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Biomedical subjects

W E Lindup

Publications and source records attributed to W E Lindup.

At least 37 records · Page 2Linked to original sources
PubMed1994

Amelioration of cisplatin toxicity in rat renal cortical slices by dithiothreitol in vitro.

1. The protective effects of dithiothreitol (DTT) on cisplatin-induced nephrotoxicity were investigated with rat renal cortical slices. 2. The nephrotoxic effects of cisplatin (2 mmol l-1) were manifested in several ways: the Na+ and water content were increased while K+ was decreased. The malondialdehyde (MDA) concentration in the slices and the lactate dehydrogenase (LDH) released into the medium were increased. The uptake of p-aminohippurate (PAH), the synthesis of glucose and the glutathione (GSH) concentration in the slices were all decreased. 3. Despite a DTT-related increase in platinum (Pt) uptake by the slices, DTT (0.5-2 mmol l-1) ameliorated all these toxic effects of cisplatin in a concentration related manner. 4. The results suggest that the protective mechanism of DTT is its antioxidative action. DTT is also a metal chelator, however, and so a protective effect via chelation of Pt by DTT cannot be excluded.

Animals↗
PubMed1993

Role of mitochondria in cisplatin-induced oxidative damage exhibited by rat renal cortical slices.

The role of mitochondria with regard to cisplatin-induced renal toxicity has been examined in vitro. The mitochondria were prepared from rat renal cortical slices which had been exposed to cisplatin. Incubation of the kidney slices with 2 mM cisplatin for various periods depleted glutathione (GSH) and increased thiobarbituric acid reactive substances (TBARS) in a time-dependent manner, a change which indicates lipid peroxidation in the mitochondria. The content of GSH was significantly depleted within 15 min of incubation, while TBARS formation was increased after 60 min of incubation. Marked depletion (30%) of GSH and increased TBARS formation (2-fold) were observed after 60 min and 120 min of incubation, respectively. Furthermore, cisplatin also depleted GSH and induced TBARS formation in the mitochondria in a concentration-dependent fashion. Cisplatin (0.5 mM) depleted GSH, but did not increase the production of TBARS. In addition, the fluorescence intensity of 8-anilino-1-naphthalenesulphonic acid (ANS)-bound to mitochondrial membranes was decreased after 120 min of incubation with 2 mM cisplatin. Several parameters were measured as indicators of damage to mitochondria and cellular integrity and they showed that cytotoxicity occurred subsequent to both GSH depletion and TBARS formation. Cisplatin-induced depletion of GSH is an early event and a determinant step in oxidative stress to mitochondria in the kidney cortex and may lead to irreversible cell injury.

Animals↗
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

Disposition and tumour concentrations of platinum in hypoalbuminaemic patients after treatment with cisplatin for cancer of the head and neck.

1 Platinum concentrations in the tumour reached a peak of 3.8 +/- 1.5 micrograms g-1 wet weight tissue at the end of an 8 h intravenous infusion of cisplatin. The tumour concentrations of platinum were higher than the corresponding plasma concentrations (2.5 +/- 0.9 micrograms ml-1) and declined more slowly. 2 Patients with squamous carcinoma of the head and neck had a significantly shorter median survival time if they had low plasma albumin concentrations (less than 40 g l(-1) compared with patients in the normal range, 133 days and 768 days respectively (P less than 0.05) after treatment with cisplatin. 3 No changes in the pharmacokinetics of platinum were detected to account for this poor response of hypoalbuminaemic patients, but plasma albumin concentration was found to be negatively correlated with the first order elimination rate constant. 4 The cumulative urinary excretion of platinum in the first 24 h was not altered by lowered plasma albumin. 5 The concentration of platinum in the tumour did not correlate with the survival time of the patient, but was found to be correlated with the volume of distribution in the post-distributive phase.

Adult↗
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↗
PubMed1990

Interaction of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, an inhibitor of plasma protein binding in uraemia, with human albumin.

The furan dicarboxylic acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in uraemic plasma and is a potent inhibitor of the binding of other anionic ligands to albumin. The interaction of 5-propyl FPA with human albumin has been investigated by equilibrium dialysis at 37 degrees and pH 7.4. Analysis of the binding data on the basis of a two-site model gave binding parameters of n1 = 0.6 and K1 = 4.8 x 10(6) M-1 for the primary binding site. 5-Propyl FPA binding was observed to decrease as the pH was raised from 6.4 to 8.3 which emphasizes the need for pH control of whole plasma or serum. Temperature, however, had little effect on binding as assessed by equilibrium dialysis at 10 degrees, 25 degrees and 37 degrees. The high affinity of 5-propyl FPA for albumin explains its retention in uraemic plasma, its potency as a binding inhibitor and points to active tubular secretion as the mechanism by which it is normally excreted by the kidney.

Furans↗
PubMed1989

Contamination by a competitive ligand as an explanation for the inverse dependence of HABA binding parameters upon the protein concentration.

