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R Howe

Publications and source records attributed to R Howe.

At least 19 recordsLinked to original sources
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

(2,6-Dimethylphenylsulphonyl)nitromethane: a new structural type of aldose reductase inhibitor which follows biphasic kinetics and uses an allosteric binding site.

Many of the complications of diabetes seem to be due to aldose reductase (aldehyde reductase 2, ALR2) catalysing the increased conversion of glucose to sorbitol. Therapy with aldose reductase inhibitors (ARIs) could, therefore, decrease the development of diabetic complications. (2,6-Dimethylphenylsulphonyl)nitromethane (ICI 215918) is an example from a newly discovered class of ARIs, and we here describe its kinetic properties. Preparations of bovine lens ALR2 exhibit biphasic kinetics with respect to glucose and various inhibitors including ICI 215918. The inhibitor sensitive form (ALR2S) has a higher affinity for glucose than does the inhibitor insensitive form (ALR2I). Only ALR2S was characterized in detail because ALR2I activity is very low at physiological levels of glucose and is difficult to measure with accuracy. Aldehyde reductase (ALR1) is the most closely related enzyme to ALR2. Inhibition of ALR1 was, therefore, investigated in order to assess the specificity of ICI 215918. The values of Ki and Kies (dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for ICI 215918 with bovine kidney ALR1 and bovine lens ALR2S have been determined. When glucose is varied, the compound is an uncompetitive inhibitor of ALR2S (Kies = 0.10 microM and Ki is much greater than Kies), indicating that ICI 215918 associates with an allosteric site on the enzyme. These kinetic characteristics would cause a decrease in the concentration required to give 50% inhibition when glucose levels rise during hyperglycaemia. ICI 215918 is a mixed noncompetitive inhibitor of ALR1 (Ki = 10 microM and Kies = 1.8 microM) when glucuronate is varied. Thus, the compound has up to 100-fold specificity in favour of ALR2S relative to ALR1. Therapeutic interest has now centred upon at least three distinct structural types of ARIs: spirohydantoins, acetic acids and sulphonylnitromethanes. Using one representative of each type, we have demonstrated kinetic competition for inhibition of ALR2S. This observation strongly suggests that the different inhibitors use overlapping binding sites.

Aldehyde Reductase↗
PubMed1991

Glutamate-immunoreactivity in the trigeminal and dorsal root ganglia, and intraspinal neurons and fibres in the dorsal horn of the rat.

Putative aspartergic and glutamatergic sensory neurons in the rat were identified by autoradiography and immunocytochemistry respectively. Approximately 3% of large L4 dorsal root ganglion neurons (diameter 18-52 microns) accumulated radiolabelled aspartate, whereas all satellite glia had high affinity for the amino acid. Glutamate-immunofluorescent (Glu-FITC) dorsal root ganglia neurons comprised 38.3% at S1, 35.6% at L2, 33.9% at C5 and 28.8% at T6. Numbers of immunoreactive neurons were higher with the more sensitive peroxidase-anti-peroxidase (Glu-PAP) method; and the cell counts totalled 42% (S1), 41.2% (L4), 35% (C5) and 34.6% (T6). The trigeminal ganglion (TG) contained 24% Glu-FITC and 32.3% Glu-PAP positive cells. The majority of glutamate-immunoreactive sensory neurons were small, ranging from 10-35 microns with median diameters of 17.5 microns (C5), 21 microns (S1), 24.2 microns (TG) and 28.5 microns (L2). It is evident therefore, that a subgroup of class B cells are glutamatergic. Glutamate immunoreactivity in the spinal cord was similar in all segments and was localized in the superficial lamina and substantia gelatinosa of the dorsal horn. Stained interneurons were located among the immunoreactive fibres. The dorsolateral funiculus contained dense plexus of immunoreactive fibres which increased in prominence after intraperitoneal injection of L-gluatamate, but penetration of exogenous glutamate into the grey matter was limited. Instead, the meninges and basal layers of the spinal blood vessels were intensely immunoreactive. The studies describe the subtypes of acidic amino acidergic neurons and relates the immunohistochemistry to a functional subclass.

Animals↗
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

The application of enhanced chemiluminescence to membrane-based nucleic acid detection.

The ECL gene detection system is a novel, sensitive, non-radioactive system for the detection of nucleic acid hybridized on both nylon and nitrocellulose membranes. It is characterized by direct labeling of probe sequences with horseradish peroxidase combined with an enhanced chemiluminescent (ECL) detection reaction; the light output is captured on blue-light sensitive film. The application of the system to a range of standard molecular biology hybridization techniques is described.

Blotting, Northern↗
PubMed1986

Expression of antigen interaction structures on resting and activated cytotoxic lymphocytes.

The expression of T-cell receptor protein and Lyt-2 was examined on resting and activated antigen-specific cytotoxic lymphocytes. Receptor expression was largely independent of the activation state of the cells. In contrast Lyt-2 expression was approximately threefold higher on activated than on resting cells. Since lytic activity varied by as much as 100-fold, it appears that lytic activity is primarily regulated by processes independent of quantitative changes in antigen interaction structures.

Animals↗
PubMed1982

Hydroxyurea versus busulfan in the treatment of chronic myelogenous leukemia.

A retrospective analysis of 67 patients with chronic myelogenous leukemia treated with hydroxyurea (41 patients) and busulfan (26 patients) compared the effectiveness of treatment and resulting survival. After 4 days of treatment, the white blood count in the hydroxyurea group fell at a rate of 31% +/- 10% per day compared to 10% +/- 8% for the busulfan group. At 6 months, the hemoglobin was similar, but in the busulfan group, the white blood count was significantly lower (12,500 vs. 29,900) (p = greater than 0.03). The platelet count was lower (311,000 vs. 481,000) in the busulfan group; however, the difference was not significant. When treatment was discontinued because of progression of the disease, the hemoglobin and white blood counts for both groups were similar. The platelet count was higher in the hydroxyurea group (762,000 vs. 269,000) (p greater than 0.02). The duration of therapy for both groups was similar. The median survival was also similar (hydroxyurea = 51 months; busulfan = 45 months). Hydroxyurea was associated with less life-threatening toxicity. Hydroxyurea is as effective as busulfan in treating chronic myelogenous leukemia.

Actuarial Analysis↗
PubMed1978

Effects of viloxazine, its optical isomers and its major metabolites on biogenic amine uptake mechanisms in vitro and in vivo.

Viloxazine hydrochloride (ICI 58,834, VIVALAN) a chemically novel antidepressant, shows selective inhibition of noradrenaline uptake into mouse heart in vivo and into rat brain in vitro. The noradrenaline uptake inhibitory activity resides primarily in one of the two optically active isomers, and it is suggested that in the conformation adopted for uptake by noradrenaline, the aryl and the amino groups are trans. In a comparison of in vivo and in vitro potency, tri- and tetracyclic antidepressants exhibit a good correlation. However, viloxazine possesses higher in vivo activity than would be expected from in vitro studies. The latter finding cannot be readily explained on the basis of known pharmacokinetic or metabolic factors.

Animals↗
PubMed1976

Optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and related compounds.

The optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine have been prepared and absolute configurations have been assigned. In their action on the central nervous system the S isomers are at least ten times more potent than the R isomers. The intermediate 4-benzyl-2-(p-toluensulfonyloxymethyl)tetrahydro-1,4-oxazine has been resolved. Its isomers provide a convenient starting point for the preparation of optical isomers of viloxazine analogues of known configuration.

Animals↗