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Biomedical subjects

B Haynes

Publications and source records attributed to B Haynes.

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

Biodistribution and kinetics of radiolabelled pyrrolidino-4-iodo-tamoxifen: prospects for pharmacokinetic studies using PET.

With a view to evaluating the role of PET imaging in early clinical studies of new anticancer drugs, we are investigating the recently developed antiestrogen compound pyrrolidino-4-iodo-tamoxifen (idoxifene). Preliminary experimental studies have been undertaken using [125,131I]idoxifene, following synthesis of a tributyl-stannyl-idoxifene precursor to facilitate radioiodination. We have investigated the tissue biodistribution and kinetics of [125I]idoxifene following i.v. infusion in hooded rats bearing the hormone-dependent transplantable mammary tumour OES.HR1. Clearance of idoxifene from the circulation is accompanied by an increase in uptake by tumour and uterus, to peak levels after 24 hours (0.33 +/- 0.037% dose/g (mean +/- 1 SD) and 0.40 +/- 0.033% dose/g, respectively). Highest uptake of idoxifene was found in the liver (11.0 +/- 0.8% dose/g), with a progressive fall after 24 hours consistent with hepatobiliary excretion of the radiotracer. No evidence of idoxifene metabolism was found in tissue extracts taken up to 48 hours. Whole body clearance of [131I]idoxifene was characterised by a single exponential decay (t1/2 = 140 hours) up to 350 hours post administration. We conclude that 124I-labelled idoxifene combined with PET imaging would facilitate human in vivo pharmacokinetic studies of this new anticancer drug and provide an opportunity to investigate relationships between drug uptake and tumour response.

Animals↗
PubMed1994

Effects of a new fish oil concentrate on plasma lipids and lipoproteins in patients with hypertriglyceridaemia.

OBJECTIVES: The effect of a fish oil preparation, K-85, in which the omega-3 fatty acid content was concentrated to 92% of total fat, on serum lipid and lipoprotein concentrations was investigated in patients with primary hypertriglyceridaemia. DESIGN: The study was a randomized, double-blind, placebo-controlled study. SETTING: Seven centres participated in the study, five secondary referral centres and two general practices. SUBJECTS: Men and women aged 18-70 years with fasting serum triglyceride concentrations between 2 and 10 mmol/l and fasting serum cholesterol concentrations > 5.2 mmol/l were studied. Patients with diabetes mellitus, hypothyroidism, serious illness in the previous 3 months or severe concurrent illness were excluded from the study, as were drug or alcohol abusers and pregnant and lactating women. Ninety-five subjects entered the study, 79 completed the study. INTERVENTIONS: Patients were randomized to receive K-85 2 g twice daily or corn oil 2 g twice daily for 14 weeks. MAIN OUTCOME MEASUREMENTS: The serum concentrations of triglycerides and cholesterol, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein (a). Fasting blood glucose and blood pressure. RESULTS: Serum triglycerides and VLDL-cholesterol were significantly lower in the group treated with K-85 than in the placebo group after 6, 10 and 14 weeks (all P < 0.01) and there was a decrease in the serum triglyceride concentration from 3.99 (2.94-9.47) to 2.87 (1.2-9.93) mmol/l (P < 0.001) and in VLDL-cholesterol from 1.47 (0.77-3.63) to 1.12 (0.21-3.67) mmol/l (P < 0.01) in patients receiving K-85. Serum HDL-cholesterol increased from 0.98 (0.95-1.01) to 1.11 (1.07-1.15) mmol/l (P < 0.01) in the patients with type IV hyperlipoproteinaemia but did not change in those with type IIb. Serum LDL-cholesterol, lipoprotein (a) and fasting blood glucose were unaffected by K-85. Diastolic blood pressure decreased from 86 +/- 11 to 80 +/- 12 mmHg (P < 0.02) and was also lower than in the placebo group (P < 0.05). The corn oil placebo did not affect any of the parameters. CONCLUSION: K-85 is effective in lowering serum triglycerides and VLDL in patients with primary hypertriglyceridaemia and may have utility as a triglyceride-lowering agent.

Adult↗
PubMed1993

Mechanism of decreased arachidonic acid in the renal cortex of rats with diabetes mellitus.

The purpose of this study was to investigate the roles of decreased synthesis and increased consumption in the depression of arachidonic acid levels in renal cortex and glomeruli of rats with streptozotocin-induced diabetes mellitus. In diabetic rats, arachidonic acid was depressed 33.2% in renal cortex, 47.4% in liver and 66.1% in heart compared to values of control rats. delta 6 Desaturase activity was depressed in renal cortex, liver and heart of diabetic rats to 53.3, 55.5 and 63.7%, respectively, of control values. delta 5 Desaturase activity was also depressed 43.7, 55.5 and 47.6% in renal cortex, liver and heart of diabetic rats, respectively. In other rats the activities of five enzymes involved in the synthesis and esterification of arachidonic acid were measured in renal cortex and in isolated glomeruli. Both tissues from diabetic rats showed depressed activities of delta 5 and delta 6 desaturases, increased activities of long-chain acyl-CoA synthetase and 1-acyl-sn-glycero-3-phosphocholine acyltransferase and no change in the activity of elongase as compared to those in control tissues. Malondialdehyde, an end product of lipid peroxidation, was lower in the renal cortex of diabetic rats than in control rats, whereas beta-oxidation of linoleic acid and arachidonic acid were similar in diabetic and in control rats. Basal and stimulated prostaglandin E2 synthesis were significantly higher in isolated glomeruli from diabetic rats compared to those in control rats. In isolated tubules, prostaglandin E2 synthesis was similarly low in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1991

Immediate hypersensitivity in colon of children with chronic Trichuris trichiura dysentery.