There is evidence that the apparent association constant (K) and/or the number of binding sites (n) are inversely dependent upon protein concentration for a number and variety of ligands with no obvious structure-activity relationships. A model recently shown to explain this effect with an inorganic ligand has now been applied to 2-(4'-hydroxybenzeneazo) benzoic acid (HABA) and also explains the inverse protein dependence of the binding of this compound to human albumin. The model explains this inverse dependence on the basis of a highly bound contaminant which competes with the ligand for the high affinity site. HABA was found to interact with human albumin at three or more sites, the high affinity site which was about 95% contaminated had an association constant of 2 x 10(5)/M, an order of magnitude higher than that found previously when the effect of a contaminant was not considered. The association constant of the competitive contaminant was estimated to be about 5 x 10(6)/M. Since the model accounts for the phenomenon in terms of a property of the protein, rather than of the ligand, it could provide a general explanation for this effect with other ligand-acceptor combinations including a wide variety of drug and hormone receptor preparations.

Albumins↗
PubMed1989

Brain uptake of L-tryptophan and diazepam: the role of plasma protein binding.

The brain uptake index (BUI) of L-tryptophan and diazepam into the right and left hemispheres and the cerebellum has been measured after a bolus injection into the carotid artery of the anaesthetised rat. The effect of a range of albumin concentrations (38 microM to 1.4 mM; 0.25-9 g/100 ml) on the viscosity and osmotic pressure of the bolus was studied as a preliminary to the brain uptake experiments. Dextran (Mr 60,000-90,000) was included in the injection to ensure constant viscosity and osmotic pressure. An increase in albumin concentration up to 2 g/100 ml substantially reduced the BUI of L-tryptophan, but a further increase in albumin concentration up to 9 g/100 ml resulted in only a slow fall in the BUI of L-tryptophan which was not proportional to the larger fall in the concentration of unbound L-tryptophan. Furthermore, the use of norharmane as an inhibitor of L-tryptophan binding did not reveal a simple relationship between its unbound concentration and BUI. A decrease in the unbound concentration of diazepam also reduced its BUI, but again there was no straightforward relationship between this and unbound diazepam concentration. The differences observed in the BUI of inulin from solutions of either dextran or albumin indicate not only that each macromolecule may exert particular effects on the BUI, perhaps by an influence on cerebral blood flow, but also show how difficult it is to devise solutions for injection which differ in respect of only one variable, that of the unbound ligand concentration.

Animals↗
PubMed1986

Practolol: aspects of its metabolism and ocular binding in the hamster.

The metabolism and ocular binding of practolol were investigated after oral administration of 14C-practolol to hamsters treated with three modifiers of mixed-function oxidase activity: piperonyl butoxide, cobalt chloride or phenobarbitone. The major urinary metabolites of practolol were 3-hydroxypractolol and polar metabolites which included glucuronide conjugates. A number of unidentified metabolites constituted a minor portion of urinary radioactivity. Each pretreatment modified both the urinary excretion pattern (0-24 h) of practolol and its metabolites and also the metabolite profile of eye extracts 24 h after an oral dose. None of the modifiers of mixed-function oxidase activity had any significant effect on the ocular binding (both extractable and non-extractable components) of practolol and its metabolites. The results indicated that the non-extractable component was neither practolol nor 3-hydroxypractolol.

Animals↗
PubMed1985

Practolol and its metabolites: tissue localization and retention in the hamster.

The disposition of [14C]practolol and its tissue association in the male Syrian hamster were investigated after p.o. administration. After an acute dose of 400 mg/kg, there was a marked persistence in the eye of total radioactivity (primarily practolol; approximate T 1/2 = 7 days) and nonextractable radioactivity which showed minimal decay over 7 days. Nonextractable radioactivity was also found in other tissues (liver, skin, small intestine and skeletal muscle examined). The level of total and nonextractable radioactivity was linearly related to dose (800 mg/kg highest dose examined). There was a marked accumulation of total and nonextractable radioactivity in the eye (7- and 14-fold, respectively) and skin (6- and 7-fold) after daily administration of 400 mg/kg for 22 days. The association of practolol metabolites with tissue macromolecules might explain the immunological changes in patients with the practolol-induced oculomucocutaneous syndrome. The adverse effects of practolol in humans have not yet been reproduced in any laboratory species and so the results must be interpreted with caution in relation to the toxicity of compound.

Animals↗
PubMed1984

Scatchard plots with a positive slope: dependence upon ligand concentration.

The inverse dependence of binding constants (nK) upon albumin concentration for 2-(4'-hydroxybenzeneazo) benzoic acid (HABA) has been investigated with bovine and human albumin by equilibrium dialysis. Data obtained by the use of a range of concentrations of either bovine or human albumin, together with a single ligand concentration, gave positive Scatchard plots indicative of binding constants inversely dependent upon protein concentration. The slope of each plot was influenced by the particular ligand concentration used and an increase in the ligand concentration in the case of both bovine and human albumin resulted in a decrease in the slope of the positive Scatchard plot. Higher concentrations of ligand produced a transformation from a positive to a negative plot with both bovine and human albumin.

Animals↗