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Biomedical subjects

D L Davies

Publications and source records attributed to D L Davies.

At least 19 recordsLinked to original sources
PubMed1992

Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension.

OBJECTIVE: To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. DESIGN: Double-blind, placebo-controlled, parallel-group study of 28 days' duration. SETTING: Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). PATIENTS: Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period. INTERVENTIONS: Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. MAIN OUTCOME MEASURES: Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. RESULTS: When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. CONCLUSIONS: Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.

Antihypertensive Agents↗
PubMed1991

Long-term ethanol-exposure markedly changes the cellular composition of cerebral glial cultures.

The vulnerability of morphologically distinct glial subpopulations to ethanol toxicity was surveyed in tissue culture. Secondary cultures of rat glia were examined at intervals during 56 days of ethanol treatment for changes in growth and cellular characteristics. Beginning at 6 days in vitro (DIV), the experimental cultures were treated with either 0.2% or 0.5% (w/v) ethanol in the medium; control cultures received ethanol-free medium. Relative to control cultures, the ethanol-treated cultures exhibited a consistent and dose-dependent suppression in cell number. The development of these cultures was documented with sequential phase-contrast photomicrography. Prior to treatment day 5 (11 DIV), the preponderance of cells were epithelioid in configuration; the astrocytic character of these cells was verified by the immunocytochemical localization of glial fibrillary acidic protein. In control cultures, a subpopulation of process-bearing cells was acquired gradually during the first 3 weeks in culture. The majority of these process-bearing cells were considered to be oligodendrocytes due to their position above the astrocytic carpet and by the immunocytochemical localization of galactocerebroside. Exposure to 0.5% ethanol markedly suppressed the acquisition of process-bearing cells. This ethanol-related suppression of process-bearing cells was apparent in the photomicrographic records of culture development and was confirmed by differential cell counts after 50 days of treatment. These results suggest a possible differential sensitivity of oligodendrocytes of their precursors to ethanol toxicity at elevated (0.5% w/v) concentrations.

Animals↗
PubMed1991

Fibroblast growth factor-induced increased survival of cholinergic mesopontine neurons in culture.

Basic fibroblast growth factor (bFGF) was found to increase the survival of immunocytochemically-identified cholinergic mesopontine neurons in dissociated cell cultures of embryonic rat midbrain. In contrast, cultures exposed to, (a) bFGF and an antibody to bFGF, (b) antibody to bFGF alone, or (c) untreated, contained approximately half the number of cholinergic neurons compared to bFGF-treated cultures.

Animals↗
PubMed1991

Delayed growth and maturation of astrocytic cultures following exposure to ethanol: electron microscopic observations.

This investigation examined the effects of ethanol on the morphologic features of cultured rat astrocytes using a treatment paradigm that provided consistent exposure to ethanol at concentrations of 0.2%, 0.5%, or 1.0% (w/v). Cultures were assessed between 4 and 8 days in vitro during the logarithmic phase of growth; differences in culture growth, cell profile area and ultrastructural configuration were found. A dose-dependent inhibition of culture growth was observed after 48 and 96 h of ethanol exposure. In control cultures, the consequences of culture growth included the progressive crowding of cells, a concomitant reduction in the cell profile area, and increased cell-cell contact. On culture day 8, electron microscopic examination of control cultures demonstrated a complex stratified cellular layer, the junction of cells by puncta adhaerentia and the acquisition of intermediate filament bundles. In contrast, the impaired growth in ethanol-exposed cultures was associated with the retention of an extensive cell profile area suggesting restrained morphologic development. At the electron microscopic level, ethanol-exposed cultures showed a dose-dependent attenuation in both the depth and complexity of the cell layer. These findings indicated that the growth kinetics and morphologic development of astrocytic cultures are vulnerable to ethanol exposure at moderate and high levels. These findings were attributed to both ethanol cytotoxicity and a deprivation of cellular interaction resulting from the restricted population size.

Animals↗
PubMed1991

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease.

We studied young adults with autosomal dominant polycystic kidney disease (ADPKD) to determine the characteristics that precede renal impairment. Nineteen affected (A) and 20 unaffected (U) offspring from families with ADPKD showed no significant differences in basal glomerular filtration rate (A: mean 97, SD 19; U: 100, SD 23 ml/min/1.73 m2) or renal functional reserve, but effective renal plasma flow was significantly lower in affected offspring (A: 532, SD 86; U: 605, SD 118 ml/min/1.73 m2, P less than 0.01). Plasma renin activity [A: median 26 (95% CI: 15 to 37); U: 14 (11 to 27) microU/ml, P less than 0.05, one-tailed test] and aldosterone [A: 2.5 (2.0 to 3.0), U: 1.0 (1.5 to 2.0) micrograms/100 ml, P less than 0.04, one-tailed test] were increased in affected offspring despite the higher systolic blood pressure (A: mean 123, SD 5; U: 115, SD 3 mm Hg, P less than 0.02) and significant expansion of total exchangeable sodium (A: 40.8, SD 2.3; U: 38.0, SD 3.5 mmol/kg, P less than 0.01). The ouabain-sensitive component of red cell sodium efflux was less in affected offspring (A: 0.258; SD 0.040; U: 0.288, SD 0.042 hr-1, P less than 0.04) and in both groups was correlated inversely with total exchangeable sodium. Echocardiography revealed no difference in left ventricular mass index nor prevalence of mitral valve prolapse. Potential cyst growth factors such as the glucocorticoids and somatomedin C were similar in both affected and unaffected groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Radiological protection guidance for radioactive patients--new data for therapeutic 131I.

