Trial of recombinant human erythropoietin: three patients with thalassemia intermedia.
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Adolescent↗
Biomedical subjects
B Sheridan
Publications and source records attributed to B Sheridan.
Insulin action and hepatic glucose cycling in essential hypertension.
Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU.kg-1.min-1. A simultaneous infusion of (2(3)H)- and (6(3)H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6(3)H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 +/- 0.3 v 10.9 +/- 0.3 mumol.kg-1.min-1) and with the 0.2 mU insulin infusion (4.9 +/- 0.5 v 4.0 +/- 0.8 mumol.kg-1.min-1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6(3)H)glucose was lower in the hypertensive group (21.8 +/- 2.4 v 29.9 +/- 2.4 mumol.kg-1.min-1, P less than .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 +/- 0.4 v 2.7 +/- 0.4 mumol.kg-1.min-1) and during insulin infusion (0.2 mU, 2.5 +/- 0.3 v 2.9 +/- 0.4; 1.0 mU, 4.7 +/- 0.3 v 5.3 +/- 1.1 mumol.kg-1.min-1 for hypertensive and control groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxybutyric Acid↗
Cyclical Cushing's syndrome first diagnosed after pituitary surgery: a trap for the unwary.
Three patients were studied after transsphenoidal microsurgery for Cushing's disease because their symptoms and signs were slow to settle and/or because they had variable endocrine results. All were established as having cyclical Cushing's syndrome, first diagnosed post-operatively. This may be a much more common finding than previously realized and emphasizes the need for detailed and ongoing endocrinological investigation after transsphenoidal surgery for Cushing's disease.
Adult↗
Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study.
OBJECTIVE: We aimed to study the effect of biosynthetic growth hormone (GH) replacement in growth hormone deficient adults. DESIGN: We performed a double-blind placebo-controlled cross-over study of 6 months biosynthetic GH, replacement and 6 months placebo separated by a 1-month's washout period. PATIENTS: Fourteen growth hormone deficient adults were studied. MEASUREMENTS: We measured total body weight, percentage fat mass, lean body mass, muscle volume, exercise capacity, maximum oxygen consumption, muscle strength, bone mineral content, a number of biochemical parameters, IGF-I, GH antibodies and psychological well-being. RESULTS: Total body weight remained unchanged, but lean body mass increased (before GH mean +/- SEM 49.8 +/- 5.5, after 53.4 +/- 5.6 kg; placebo before 51.2 +/- 5.4, after 50.4 +/- 5.1 kg; P less than 0.05 and fat mass decreased (before GH 21.5 +/- 4.1, after 19.3 +/- 4.3; placebo before 19.3 +/- 4.0, after 22.5 +/- 4.5 kg; P less than 0.05). Thigh muscle volume increased: (before GH 94.1 +/- 7.7, after 99.5 +/- 8.4 ml; placebo before 99.3 +/- 8.6, after 95.4 +/- 7.8 ml/0.8 mm computerized tomographic slice; P less than 0.05). Exercise capacity increased (before GH 174 +/- 15, after 199 +/- 18.9 watts; placebo before 162.5 +/- 2.3, after 154 +/- 19.8 watts; P less than 0.05), as did maximum oxygen consumption (before GH 1.93 +/- 0.2, after 2.17 +/- 0.2 l/m; placebo before 1.92 +/- 0.3, after 1.98 +/- 0.2 l/m; P less than 0.05). There was no change in quadriceps muscle strength. Alkaline phosphatase increased (before GH 87.5 (32-158), after 106.0 (49-179) U/I, placebo 99.5 (50-145), after 72.0 (40-111) U/I; P less than 0.05) without a change in the spinal bone density. IGF-I increased (before GH 62 (36-97), after 216 (62-362) micrograms/l; placebo before 59 (52-112), after 60.5 (38-94) micrograms/l; P less than 0.05). Carbohydrate tolerance remained unchanged as did fasting lipids, serum sodium, potassium, urea, calcium, phosphate and liver transaminases. Psychological well-being remained unchanged. No growth hormone antibodies were detected before or after GH treatment. CONCLUSIONS: GH alters the body composition of growth hormone deficient adults and leads to improved exercise capacity; alkaline phosphatase activity increases but without a change in spinal bone density, and carbohydrate tolerance remains unaltered.
Adult↗
Influence of growth hormone on glucose-glucose 6-phosphate cycle and insulin action in normal humans.
