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Biomedical subjects

D Wade

Publications and source records attributed to D Wade.

71 records · Page 4Linked to original sources
PubMed1987

Kinetic isotope effect on the demethylation and denitrosation of N-nitrosodimethylamine in vitro.

Deuteration of N-nitrosodimethylamine (NDMA) has been shown to decrease the carcinogenicity of this compound. This result is believed to be due to a kinetic isotope effect on the metabolic activation of this carcinogen, but conflicting views exist concerning whether the isotope substitution affects the Km or Vmax of the reaction. In order to elucidate the molecular basis of these observations, as well as the mechanisms of the demethylation and denitrosation reactions, the metabolism of NDMA and deuterated NDMA (NDMA-d6) was studied using acetone-induced rat-liver microsomes. The demethylation of NDMA displayed a Km of 0.06 mM and a Vmax of 7.9 nmol/min per mg protein. Deuteration of NDMA increased the Km value by five fold but did not appreciably affect the Vmax. The denitrosation of NDMA also displayed a Km of 0.06 mM, but the Vmax was 0.83 nmol/min per mg; deuteration again increased the Kmax several fold but had no effect on the Vmax. The results indicate that deuteration inhibits the metabolism of NDMA by increasing the Km but not the Vmax and suggest that there is a close relationship between the demethylation and denitrosation reactions.

Acetone↗
PubMed1984

Binding of ethidium and bis(methidium)spermine to Z DNA by intercalation.

The interaction of ethidium bromide, a DNA intercalating drug, and bis( methidium )spermine, a DNA bis-intercalating compound, with the left-handed Z form of poly(dG-dC) has been studied in 4.4 M NaCl. Spectrophotometric analysis using absorption, fluorescence and circular dichroism indicates that the complex formed between ethidium and Z DNA resembles very closely that formed with B DNA. This suggests that ethidium binds to Z DNA by intercalation. 31P NMR spectra are presented showing both the conversion of the Z form to the B form with increasing amounts of drug and the typical Z form spectrum at low binding densities. Data are also presented which show that the bifunctional intercalator bis( methidium )spermine binds to Z DNA in a manner similar to its binding to B DNA, i.e., by bis-intercalation. These results are important for our understanding the behavior of Z DNA and its biological significance.

Animals↗
PubMed1983

Clonidine raises blood pressure in severe idiopathic orthostatic hypotension.

The hemodynamic effects of clonidine were studied in four patients with sever idiopathic orthostatic hypotension and one patient with baroreceptor dysfunction. No depressor response to clonidine was observed in any patient with idiopathic orthostatic hypotension at any dosage. Rather, two patients responded to 0.4 mg of oral clonidine with a 40 mm Hg increment in systolic blood pressure lasting several hours. Each has been receiving clonidine, 0.4 mg twice daily, for one year with greatly increased functional capacity. The other two patients with idiopathic orthostatic hypotension had an even greater pressor response to 0.8 mg of oral clonidine, but adverse effects prevented continued therapeutic use. In marked contrast, the patient with baroreceptor dysfunction had a profound depressor response to 0.2 mg of clonidine. In the treatment of idiopathic orthostatic hypotension, the major advantage of clonidine over other pressor agents is its longer duration of action. The major adverse effects of the drug in these patients are sedation, dry mouth, altered mentation, and excessive hypertension. The drug should not be given to patients with mild idiopathic orthostatic hypotension or selective baroreceptor dysfunction, since severe hypotension may result.

Aged↗
PubMed1983

Effects of phenytoin, phenobarbital, and ascorbic acid on misonidazole elimination.

The kinetics of an oral dose (1.0 gm/m2) of the 2-nitroimidazole radiosensitizer misonidazole were studied in three groups of six healthy subjects before and after a 1-wk course of phenytoin, phenobarbital, or ascorbic acid. Phenytoin and phenobarbital decreased mean misonidazole half-life by 27% and 23% and the decrease was associated with the respective increases in mean clearance of 42% and 31%. The area under the plasma concentration-time curve for the metabolite O-desmethylmisonidazole increased correspondingly. Volume of distribution of misonidazole was unchanged. After treatment with ascorbic acid there was a very small increase in the mean clearance of misonidazole, but there was no significant change in other kinetic parameters. Induction by phenytoin and phenobarbital of the oxidative metabolism of misonidazole is the most likely mechanism responsible. Deliberate induction of a patient's metabolism may help to reduce the neurotoxicity associated with the use of the drug. The efficacy of the radiosensitizing action of the drug is unlikely to be compromised under these conditions since peak plasma concentrations of misonidazole were not affected by treatment with either phenytoin or phenobarbital. The potentiation of the cytotoxic effects of misonidazole by ascorbic acid is unlikely to be related to a direct effect on the oxidative metabolism of misonidazole.

Adult↗
PubMed1981

Postprandial alterations in cardiovascular hemodynamics in autonomic dysfunction states.

The effect of food ingestion of supine blood pressure was assessed during 25 studies in 10 subjects with autonomic dysfunction. Profound decreases in both systolic and diastolic pressure occurred. The mean (+/- standard error of the mean) maximal reduction in systolic blood pressure for the entire group was 49 +/- 6 mm Hg (range 22 to 98). The response also occurred in hypertensive subject after surgical sympathectomy and during alpha adrenergic blockade and hence appears to be a general phenomenon when sympathetic vasoconstrictor function is impaired. The depressor effect of food ingestion was enhanced by propranolol, attenuated by indomethacin and unaffected by diphenhydramine and cimetidine. The phenomenon is thus not explained by histamine release, and can only partly be accounted for by release of arachidonic acid metabolites. Evidence that insulin may play a role in the phenomenon is discussed. Manipulation of diet may prove to be an important adjunct in the management of patients with autonomic dysfunction.

