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Biomedical subjects

M D Page

Publications and source records attributed to M D Page.

53 records · Page 3Linked to original sources
PubMed1990

Long-term treatment of acromegaly with a long-acting analogue of somatostatin, octreotide.

We have treated 16 acromegalic patients for up to 44 months with octreotide in varying doses. Growth hormone levels were suppressed in 14 patients with associated clinical improvement. IGF-1 levels were measured in 12 and fell into the normal range in 10. Prolactin was suppressed in six hyperprolactinaemic patients but was unaltered in normoprolactinaemic acromegalic patients. Post-prandial hyperglycaemia with impaired insulin secretion was noted in all patients, and one patient required oral hypoglycaemic agents. Octreotide did not affect thyroid function. CT scans from before and after six months of treatment demonstrated minimal tumour shrinkage in only two patients. Octreotide was well tolerated with no serious haematological or biochemical disturbance and no evidence of malabsorption. Two patients developed gallstones. Octreotide is effective in acromegaly. The development of gallstones is the only serious adverse event we have encountered.

Acromegaly↗
PubMed1989

The energy-conserving nitric-oxide-reductase system in Paracoccus denitrificans. Distinction from the nitrite reductase that catalyses synthesis of nitric oxide and evidence from trapping experiments for nitric oxide as a free intermediate during denitrification.

1. A Clark-type electrode that responds to nitric oxide has been used to show that cytoplasmic membrane vesicles of Paracoccus denitrificans have a nitric-oxide reductase activity. Nitrous oxide is the reaction product. NADH, succinate or isoascorbate plus 2,3,5,6-tetramethyl-1,4-phenylene diamine can act as reductants. The NADH-dependent activity is resistant to freezing of the vesicles and thus the NADH:nitric-oxide oxidoreductase activity of stored frozen vesicles provides a method for calibrating the electrode by titration of dissolved nitric oxide with NADH. The periplasmic nitrite reductase and nitrous-oxide reductase enzymes are absent from the vesicles which indicates that nitric-oxide reductase is a discrete enzyme associated with the denitrification process. This conclusion was supported by the finding that nitric-oxide reductase activity was absent from both membranes prepared from aerobically grown P. denitrificans and bovine heart submitochondrial particles. 2. The NADH: nitric-oxide oxidoreductase activity was inhibited by concentrations of antimycin or myxothiazol that were just sufficient to inhibit the cytochrome bc1 complex of the ubiquinol--cytochrome-c oxidoreductase. The activity was deduced to be proton translocating by the observations of: (a) up to 3.5-fold stimulation upon addition of an uncoupler; and (b) ATP synthesis with a P:2e ratio of 0.75. 3. Nitrite reductase of cytochrome cd1 type was highly purified from P. denitrificans in a new, high-yield, rapid two- or three-step procedure. This enzyme catalysed stoichiometric synthesis of nitric oxide. This observation, taken together with the finding that the maximum rate of NADH:nitric-oxide oxidoreductase activity catalysed by the vesicles was comparable with that of NADH:nitrate-oxidoreductase, is consistent with a role for nitric-oxide reductase in the physiological conversion of nitrate or nitrite to dinitrogen gas. 4. Intact cells of P. denitrificans also reduced nitric oxide in an antimycin- or myxothiazol-sensitive manner. However, nitric oxide was not detected by the electrode during the reduction of nitrate. Nitric-oxide synthesis from nitrate could be detected with cells in the presence of very low concentrations of Triton X-100 which selectively inhibits nitric-oxide reductase activity. 5. Nitric oxide was detected as an intermediate in denitrification by including haemoglobin with an anaerobic suspension of cells that was reducing nitrate. The characteristic spectrum of the nitric oxide derivative of haemoglobin was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytoplasm↗
PubMed1989

Cholinergic blockade with pirenzepine improves carbohydrate tolerance and abolishes the GH response to meals in normal subjects.