There are few data on mucosal immune responses to intestinal helminths in human beings, especially those involving the IgE system, which is thought to be important in parasite expulsion. We sought evidence of an immediate hypersensitivity reaction in the colon of children with chronic dysentery due to Trichuris trichiura. 28 children with Trichuris dysentery syndrome (TDS) were compared with 16 control children (with no TDS or worms visible on colonoscopy). All children were aged 1-11 years. Rectal biopsy samples were taken before and after expulsion of the worms by means of mebendazole treatment. Children with TDS had significantly greater numbers than controls of mast cells (mean [SD] 10.9 [1.3] vs 3.9 [0.6]% of all cells; p less than 0.0003) and of cells with surface IgE (median [range] 11.1 [7.5-11.6] vs 1.0 [0-1.5]%; p less than 0.001) in the subepithelial region of the mucosa. On electronmicroscopy, degranulating mast cells were prominent in parasitised children. In culture, rectal biopsy samples from parasitised children showed high rates of spontaneous histamine release, but only low rates of antigen-specific release. After treatment, spontaneous histamine release was significantly reduced and antigen-specific histamine release could be provoked. Thus, an IgE-mediated immune mucosal response to a helminth infection does occur in human beings but is not sufficient to cause appreciable parasite expulsion.

Anaphylaxis↗
PubMed1991

The influence of CGS 16949A on peripheral aromatisation in breast cancer patients.

The influence of a new aromatase inhibitor, CGS 16949A on peripheral aromatisation of androstenedione into oestrone was investigated in postmenopausal women with breast cancer. A mixture of 3H androstenedione and 14C oestrone was injected, and all urine was collected for the following 96 h. The isotope ratio was determined in the urinary oestrogen metabolites after isolation by HPLC. Eight patients were investigated before and during treatment with CGS 16949A. At a dose of 1 mg b.d. (eight patients) CGS 16949A inhibited aromatisation by a mean value of 82.4% (range 71.3 to 93.7%). When the drug dose was escalated to 2 mg b.d. (three patients) aromatisation was inhibited by a mean of 92.6% (range 90.6 to 95.8%), these results suggest that CGS 16949A at a dose of 1 mg b.d. causes submaximal aromatase inhibition in many patients, while a dose of 2 mg b.d. seems to result in greater than 90% aromatase inhibition. These data are consistent with previous observations that the higher dose is more effective in suppression of plasma oestradiol levels.

Aged↗
PubMed1991

Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients.

The aromatase inhibitor, 'pyridoglutethimide' (PyG), has been shown previously to suppress serum oestrogen levels in postmenopausal breast cancer patients and to achieve clinical responses at a dose of 500 mg twice daily (b.d.). This report gives the results of a detailed pharmacokinetic and endocrine study of PyG in ten patients. Four doses were tested at intervals of 2 weeks in the following order: 200 mg b.d., 400 mg b.d., 800 mg b.d., 1200 mg b.d. Concentration-time profiles of serum levels of PyG were curvilinear in all patients probably reflecting a saturation of metabolic enzymes. During repeat-dosing metabolism was enhanced approximately 2-fold. Plasma levels of oestradiol were significantly suppressed by the lowest dose of PyG. Although higher doses appeared to achieve greater suppression this was not statistically significant in this small group of patients. There were no significant effects at any dose on the serum levels of cortisol, aldosterone, luteinising hormone, follicle stimulating hormone, prolactin, sex hormone binding globulin or thyroid stimulating hormone. There was a dose-related increase in 17 alpha-hydroxyprogesterone levels and a dose-related decrease in levels of dehydroepiandrosterone sulphate (DHAS). The androgens DHA, testosterone and androstenedione also were significantly suppressed with at least one of the doses of PyG. Synacthen tests did not support these changes being a result of inhibition of 17,20 lyase. It is possible that they are due to enhanced clearance of DHAS. Two patients experienced no toxicity throughout the study, whilst a total of four patients were withdrawn because of side-effects: one at 400 mg b.d., two at 800 mg b.d., and one at 1200 mg b.d. The most frequent side-effects were nausea and lethargy. One patient showed an objective response to treatment.

Aged↗
PubMed1991

Measurement of aromatisation by a urine technique suitable for the evaluation of aromatase inhibitors in vivo.