Aged↗
PubMed1981

Tolerance to the humoral and hemodynamic effects of caffeine in man.

Acute caffeine in subjects who do not normally ingest methylxanthines leads to increases in blood pressure, heart rate, plasma epinephrine, plasma norepinephrine, plasma renin activity, and urinary catecholamines. Using a double-blind design, the effects of chronic caffeine administration on these same variables were assessed. Near complete tolerance, in terms of both humoral and hemodynamic variables, developed over the first 1-4 d of caffeine. No long-term effects of caffeine on blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines could be demonstrated. Discontinuation of caffeine ingestion after 7 d of administration did not result in a detectable withdrawal phenomenon relating to any of the variables assessed.

Adult↗
PubMed1977

Pigmentation and musculoskeletal abnormalities in an aged state hospital population.

In a State hospital population, 686 patients (mean age, 65 years) were examined for patterned pigmentation on unexposed areas of the body. Of these patients, 285 (41.5 percent) met the criteria for pigmentation. There were no sex or age differences. Psychosis had been diagnosed in 96 percent of the pigmented group. All of the 239 patients examined orthopedically had vertebral malalignment greater than 15 degrees and often had other bony deformities. Nearly all of the pigmented group displayed dyskinetic activity. A possible mechanism for the production of the pigmentation-psychosis-skeletal deformity triad could be an alteration in the concentration of available melatonin. Continued research along these lines may lead to an effective means of pharmacologic treatment as well as better psychologic and physical care.

Adult↗
PubMed1977

Use of the Seldinger technique in sialography.

The authors describe a modified Seldinger Technique for sialography which is especially helpful in cannulization of the submandibular ducts. This procedure was successful in 2. of 30 patients tested.

Catheterization↗
PubMed1968

Title 19.

Explore the source record for details and available documents.

History, 20th Century↗
PubMedDate not supplied

Deuterium isotope effect in the interaction of N-nitrosodimethylamine, ethanol, and related compounds with cytochrome P-450IIE1.

Deuteration of N-nitrosodimethylamine (NDMA) decreases its carcinogenicity and produces an isotope effect on its metabolism. Our previous results showed that deuteration causes a 5-fold increase in the apparent Km, but not the Vmax, for the demethylation and denitrosation of NDMA in microsomes. In the present work, we studied the nature of this deuterium isotope effect with several compounds using acetone-induced microsomes as a source of cytochrome P-450IIE1. In the microsomal N-nitrosodiethylamine deethylase reaction, NDMA and [2H6]NDMA were competitive inhibitors and displayed apparent Ki values of 59 and 441 mM, respectively, showing an isotope effect of 0.13. Similarly, in the p-nitrophenol hydroxylase reaction, a deuterium isotope effect of 0.21 on the Ki was observed. With acetone as an inhibitor for p-nitrophenol hydroxylase, the isotope effect on the Ki was 0.11. Similar deuterium isotope effects were also observed with acetone and dimethylformamide as competitive inhibitors for NDMA demethylase. When the oxidation of ethanol, [1,1-2H2]ethanol, [2,2,2-2H3]ethanol, and [2H6]ethanol was compared, an isotope effect of about 5 was found in the Vmax/Km due to the deuteration of the methylene group (carbon 1) but not due to the methyl group. However, the Vmax was not affected. A corresponding deuterium isotope effect was observed in the Ki when these compounds were used as competitive inhibitors for the NDMA demethylase reaction. The results demonstrate that deuteration of NDMA, ethanol, and related compounds results in an increase in the Km or Ki with little change in the Vmax of P-450IIE1-catalyzed reactions. The molecular basis of this isotope effect is discussed.

Acetone↗
PubMedDate not supplied

The national sentinel audit for stroke: a tool for raising standards of care.

STUDY OBJECTIVE: To assess the quality of inpatient care and follow-up for stroke in England, Wales and Northern Ireland. DESIGN: Retrospective audit of case notes and service organisation. SETTING: 197 trust (80% of eligible trusts in England, Wales and Northern Ireland). PATIENTS: 6,894 consecutive stroke patients admitted between 1 January 1998 and 31 March 1998 (up to 40 per trust). AUDIT TOOL: The Intercollegiate Stroke Audit. RESULTS: Most patients were admitted to acute hospitals with access to the appropriate acute investigations and treatments. Only 64% of trusts had a physician with responsibility for stroke and only 50% had a stroke team. Involvement of different members of the multidisciplinary team within appropriate time-frames varied from 37% to 61%. Assessment of impairments specific to stroke was inadequate (screening for swallowing disorders in only 55%, cognitive function tests in 23% and visual field examination in 44%). Rehabilitation goals were agreed by the multidisciplinary team in only 55% of eligible cases. 41% of patients were contacted by their GP within 3 days of discharge. The best compliance with standards was achieved for the 18% of patients who spent at least 50% of their time in a stroke unit. CONCLUSIONS: This national audit demonstrates that care is suboptimal in many areas, and that there is wide variation in standards for the management of stroke across the country. This may have implications for clinical governance.

Aftercare↗