Increased activity of the hepatic glucose-glucose 6-phosphate (G/G-6-P) cycle is associated with hepatic and peripheral insulin resistance in acromegaly. To determine whether a similar association occurs after short-term growth hormone (GH) elevation within the physiological range, two-step euglycemic hyperinsulinemic clamps were performed in normal human males after 12-h GH (2.2 ng.kg-1 x h-1) and control infusions. G/G-6-P cycle activity and endogenous glucose production (EGP) were determined by [2-3H]- and [6-3H]-glucose using labeled exogenous glucose infusions and selective enzymatic detritiation. GH increased levels of circulating lipid intermediates despite a twofold increase in basal insulin (P < 0.005), but plasma glucose, EGP, and G/G-6-P cycle activity were unchanged. GH impaired insulin suppression of EGP and lipid intermediates and impaired insulin stimulation of glucose disposal, but G/G-6-P cycle activity was unchanged. We conclude that increased activity of the G/G-6-P cycle does not contribute to the hepatic insulin resistance induced by GH under these conditions but that changes in fatty acid metabolism may be partly responsible for the impairment in hepatic and peripheral insulin action.
Adult↗
The effect of indomethacin on basal and saline-stimulated plasma atrial natriuretic factor levels in normal man.
Surprisingly inappropriately high levels of plasma atrial natriuretic factor (ANF) in subjects with Bartter's syndrome are lowered by indomethacin therapy. Indomethacin in normal man causes sodium retention. One might therefore expect plasma ANF to increase in subjects taking indomethacin as a secondary phenomenon. On the other hand a decrease of plasma ANF in normal man similar to that reported in Bartter's subjects may explain the sodium retention caused by the drug in normals. We have studied plasma ANF before and during a two litre, four hour normal saline infusion in eight healthy male subjects both before and following five days of oral indomethacin. Plasma ANF basally was 4.2 +/- 0.9 pmol/l (mean +/- SEM) on no drug and 5.2 +/- 0.6 pmol/l on indomethacin (NS). It increased in response to saline in both studies (7.8 +/- 1.5 pmol/l after two litres of saline on control day; 10.6 +/- 1.5 pmol/l on the drug at the equivalent time, both p less than 0.05 vs basal value). Overall response to saline as assessed by the area under the curve above the basal value of hourly measurements, was not different in the two studies. Basal serum aldosterone and plasma renin activity were reduced by indomethacin. Urinary sodium excretion was not different between groups during the 12 hours before, four hours during and eight hours after the infusion. We have shown that indomethacin does not alter basal or saline stimulated plasma ANF in normal man, a finding in contrast to that reported in subjects with Bartter's syndrome. The sodium retention caused by indomethacin in normal man is not therefore due to a decrease of plasma ANF.
Administration, Oral↗
A long-term dose-response study of somatostatin analogue (SMS 201-995, octreotide) in resistant acromegaly.
Ten acromegalic subjects were studied in a trial designed to ascertain the optimum dosage of the somatostatin analogue SMS 201-995 (octreotide) in active acromegaly. Twenty-four-hour growth hormone (GH) profiles were assessed monthly for 6 months and again after 1 year of continuous therapy. After basal assessment octreotide was administered subcutaneously at a dose of 100 micrograms three times a day throughout the first month. The dose was increased by 300 micrograms/day at monthly intervals to a maximum of 1500 micrograms/day, unless serum GH fell to within set criteria. Eight patients completed the trial. One patient withdrew because of intractable diarrhoea while another died of causes related to his acromegaly and we have no evidence that octreotide played any part in his death. Mean 24-h GH fell from a basal level of 34.3 +/- SEM 7.6 mU/l to 8.0 +/- 1.3 mU/l (P less than 0.05) after 6 months. At 1 month (300 micrograms/day) mean GH was 13.6 +/- 2.2 mU/l and at 2 months (600 micrograms/day) 10.8 +/- 2.2 mU/l (P less than 0.05 vs 300 micrograms/day dose), and at 5 months (1500 micrograms/day) 11.3 +/- 2.0 mU/l (all P less than 0.05 vs basal). Analysis of group means revealed no significant difference between any dose schedules above 600 micrograms/day. After 1 year the mean GH of the group (n = 8) was 7.5 +/- 1.3 mU/l (P less than 0.05 vs basal). Three patients developed a deterioration and one an improvement in their glucose tolerance and three developed asymptomatic gallstones during the year of therapy. In conclusion, octreotide lowered GH levels in acromegaly over a 1-year period. We found no evidence that routinely increasing the dose beyond 600 micrograms/day was helpful.
Acromegaly↗
Physiological growth hormone secretion in adult growth hormone deficiency: comparison with normal controls.