Patients leaving hospital after 131I treatment for thyrotoxicosis face restrictions on their contact with other members of the public. These restrictions depend on the level of residual body radioactivity which for practical purposes can be taken to be almost entirely in the thyroid gland. This study provides an appropriate data base from which to draw advice to patients consistent with current radiological protection requirements in terms of the duration of these restrictions. Thyroidal retention of 131I was measured in 77 thyrotoxic patients over a period of 1-50 days after a first therapeutic administration of the radionuclide. Mean 131I activity in the gland (+/- S.D.) at 1 day was 56.1 +/- 11.1% of the administered dose activity and thereafter retention followed a single exponential decay pattern with a mean effective half-life (+/- S.E.M.) of 6.35 +/- 0.14 days. In patients who required further 131I therapy, there was evidence that retention could be markedly reduced if there was virtual ablation of thyroid tissue. It is proposed that these retention data can be used to determine body radioactivity at any interval after the administration of 131I for treatment of thyrotoxicosis, thus obviating the need for serial measurements in every individual patient.

Adult↗
PubMed1991

Nuclear protein phosphorylation in rat cerebral cells following acute exposure to ethanol.

The sequelae of acute ethanol toxicity encompass a broad spectrum of metabolic and cellular derangements, including the induction of stress proteins in cells exposed to high levels of ethanol. In this investigation, the effects of ethanol exposure on nuclear protein synthesis and phosphorylation were compared by two-dimensional gel electrophoresis in glial-enriched cultures, adult rat cerebrum and regenerated liver. Cellular exposure to ethanol was at clinically relevant levels and tissue was analyzed at 1 h and 48 h after exposure. Cell nuclei were stained with propidium iodide, a DNA specific fluorochrome and flow cytometrically sorted to obtain cell cycle phase populations of nuclei for analysis. Ethanol treatment of intact rats and glial-enriched cultures induced phosphorylation of specific nuclear proteins, which were detected by two-dimensional electrophoresis and autoradiography. The autoradiographs of [32P]phosphate and [3H]leucine labeled proteins from glial-enriched cultures and from the G0/G1 phase of the regenerating liver tissue exhibited intense labeling indicative of active protein synthesis and phosphorylation. In contrast, the autoradiographs of proteins from adult rat cerebra showed substantial phosphorylation, but weak protein synthesis. Ethanol treatment was associated with phosphorylation of a 50,000 Mr protein in G0/G1 phase cells of the cultures and in predominantly G0 cells of the adult rat cerebra. A protein with similar characteristics was not found in ethanol exposed regenerating rat liver tissue and has not been observed in other 'heat shock' or 'stress' protein systems which we have previously studied.

Animals↗
PubMed1990

Effect of perinatal administration of ethanol on the CA1 pyramidal cell of the hippocampus and Purkinje cell of the cerebellum: an ultrastructural survey.

Previous studies of Golgi-impregnated material demonstrated the vulnerability of the dendritic arbors of the CA1 pyramidal cells of the hippocampus and the Purkinje and granule cells of the cerebellum to perinatal exposure to ethanol. The purpose of this investigation was to determine whether the alterations seen in the Golgi material could be corroborated at the ultrastructural level, and to qualitatively survey the neuropil surrounding the affected neurons. Pregnant mice were maintained on either a chocolate-flavoured liquid diet containing 25% of its caloric value as ethanol (5.4% v/v) or a chow and water diet. The treatment period began on gestational day 12 and continued until postnatal day 7, at which time the ethanol-exposed animals were returned to a chow and water diet. Pups were killed on postnatal day 14, and the tissue was processed for ultrastructural and Golgi analysis. The results confirm our Golgi findings that ethanol severely compromises the dendritic arbor, and also indicate that ethanol exposure produces changes in the organization of the neurophil, as well as alterations in the organization of the perikaryal organelles, and glial swelling.

Animals↗
PubMed1990

Hilus cell pathology and hirsutism.

Hilus cell abnormalities are uncommon causes of hirsutism with virilization. Although hilus cell tumours have been well described, hilus cell hyperplasia is rare and is poorly defined clinically. We describe three cases of hilus cell hyperplasia and compare them with a case of hilus cell tumour. Both pathologies were associated with increased testosterone and oestradiol secretion. Suppression of testosterone to the 'normal range' in response to exogenous oestrogen was seen only in the cases with hyperplasia; only partial responsiveness was seen in the case with hilus cell tumour. Bilateral oophorectomy offers the potential for cure for both hilus cell hyperplasia and tumour.

