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D Stribling

Publications and source records attributed to D Stribling.

At least 19 recordsLinked to original sources
PubMed2001

[Platinum compounds in cancer therapy--past, present, and future].

Platinum cytotoxics play an important role globally in the management of solid tumours. Cisplatin sets the standard for efficacy in both regions with careful administration to reduce nephrotoxicity. Carboplatin is associated with neurotoxicity, but has become the leading product in the US due largely to the easier to manage toxicity profile. Both agents have been widely used in both registered and non registered indications and are frequently combined with other cytotoxics. In Japan, cisplatin has been used successfully at low doses in combination with 5-FU based regimens and appears to achieve a synergistic effect, but controlled data are not yet available. More recently oxaliplatin (Europe) and nedaplatin (in Japan) have been introduced, but their clinical roles in therapy have yet to be established. One of the limiting features of the first generation of platinum compounds is that a significant proportion of tumours develop cross resistance to platins due to either changes in uptake or excretion, intracellular detoxification or accelerated DNA repair. The forum discussed the possibility for the development of better new platinum compounds, A new platin agent which had lower toxicity and higher efficacy across a wide range of cancers without the development of resistance would be a significant step forward. If the tolerability profile was suitable, an oral formulation may improve the quality of life for patients but this must not be at the expense of efficacy. Even after the introduction of new target based drugs, platinum cytotoxics are likely to be used to reduce the tumour mass and in some cases can be expected to potentiate the effects of the new agents. In preclinical studies, ZD0473 has been shown to by-pass some major mechanisms of resistance and has the potential to achieve these objectives and is now being evaluated in clinical studies in both Japan and the West.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

[Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development].

A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will result in a convergence of treatment paradigms and some improvement in acute response in many tumour types. However, world wide there is a need for new improved therapies in all cancers evaluated. Particular needs are in the management of NSCLC, advanced disease and cancers which form micrometastases. The eventual hope is that cancer can be turned from a lethal disease into a chronic disease where patients maintain a good QOL. Apart from anti hormonal therapies, the usual approach has been to kill the cancerous cells. However, the new approaches to intervening in the growth and migration of cancerous cells or the host tissue response by molecular targeting offer the promise of achieving a step change in therapy. Although EGF tyrosine Kinase inhibitors such as ZD 1839 have been shown to cause a conventional tumour response in NSCLC, many of these new approaches are unlikely to show a short term response even if they have the capacity to affect tumour development and increase disease free survival. Some compounds will require combination therapy with a conventional cytotoxic or radiotherapy to show their full benefit. For conventional cytotoxics, the usual approach to development has been to select the maximum tolerated dose and then evaluate the efficacy in advanced disease. However, for the new approaches which will not have such severe dose limiting toxicities, it will be necessary to select a surrogate marker of the intended biological effect to select the optimal biological dose (OBD) and dose regimen in phase I/II studies for further evaluation in phase II or III studies which are designed to show the expected patient benefit. The tumour target, the stage of the disease and the possible need for concomitant therapy will also have to be considered according to the mechanism of action of the product.

Angiogenesis Inhibitors↗
PubMed1999

[Early detection and prevention of cancers in various therapeutic areas. Discussion].

As illustrated by prostate cancer screening provides an opportunity for early intervention and treatment. However the screening test needs to detect patients with cancer with a low rate of false positives and at a stage which can be treated. Recently the concept of treating patients at high risk of developing breast cancer or suffering a recurrence has been highlighted by the western studies with Nolvadex (tamoxifen). Thus roundtable discussion (held in Tokyo) discussed the different strategies in Japan compared to US & Europe for screening & early intervention/prevention of cancer for breast, prostate, bladder, liver, lung, gynaecological & GI cancers. The range of strategies for cancer screening, how it is funded, whether it is appropriately targeted and whether there is any evidence for a beneficial effect on morbidity or mortality & future prospects for improved sensitivity through new methodology or markers were discussed. Although the relative rates of cancer vary between Japan & the West, the same factors seem to influence cancer development & the data on intervention were seen to be valid. The changing patterns of cancer in Japan suggest a clear opportunity for reducing, the incidence of cancer through lifestyle modification. For some cancers, e.g. cervical & bladder where there is a clear link between abnormal cytology & development cancer true prevention is already practiced. In other cases, preventive treatment is limited by the efficacy of available therapies. As far as drug treatment is concerned, funding of healthcare in Japan does not recognise the concept of prevention although there is, in practice, no barrier to the use of interventions where there is a clear link between biochemical/histological markers & development of cancer.

Breast Neoplasms↗
PubMed1992

Selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis. 1. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetates.