Pretreatment of normal male volunteers with the cholinergic muscarinic receptor-blocking drug pirenzepine (200 mg p.o.) abolishes the delayed GH response to a meal stimulus. In addition, the glycaemic and insulin responses to meals are significantly reduced following this dose of pirenzepine. The data suggest that the effect of pirenzepine on the glucose response to meals is at least partly independent of the inhibition of GH release. Our findings are of relevance to the further investigation of cholinergic muscarinic antagonist in diabetes mellitus.

Adult↗
PubMed1989

A bacterial c-type cytochrome can be translocated to the periplasm as an apo form; the biosynthesis of cytochrome cd1 (nitrite reductase) from Paracoccus denitrificans.

An apo form of cytochrome cd1 (nitrite reductase) of Paracoccus denitrificans has been detected immunologically in the periplasm of a mutant that lacks all c-type cytochromes. A method for the preparation of apo-nitrite reductase (lacking both c- and d-type haem) from the holoenzyme of wild-type cells has been developed. The apoprotein synthesized by the mutant is indistinguishable from the chemically prepared apoprotein in respect of: (i) subunit molecular weight; (ii) formation of a homodimer; (iii) properties on anion exchange chromatography. The holoenzyme has similar properties in respect of (i) and (ii) but behaves differently during anion exchange. A suggested mode of assembly of cytochrome cd1 is translocation into the periplasm of a precursor polypeptide, maturation by a signal peptidase to give an apoprotein identical to that prepared chemically from the holoenzyme, followed by insertion of c-type and d-type haem in an as yet unknown order.

Apoproteins↗
PubMed1988

Alpha-2-adrenergic pathways release growth hormone via a non-GRF-dependent mechanism in normal human subjects.

Administration of a supramaximal dose of GRF 1-44 (200 micrograms, i.v.) to normal human volunteers increased GH levels while a further bolus of GRF (200 micrograms i.v.) given 2 hours later failed to increase plasma GH levels. In contrast, alpha-adrenergic receptor agonism with either propranolol-adrenaline infusion or clonidine increased plasma GH levels at a time when GH responses to this supramaximal dose of GRF were absent. This indicates that alpha-adrenergic pathways stimulate GH secretion through a non-GRF-dependent mechanism in normal human subjects.

Adult↗
PubMed1988

Growth hormone (GH) responses to arginine and L-dopa alone and after GHRH pretreatment.

In order to investigate the mechanisms by which arginine and L-dopa cause GH release in humans we measured the GH response to GHRH 1-44 (200 micrograms i.v.), arginine (30 g i.v. over 30 min) and L-dopa (500 mg orally) administered alone and 120 minutes following pretreatment with GHRH 1-44 (200 micrograms i.v.) in normal male subjects. Prior GHRH administration abolished the GH response to subsequent GHRH. Arginine infusion induced a rise in GH levels maximal at 45 min. Following GHRH pretreatment the GH response to arginine was enhanced, with peak values of 19.3 +/- 6.4 vs 53.3 +/- 16.5 mU/l (mean +/- SEM) respectively (P less than 0.02). L-dopa alone induced a rise in GH levels maximal at 90 min (17.6 +/- 7.4 mU/l, mean +/- SEM) but this rise was abolished by pretreatment with GHRH.

Adult↗
PubMed1988

Somatostatin: a historical perspective.

Following the discovery and biochemical characterization of natural somatostatin its action profile has been thoroughly investigated. Although the name somatostatin was coined in virtue of its growth hormone release-inhibiting properties, a number of central and peripheral endocrine and paracrine actions have been ascribed to this peptide. Its inhibitory effect on a series of pituitary and gastrointestinal hormones has characterized somatostatin as a classical brain-gut hormone. Circulating and tissue levels of somatostatin and its possible physiological role are analyzed and clinical implications are drawn.

Animals↗
PubMed1988

Growth hormone and its modulation.