By modification of a recently developed method for separation of radio-labelled urinary oestrogens we were able to separate oestrogen metabolites and measure their isotope ratios in urine following injections of [3H]delta 4-androstenedione and [14C]oestrone. This method provides a useful tool for studying in vivo aromatisation of delta 4-androstenedione into oestrone in breast cancer patients before and during treatment with aromatase inhibitors.

Aminoglutethimide↗
PubMed1991

SIV vaccine protection of rhesus monkeys.

Rhesus macaques (M. mulatta), immunized with an inactivated whole SIVmac vaccine and muramyl dipeptide or Freund's incomplete adjuvant, were protected against IV challenge infection with 10 animal infectious doses of the homologous virus. The protection in these animals appeared to be complete, with no breakthrough of latent virus infection over a 10-month period. Vaccine protection in this model was correlated generally with a high level of SIVmac envelope antibody by ELISA and immunoblot, high titers of syncytial inhibiting antibody, and, more specifically, with the presence of antibodies binding to a putative V3 loop synthetic peptide of the SIVmac outer envelope. This model can now be used for further identification of the protective epitopes and protective host immune responses as well as for development of novel and better AIDS vaccines.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

A method for fixation of elastin demonstrated by stress/strain characterization.

In the process of examining the effects of oxidants on the mechanical properties of purified ligamentum nuchae elastin, it was found that sodium hypochlorite as constituted in Clorox will fix elastin at any preset extension. The treatments were carried out at a 1 to 5 dilution and at 0, 20 and 40% extensions. In each case, the new resting length was near the preset length and the elastic modulus increased remarkably, for example, from 1 to 5 x 10(7) dynes/cm2 for the sample preset at 20% extension. As reflected in the increased elastic modulus, the fixation was achieved by the formation of irreversible cross-links. Due to the near absence of side chains containing chemically reactive groups suitable for contributing to the formation of additional cross-links required in fixation, this is the first method whereby irreversible fixation of elastin has been achieved. The absence of a suitable fixative for elastic tissues such as lung, arteries, etc. has limited the microscopic characterization of functional extended states of these tissues.

Animals↗
PubMed1988

Mechanochemical coupling in synthetic polypeptides by modulation of an inverse temperature transition.

For the polypentapeptide of elastin, (L-Val-L-Pro-Gly-L-Val-Gly)n, and appropriate analogs when suitably cross-linked, it has been previously demonstrated that development of elastomeric force at fixed length and length changes at fixed load occur as the result of an inverse temperature transition, with the temperature of the transition being inversely dependent on the hydrophobicity of the polypeptide. This suggests that at fixed temperature a chemical means of reversibly changing the hydrophobicity could be used for mechanochemical coupling. Evidence for this mechanism of mechanochemical coupling is given here with a 4%-Glu-polypentapeptide, in which the valine in position 4 is replaced in 1 out of 5 pentamers by a glutamic acid residue. Before cross-linking, the temperature for aggregation of 4%-Glu-polypentapeptide is remarkably sensitive to pH, shifting from 25 degrees C at pH 2 to 70 degrees C at pH 7.4 in phosphate-buffered saline (PBS). At 37 degrees C, the cross-linked 4%-Glu-polypentapeptide matrix in PBS undergoes a pH-modulated contraction and relaxation with a change from pH 4.3 to 3.3 and back. The mean distance between carboxylates at pH 4.3 in the elastomeric matrix is greater than 40 A, twice the mean distance between negatively charged species in PBS. Accordingly, charge-charge repulsion is expected to make little or no contribution to the coupling. Mechanochemical coupling is demonstrated at fixed load by monitoring pH dependence of length and at constant length by monitoring pH dependence of force. To our knowledge, this is the first demonstration of mechanochemical coupling in a synthetic polypeptide and the first system to provide a test of the recent proposal that chemical modulation of an inverse temperature transition can be a mechanism for mechanochemical coupling. It is suggested that phosphorylation and dephosphorylation may modulate structure and forces in proteins by locally shifting the temperatures of inverse temperature transitions.

Amino Acid Sequence↗
PubMed1986

Temperature dependence of length of elastin and its polypentapeptide.

Comparison of the temperature dependence of elastomer length of the cross-linked protein, elastin, and of gamma-irradiation cross-linked poly(VPGVG), the polypentapeptide of elastin, with that of latex rubber demonstrate markedly dissimilar behaviors between a classical rubber and the protein and polypeptide elastomers. In the absence of a load latex rubber expands with increasing temperature as is known for classical rubbers comprised of a network of random chains whereas the protein and polypeptide elastomers markedly decrease in length. When under load with a constant applied force, as a classical rubber, latex linearly decreases length with increasing temperature whereas the decrease in length is very non-linear with temperature increase for the protein and polypeptide elastomers. The protein and polypeptide elastomers examined here do not exhibit the characteristic and fundamental temperature dependence of length considered typical of networks of random chains. Accordingly the more complex and even inverse behavior of elastin and the polypentapeptide of elastin in the absence of load require consideration of structural perspectives different from those of a random chain network with negligible interchain interactions.

Amino Acid Sequence↗