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (8) has been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 10. Potency was generally markedly reduced by placing substituents on the phenyl ring of the phenoxypropanolamine unit of 8; only the 2-fluoro analogue 16 had comparable potency to 8. Other structure-activity relationships are discussed. Further testing of 8 (ICI 198157) has shown that in the rat it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1 and beta 2 adrenergic receptors in other tissues. It increases metabolic rate, as judged by an increase in oxygen consumption, and in the genetically obese Zucker rat it causes a reduced rate of weight gain. This class of compound may be useful in the treatment of obesity in man.

Adipose Tissue, Brown↗
PubMed1992

Selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis. 2. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetamides.

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (1) (R1 = OMe) had previously been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 1 (R1 = OH). Amides have been examined to determine whether they have advantages over the ester. In particular, in the rat and dog the half-lives of amides of appropriate potency were no longer than those of the ester. The amide (S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2- methoxyethyl)phenoxyacetamide [S-27, ICI D7114] was selected as having properties consistent with a sustained-release formulation should that prove necessary. Unlike the ester it is resistant to hydrolysis in the gut lumen. Further testing of ICI D7114 has shown that in the rat, cat, and dog it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1- and beta 2-adrenergic receptors in other tissues. Slimming effects were observed in the dog. ICI D7114 may be a selective thermogenic agent in man and may be useful in the treatment of obesity and diabetes.

Adipose Tissue, Brown↗
PubMed1992

ICI D7114: a novel selective adrenoceptor agonist of brown fat and thermogenesis.

Increasing energy expenditure by treatment with thermogenic drugs is not new, but available drugs have suffered from the problem of lack of selectivity. In the last decade two key findings have allowed the development of selective thermogenic drugs that have promise in the treatment of obesity. 1) The recognition that brown adipose tissue (BAT) plays a role in compensatory increases in energy expenditure has allowed an approach directed at a target organ. 2) The demonstration showing that increases in the activity of BAT may be modulated by an atypical (beta 3) adrenoceptor has led to the development of a new peripherally acting beta-adrenoceptor agonist ICI D7114, which stimulates thermogenesis at doses that have little effect on beta 1 or beta 2 adrenoceptors. Treatment with the compound activates BAT and thermogenesis even in species and situations where the intrinsic capacity is low. 3) The compound has beneficial effects in animal models of obesity and disturbed glucose and lipid homeostasis.

Adipose Tissue, Brown↗
PubMed1991

ICI D7114 a novel selective beta-adrenoceptor agonist selectively stimulates brown fat and increases whole-body oxygen consumption.

1. ICI D7114 is a novel, beta-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg-1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)-binding (ED50, 0.15 mg kg-1, p.o.) with no chronotropic effects on the heart at these doses. 2. Reference beta-adrenoceptor agonists, isoprenaline and clenbuterol, also stimulated oxygen consumption and BAT activity but were less selective because they also produced effects on heart rate at these doses. 3. Treatment of conscious rats with ICI D7114 did not attenuate the chronotropic effects on the heart of a subsequent isoprenaline challenge. 4. Administration of ICI D7114 or of its acid metabolite had no effect in a cat soleus muscle model of tremor or on blood potassium levels in the conscious dog, indicating lack of effects at beta 2-adrenoceptors. 5. The results indicate that ICI D7114 may have activity at atypical beta-adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.

Adipose Tissue, Brown↗
PubMed1990

Clinical trials with aldose reductase inhibitors.

Following the identification of potent, orally active inhibitors of aldose reductase, the next challenge comes in demonstrating clinical utility in the treatment of diabetic complications. It is not feasible to conduct pivotal studies in all indications within the same trial and neuropathy evolved as the lead indication. There was little precedent for clinical trials in any diabetic complication and one of the challenges has been the derivation of standardized methodology for quantifying changes. In order to establish the value of any intervention in a chronic disease, it is necessary to demonstrate sustained benefit in long-term trials. This has been complicated by the absence of quantitative prospective data on the natural history of the disease process. In well-controlled clinical trials, patients are likely to improve their diabetic control which will have an additional effect over and above the usual placebo effect seen in any trial. In the absence of any standard therapy, the definition of clinical as opposed to statistical significance of any effect needs to be established. In the case of neuropathy this is further complicated by the heterogeneity of the disease and questions over the relevance of small changes in electrophysiology as an index of improvement in histopathology. The majority of the animal studies have concentrated on prevention of changes rather than reversal. However, in diabetics, complications develop slowly and significant tissue damage has occurred before clinical signs can be detected. To date, all clinical studies have concentrated on treatment of complications. The dose of ARI chosen for such studies has been based on the surrogate of erythrocyte aldose reductase activity confirmed by short-term studies on disease reversal.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1990

Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine.