Our knowledge of the mechanisms involved in the regulation of somatotroph cell growth is scanty and much work is still needed to elucidate the role of different growth factors and the mechanisms involved in oncogene activation in both normal and tumour cell growth. However, there are several recent, important clinical ramifications from our improved understanding of GH neuroregulation. The use of long-acting SS analogues is valuable in the treatment of acromegaly, probably in acute variceal haemorrhage and it also produces symptomatic improvement in patients with vipomas and glucagonomas. GHRH may be of value in the treatment of short stature due to hypothalamic GHRH deficiency but further definitive studies are now required to provide convincing evidence that this line of treatment is of greater benefit than the use of synthetic recombinant human GH. Inhibition of GH release may be of value in prevention of both acute and chronic complications of insulin-dependent diabetes mellitus. The use of cholinergic muscarinic receptor blockade in this context may be particularly useful because of a probably sparing of the counter-regulatory GH response to hypoglycaemia. In view of the relative ease with which nocturnal GH secretion can be abolished, we think it reasonable to consider the possible existence of a permissive or mediating role of GH in other disease states, either directly or by maintaining production of either local tissue or circulating growth factors or both.

Acromegaly↗
PubMed1987

Cholinergic muscarinic receptor blockade with pirenzepine abolishes slow wave sleep-related growth hormone release in young patients with insulin-dependent diabetes mellitus.

Cholinergic receptor blockade has been shown to abolish GH secretion in a variety of physiological and pharmacological situations in normal subjects. We have investigated the effect of pirenzepine on nocturnal GH secretion in young adult patients with Type I insulin-dependent diabetes mellitus. Five patients (three male, two female; aged 20-27 years) were studied in a randomized order on two days separated by at least 1 week. All patients showed episodes of slow wave sleep on each occasion and this was followed by peaks of GH release when placebo alone was administered (range of GH peaks 6-115 mU/l). In contrast, cholinergic muscarinic receptor blockade with pirenzepine (100 mg orally at 2200 and 2400 h) completely abolished nocturnal GH release in each individual without altering the occurrence of slow wave sleep itself. Mean plasma glucose levels at each sampling time between each study did not differ significantly. The ability to abolish nocturnal GH secretion may be important in the field of diabetes, since excess GH secretion is implicated in several acute metabolic and chronic microvascular complications of the disease.

Adult↗
PubMed1987

Effect of oral administration of melatonin on GH responses to GRF 1-44 in normal subjects.

In order to investigate the role of melatonin on the neuroregulation of GH secretion, eight healthy male volunteers each underwent four separate tests in random order separated by at least 1 week. Following oral administration of melatonin (500 mg at -60 min and at -30 min) plasma GH levels were higher than after placebo at 45 min (mean +/- SEM 2.9 +/- 0.8 vs 0.9 +/- 0.4 ng/ml, P less than 0.01) and 60 min (mean +/- SEM 2.9 +/- 0.4 vs 0.8 +/- 0.1 ng/ml, P less than 0.05). Likewise, after prior administration of melatonin, GH responses to GRF 1-44 (1 micrograms/kg i.v. at 0 min) were greater than placebo plus GRF at 15 min (mean +/- SEM 22.4 +/- 6.1 ng/ml vs 11.3 +/- 2.3 ng/ml, P less than 0.05), 45 min (mean +/- SEM 26.2 +/- 5.3 ng/ml vs 13.3 +/- 2.5 ng/ml, P less than 0.01) and 60 min (mean +/- SEM, 24.7 +/- 7.4 ng/ml vs 11.1 +/- 2.5 ng/ml, P less than 0.05). In contrast we did not observe any effect of either 10(-9)M, 10(-7)M melatonin on in-vitro basal GH release and GH responses to 10(-8)M GRF by rat anterior pituitary cells in monolayer culture. These data suggest that melatonin plays a facilitatory role in the neuroregulation of GH secretion, probably by acting at the hypothalamic level.

