37 degrees C. 2 Acute renal failure induced by bilateral ligation of the ureters produced a greater than threefold increase in the unbound fraction of o-methyl red relative to normal rat plasma. Unbound dye concentration in plasma from sham-operated control rats was also significantly increased but to a lesser extent. 3 Glycerol-induced acute renal failure produced a significant increase in the unbound fractions of o-methyl red, methyl orange, bromocresol green (BCG), 2-(4'-hydroxybenzeneazo) benzoic acid (HABA), phenytoin and salicylic acid. A marginally significant increase in unbound warfarin concentration was observed. 4 Glycerol-induced renal failure had no effect on total plasma protein concentration and experiments with o-methyl red and salicylic acid indicated that a direct effect of glycerol was not responsible for the diminution of binding. 5 Glycerol-induced acute renal failure, which produced decreases in drug and dye binding similar to those reported for human uraemic plasma, provides a convenient non-surgical animal model for the investigation of this phenomenon.

Acute Kidney Injury↗
PubMed1979

Investigation of the drug-binding defect in plasma from rats with glycerol-induced acute renal failure.

The binding defect in plasma from rats with glycerol-induced acute renal failure has been studied. The protein binding of phenytoin, salicylic acid, o-methyl red and methyl orange in uremic rat plasma, measured by equilibrium dialysis at 37 degrees C, was significantly decreased. Analysis of the data by a modified Scatchard plot revealed that in uremic plasma the total binding capacity (nkP) was decreased mainly as the result of a decrease in apparent association constant (k). Charcoal extraction significantly increased the ability of uremic rat plasma to bind the four ligands and restored the binding to about that of the control plasma. Extraction with organic solvents or silicic acid and pre-dialysis against defatted human albumin produced no significant removal of the binding defect. The thiol concentrations of male rat plasma and female rat serum were significantly decreased in uremia. Dithiothreitol decreased the binding of o-methyl red to both control and uremic rat plasma and thereby largely removed the pretreatment difference in unbound fraction of dye. The results suggest the presence of endogenous binding inhibitors.

Acute Kidney Injury↗
PubMed1976

Gastrointestinal absorption of carbenoxolone in the rat determined in vitro and in situ: deviations from the pH-partition hypothesis.

The absorption of [14C] carbenoxolone from everted rat ileum in vitro and from rat stomach and ileum in situ has been examined. The rate of its mucosal to serosal transfer in vitro increases as pH increases from 5 to 8 whereas the amount bound to ileum tissue decreases with increased pH; absorption closely parallels the drug's solubility. The uptake of carbenoxolone in situ is bi-exponential and the rate constants for the two processes, have been calculated. Absorption in situ, and biliary excretion, of the drug increases with increasing pH from 5.0 to 7.4. Tissue binding to the ileum in situ is not dependent on pH except below pH 5.0 when extensive tissue accumulation of carbenoxolone occurs because of its low solubility. Tissue binding to the stomach increases markedly with decrease of pH from 7.4 to 6.5 and at pH 6.5 is 80 times greater than binding to the intestine. The rate of absorption from the stomach, at pH 6.5-7.4, was much less than that from the intestine in situ. When allowance is made for the binding of carbenoxolone to the stomach, contrary to the pH-partition hypothesis, correlation is apparent between its absorption and the amount present in the ionized form.

Animals↗