The synthesis of 2-benzylmorpholine from allylbenzene together with its resolution into its (+)- and (-)-enantiomers is reported. Oral dosing of the racemate to dogs caused appetite suppression with an ED50 of 3 and 5.5 mg kg-1 at 1 and 2 h, respectively, after access to a meat meal. No stimulant activity was observed in dogs given oral doses of 200 mg kg-1 but the appetite suppressant effect in dogs declined during 20 days of chronic oral dosing at 10 mg kg-1. Appetite suppression activity was shown to reside in the (+)-enantiomer.

Administration, Oral↗
PubMed1988

Ultrastructural observations on myelinated fibres in experimental diabetes: effect of the aldose reductase inhibitor ponalrestat given alone or in conjunction with insulin therapy.

Six groups of rats were studied over a 12-week period: onset and end controls, untreated diabetics, ponalrestat-treated diabetics, insulin-treated diabetics, and diabetics treated with ponalrestat and insulin. The concentrations of glucose, sorbitol and fructose significantly increased and that of myo-inositol significantly decreased in the sciatic nerve of untreated diabetic animals. Ponalrestat administration completely normalized sorbitol levels and partially corrected fructose and myo-inositol concentrations without altering nerve glucose levels. The biochemical abnormalities were also corrected in both the insulin-treated and insulin and ponalrestat-treated diabetic animals. Myelinated fibre cross-sectional areas and axonal areas were significantly less in the tibial nerve of diabetic animals as compared with age-matched controls. Insulin treatment partially corrected the reduction in fibre and axonal area but teased fibre preparations showed an excess of axonal degeneration as compared with controls, untreated diabetics and ponalrestat-treated diabetics. Ponalrestat given alone or in conjunction with insulin therapy did not correct the reduction in fibre or axonal area and single isolated fibres from diabetic animals treated with ponalrestat and insulin showed a marked excess of axonal degeneration, probably related to hypoglycaemia. The study fails to reveal any significant beneficial effect of aldose reductase inhibition on the structural abnormalities in peripheral nerve in experimental diabetes.

Aldehyde Reductase↗
PubMed1986

Purified rat lens aldose reductase. Polyol production in vitro and its inhibition by aldose reductase inhibitors.

The production of polyols in vitro by highly purified aldose reductase (EC 1.1.1.21) was monitored by g.l.c. In the presence of NADPH aldose reductase reduced glucose, galactose and xylose to the respective polyols sorbitol, galactitol and xylitol. The rates of formation of these polyols closely mirrored the Km values for the substrates obtained from kinetic measurements that monitored the rate of disappearance of NADPH. No polyol production occurred in the absence of purified aldose of purified aldose reductase, and analysis by g.l.c. revealed only the presence of unchanged monosaccharides. Addition of the aldose reductase inhibitor sorbinil to purified rat lens aldose reductase incubated with xylose in the presence of NADPH resulted in decreased xylitol production. However, aldose reductase inhibitors produced no effect in altering the rate of Nitro Blue Tetrazolium formation from either glucose or xylose, indicating that the observed inhibition in vitro does not result from a free-radical-scavenger effect.

Aldehyde Reductase↗
PubMed1986

The effect of continuous subcutaneous insulin infusion therapy on morphological and biochemical abnormalities of peripheral nerves in experimental diabetes.

Diabetes mellitus was induced in rats by the administration of streptozotocin and observations have been made over a period of 2 months in 3 groups of animals: controls, untreated diabetics and diabetics treated with continuous subcutaneous insulin infusion (CSII) therapy, using a 14-day Alzet osmotic minipump. Optimal control of day-to-day and 24-h blood glucose levels was achieved in diabetic animals treated with CSII. Body weight and skeletal growth, assessed by measurements of tibial length, were decreased in untreated diabetic rats and were normalized by insulin treatment. The concentrations of glucose, sorbitol and fructose in the nerves of diabetic animals were significantly increased and that of myoinositol significantly decreased; CSII therapy normalized these levels to those of age-matched controls. External myelinated fibre diameter in the tibial nerve was significantly less in untreated diabetic rats as compared with age-matched controls. In the insulin-treated group, fibre diameter significantly increased as compared with untreated diabetics and there was no significant difference between insulin-treated and control animals. Teased fibre preparations from the tibial nerve revealed very few abnormal fibres in all the three groups and no significant difference was detected between any of the groups. Continuous subcutaneous insulin infusion therapy, therefore, corrected biochemical abnormalities and also normalized myelinated fibre diameter in the peripheral nerves of experimental diabetic animals. The paradoxical excess of axonal degeneration that has been reported with conventional insulin treatment was not observed.