Administration, Oral↗
PubMed1987

Additive effects of growth hormone releasing factor and insulin hypoglycaemia on growth hormone release in man.

We have measured GH and PRL changes following separate and combined administration of insulin and GH releasing factor (GRF) in six normal males. Peak GH responses to separate administration of insulin and GRF were comparable (71.4 +/- 10.2 vs 70.1 +/- 27.7 mU/l; mean +/- SEM). However, the peak GH response following combined administration was significantly higher (120.8 +/- 29.7, P less than 0.05) as was the total GH released as calculated by measuring the area under the curve (P less than 0.05). In contrast the PRL response to hypoglycaemia was not altered by the combined administration of insulin and GRF. This effect was not due to any direct action of hypoglycaemia or insulin at pituitary level since basal and 10(-8) M GRF stimulated GH release from rat anterior pituitary cells in vitro was not influenced by varying glucose and insulin levels. Our findings support the hypothesis that GRF and insulin-induced hypoglycaemia release GH via different pathways which are, at least in part, additive.

Adult↗
PubMed1986

Cholinergic muscarinic receptor blockade with pirenzepine abolishes slow wave sleep-related growth hormone release in normal adult males.

Cholinergic pathways play an important role in the regulation of GH secretion from the anterior pituitary gland, and in this study we have investigated whether cholinergic muscarinic receptor blockade with pirenzepine displayed any inhibitory action on slow wave sleep-related GH release in normal subjects. Six adult males (ages 24-37 years) were studied in a randomized order and fasted from 1800 h on each study day. All subjects showed episodes of slow wave sleep on each occasion and this was followed by peaks of GH release when placebo alone was administered (range of GH peaks 4-50 mU/l). In contrast, pirenzepine treatment (100 mg p.o. at 2200 and 2400 h) completely abolished nocturnal GH release in each individual without altering the occurrence of slow wave sleep itself. These data demonstrate clearly that cholinergic muscarinic receptor blockade completely abolishes slow wave sleep-related GH release in normal adult subjects. Because of the striking effects it is reasonable to conclude that acetylcholine plays an important stimulatory role in mediating slow wave sleep-related GH release. This finding may have investigational and therapeutic applications in young patients with Type 1 diabetes mellitus since GH is implicated in some acute metabolic and chronic microvascular complications of this disease.

Adult↗
PubMed1986

Thyroid function in patients with hyperprolactinaemia: relationship to dopaminergic inhibition of TSH release.

It has been reported recently that patients with hyperprolactinaemia may develop hypothyroidism as a consequence of the increased inhibition of TSH release by dopamine which occurs in the majority of such patients. In this study we have evaluated thyroid function in a large number of hyperprolactinaemic patients in order to delineate more precisely the relationship between thyroid status, free thyroid hormone levels and the control of TSH release by dopamine. Biochemical euthyroidism was present in the majority of the hyperprolactinaemic patients. Our data indicate that the increased dopaminergic inhibition of TSH release does not lead to hypothyroidism. Instead, the slightly elevated basal TSH levels and TSH responses to TRH (within the normal range) may reflect the operation of a compensatory mechanism to maintain euthyroidism in the face of te increased inhibition of TSH release by hypothalamic dopamine.

Adult↗
PubMed1973

Rapid microbiological assay for 5-fluorocytosine.

A microbiological assay was developed for 5-fluorocytosine based on inhibition by the drug of the fall in pH produced by Candida albicans in a synthetic liquid culture medium. Serum and urine levels of the drug could be measured reproducibly in four hours.

Antifungal Agents↗
PubMed1973

Use of 5-fluorocytosine in patients with impaired renal function.

The plasma level and elimination of 5-fluorocytosine (5-FC) was measured in normal subjects and patients with impaired renal function. Prolongation of the half-life of the drug in renal failure has been confirmed. Renal clearance of 5-FC was about 75% of the creatinine clearance and a corresponding modification of drug dosage should be made in patients with renal insufficiency.

Antifungal Agents↗