Aged↗
PubMed1990

Effects of dexamethasone on body fluid and electrolyte composition of rats.

Low-dose infusions of dexamethasone (2 micrograms/day for 2 and 4 weeks) increased systolic blood pressure and decreased body weight gain in male rats. Total body sodium, calcium and magnesium were increased by dexamethasone treatment; potassium was unaffected. These changes have been evaluated bearing in mind that glucocorticoids have profound catabolic effects. Relative to pretreatment values, dexamethasone decreased exchangeable body sodium for the first two weeks of treatment although values were not significantly different from vehicle-treated controls. Hematocrit, plasma cholesterol and transaminase activities were increased by dexamethasone; white cell numbers and plasma volumes were decreased; plasma Na+, K+ and Ca2+, red cell numbers, extracellular fluid volume, and glomerular filtration rate were not significantly affected. It is concluded that glucocorticoids cause plasma volume to contract, possibly as a result of glucocorticoid-induced natriuresis. Any effects of dexamethasone on whole-body ionic composition are obscured by simultaneous changes of intermediary metabolism.

Animals↗
PubMed1989

Secretion of antidiuretic hormone in neurosurgical patients: appropriate or inappropriate?

In neurosurgical patients with hyponatraemia (plasma sodium less than 130 mmol/l) and natriuresis, increased antidiuretic hormone (ADH) secretion may be appropriate rather than inappropriate. Ten such patients were studied prospectively to assess circulating ADH concentration and body fluid volumes. Compared with a control group, the mean plasma ADH level was significantly elevated (0.9 pmol/l (s.e.m. = 0.2) versus 0.2 pmol/l (s.e.m. = 0.1], the total body water was normal (101% (s.e.m. = 3) versus 100% (s.e.m. = 6], while the blood volume was significantly reduced (89% (s.e.m. = 3) versus 104% (s.e.m. = 5]. The elevated ADH level was therefore appropriate to a reduced blood volume. This suggests that, in neurosurgical patients with hyponatraemia, fluid restriction could be dangerous. Serial observations in this small group of patients showed that salt replacement and normal fluid intake resulted in a fall in the elevated ADH levels.

Acute Disease↗
PubMed1989

Twice-daily low-dose captopril in diuretic-treated hypertensives.

Twice-daily captopril (25 mg) and placebo were compared in ten hypertensive patients who were already receiving bendrofluazide. After six weeks therapy, captopril produced significant antihypertensive effects one to six hours after dosing but these did not persist at eleven to twelve hours. Plasma renin concentration was increased for twelve hours after captopril but inhibition of angiotensin II activity was lost by twelve hours. During the period when captopril reduced blood pressure significantly, effective renal plasma flow and hepatic blood flow were unchanged although renal vascular resistance was reduced. There was no evidence that captopril altered plasma sodium, potassium or magnesium concentrations following bendrofluazide. Thus, in thiazide-treated patients, captopril 25 mg produces significant blood pressure reduction for at least six hours after dosing, without impairing renal or hepatic blood flow. However, twice-daily low-dose captopril does not adequately control blood pressure throughout the dosage interval.

Adult↗
PubMed1988

Failure of chronic administration of growth hormone to affect blood pressure, vascular reactivity and sodium metabolism in normal rats.

To examine the effects of exogenous growth hormone on the cardiovascular system and sodium metabolism, ovine growth hormone was given daily to female rats for 5 weeks. Growth hormone resulted in a significant increase in body mass compared with controls. However, blood pressure in the treated rats was not significantly different from that in controls. Following treatment, the baseline resistances and pressor responses of the isolated mesenteric beds did not differ between the two groups. In addition, exchangeable sodium, erythrocytic intracellular sodium and transmembrane sodium efflux rate constants were not altered significantly by growth hormone treatment. The failure to observe cardiovascular or sodium effects of growth hormone despite significant potentiation of growth is, at present, unexplained.

Animals↗
PubMed1988

Clinical response of thyrotropin-secreting macroadenoma to bromocriptine and radiotherapy.

A patient presenting with hyperthyroidism was treated initially with antithyroid drugs and subsequently radioiodine. Thereafter he was noted to have inappropriately elevated thyrotropin. A bitemporal visual field defect was noted and CT scan confirmed the presence of a pituitary tumour. TSH was elevated and unresponsive to TRH stimulation. alpha subunit was not elevated. Long-term bromocriptine therapy (doses up to 50 mg/day) resulted in partial, but incomplete suppression of thyrotropin secretion. Following radiotherapy there was resolution of the visual field defect; the TSH, however, remains elevated at greater than 20 mU/l. Radiotherapy and bromocriptine may provide a clinically useful alternative to pituitary surgery in patients with TSH-secreting macroadenoma with suprasellar extension.

Adenoma↗