Animals↗
PubMed1986

(S)-3-[(benzyloxy)methyl]morpholine hydrochloride: a nonstimulant appetite suppressant without conventional neurotransmitter releasing properties.

The synthesis and appetite-suppressant activity of (S)-3-[(benzyloxy)methyl]morpholine hydrochloride in dogs are reported. The oral ED50 for appetite suppression in dogs of 3 was 12 mg/kg, and it was tolerated up to 200 mg/kg. 3 had no inhibitory effect on the release or uptake of noradrenaline, dopamine, or serotonin at 10(-5) M. The (R) enantiomer of 3 was not anorexiant.

Animals↗
PubMed1985

Properties of ICI 128,436, a novel aldose reductase inhibitor, and its effects on diabetic complications in the rat.

ICI 128,436 (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid) is a chemically novel, potent inhibitor of aldose reductase. It inhibits partially purified aldose reductase isolated from a number of sources including human tissue (human lens - IC50 2.0 X 10(-8) mol/L). Dulcitol accumulation in erythrocytes and sciatic nerves of galactose loaded rats was inhibited by five days of treatment with ICI 128,436 (oral ED50's 2.21 mg/kg and 8.56 mg/kg, respectively). On oral administration for five days to streptozotocin diabetic rats, ICI 128,436, reduced sorbitol levels in sciatic nerve, lens, retina, and renal cortex. The ED50 for inhibition of nerve sorbitol accumulation was 5 mg/kg. The effect of a single dose of ICI 128,436 in diabetic rats was prolonged, with little increase in nerve sorbitol for 48 hours. No tolerance to the ability of ICI 128,436 to reduce nerve sorbitol was found on treatment for 74 days. ICI 128,436 was effective in rodent models of the neural and lenticular complications of diabetes. At doses as low as 25 mg/kg/d it completely prevented the development of cataracts in diabetic rats. The deterioration in motor nerve conduction velocity velocity found in diabetic rats was ameliorated by treatment with ICI 128,436 (3.125 mg/kg/d). Thus, ICI 128,436 constitutes a chemically novel aldose reductase inhibitor that is now being assessed for therapeutic value in the diabetic patient.

Aldehyde Reductase↗
PubMed1985

The thermogenic role of adipose tissue in the dog.

Brown adipose tissue was clearly present in neonatal dogs. In the adult the tissue was superseded by a tissue with the gross characteristics of white adipose. However despite their appearance adult adipose tissue depots may contribute to non-shivering thermogenesis. Regional blood flow measurements using injected radioactive microspheres indicated large increases in blood flow to adipose depots during infusion of noradrenaline. Coupled with blood flow estimations, measurement of arteriovenous differences in dissolved oxygen across the bladder fat depot demonstrated a quantitative increase in oxygen extraction by the depot during noradrenaline infusion. Acute activation of non-shivering thermogenesis in the dog was not associated with increased mitochondrial GDP-binding in adipose tissue. However chronic treatment with a beta-stimulant (LY79730) which increased capacity for non-shivering thermogenesis was associated with increased mitochondrial GDP-binding and cytochrome oxidase activity in peri-renal adipose tissue.

2-Hydroxyphenethylamine↗
PubMed1984

Effect of noradrenaline on oxygen consumption and tissue blood flow in young pigs.

Metabolic rate and tissue blood flow were measured by indirect calorimetry and the radioactive microsphere technique, respectively, in anaesthetized pigs aged 10, 17, and 28 days during infusions of saline or noradrenaline. Noradrenaline produced a rise in oxygen consumption in all pigs but the magnitude of the response declined with age in Large White pigs (percent increase: 10 days old, 29.5 +/- 3.3; 17 days old, 15.3 +/- 3.2; 28 days old, 5.4 +/- 0.17) and was less in 10-day-old Minipigs (9.1 +/- 5.1). Regional blood flow per gram of tissue was similar for pigs of all ages and noradrenaline produced increases in flow to heart and skin, and small reductions in blood flow to skeletal muscle. Noradrenaline increased average blood flow to adipose tissue (four sites) by 21-fold in 10-day-old Large White pigs, but had less effect in 10-day-old Minipigs (9.5-fold) and in older Large White pigs (9-fold), where the effect on metabolic rate was diminished. It is calculated that adipose tissue could be responsible for the increase in metabolic rate during infusion of noradrenaline. Macroscopically there are no gross differences between various adipose tissue depots in the pig but those which showed the greatest response to noradrenaline correspond to areas where brown adipocytes have previously been identified by electron microscopy.

Adipose Tissue↗