A comparison was made between the pulsatile pattern of growth hormone secretion in 14 growth hormone deficient adults (serum growth hormone less than 7 mU/I following insulin-stimulated hypoglycaemia) and 14 age and sex matched controls. The 24-h secretory profile was generated by 2-hourly sampling from 0800 to 2200 h, and 30-min sampling from 2200 to 0600 h. Plasma GH in each sample was measured using a double antibody radioimmunoassay. The profiles were analysed using a computer program (Pulsar). Sleep-electroencephalography was recorded in all subjects. The total amount of GH secreted in a 24-h period (area under the curve over baseline) was significantly less in the growth hormone deficient group (P less than 0.002). The pulse frequency, amplitude, height and percentage GH secreted in peaks were also significantly less in the growth hormone deficient group (P less than 0.002 respectively). We conclude that adults deficient in GH, as defined by conventional pharmacological stimuli, are in addition physiologically deficient of pulsatile GH secretion.
Adult↗
The effects of low dose insulin infusions on the renin angiotensin and sympathetic nervous systems in normal man.
To examine the effects of physiological insulin concentrations on the renin-angiotensin and sympathetic nervous systems, healthy volunteers were studied by the euglycaemic glucose clamp technique with sequential 60 min 0.5 and 1.0 mU kg-1 min-1 insulin infusions and, subsequently, by a control infusion simulating clamp conditions. Plasma renin activity increased from 0.8 +/- 0.1 ng ml-1 h-1 basally to 1.0 +/- 0.2 ng ml-1 h-1 during the 0.5 mU infusion to 1.4 +/- 0.1 ng ml-1 h-1 during the 1 mU infusion but did not change during control infusion (0.9 +/- 0.3 ng ml-1h-1 to 0.9 +/- 0.2 ng ml-1h-1 to 1.0 +/- 0.1 ng ml-1h-1) (P less than 0.001 insulin vs. control by ANOVAR). Plasma angiotensin II increased during insulin (21.2 +/- 1.8 to 25.2 +/- 2.3 to 29.3 +/- 2.4 pg ml-1) but not during control infusion (24.0 +/- 2.8 to 23.6 +/- 2.6 to 23.5 +/- 2.5 pg ml-1) (P less than 0.001 insulin vs. control). Serum aldosterone did not change significantly during either infusion (insulin: 239 +/- 89 pmol l-1 to 237 +/- 50 pmol l-1 to 231 +/- 97 pmol l-1, control: 222 +/- 79 to 237 +/- 50 to 213 +/- 97 pmol l-1). Plasma noradrenaline increased to a greater extent during insulin (1.03 +/- 0.2 to 1.14 +/- 0.8 to 1.27 +/- 0.17 nmol l-1) than control infusion (0.86 +/- 0.09 to 0.97 +/- 0.09 to 0.99 +/- 0.09 nmol 1-1 (P less than 0.01 insulin vs. control). Changes in mean systolic blood pressure during insulin infusion were significantly different from control (+ 3 vs. -4 mmHg, P less than 0.001). In conclusion acute hyperinsulinaemia within the physiological range increases circulating hormones of the renin-angiotensin and sympathetic nervous systems and also increases systolic blood pressure.
Adult↗
Basal and stimulated plasma atrial natriuretic factor in patients with type 1 diabetes with and without nephropathy.
Hypertension is linked to the development of nephropathy in Type 1 diabetes. Total exchangeable sodium is elevated in patients with Type 1 diabetes in good metabolic control, and correlates with blood pressure. Atrial natriuretic factor has been shown to have effects on sodium and blood pressure homeostasis in man. Basal and NaCl-stimulated plasma atrial natriuretic factor was therefore studied in 33 patients with Type 1 diabetes. Seventeen had no evidence of nephropathy, 11 had incipient nephropathy (albumin excretion rate 20-199 micrograms min-1) and five had overt nephropathy. Seventeen age- and sex-matched normal control subjects were also studied. Subjects fasted from 2200 h, rose at 0745 h and remained ambulant until 0945 h. After 15 min supine, 2 l 0.15 mmol l-1 NaCl was infused over 4 h. Basal erect (0945 h) plasma atrial natriuretic factor was 4.2 +/- 0.5, 3.5 +/- 0.4, 2.5 +/- 0.2, and 2.5 +/- 0.3 pmol l-1 in the control, non-nephropathic, incipient-nephropathic, and overt nephropathic diabetic groups, respectively (all NS). Levels in all groups increased in response to NaCl infusion, and the responses were not different between groups. Urinary sodium excretion for 12 h before NaCl infusion was not different between groups, but during the 12 h after the start of the infusion was significantly (p less than 0.05) less in the Type 1 diabetic group without nephropathy than in the control group. These results suggest that atrial natriuretic factor does not play a major role in the development of changes in sodium balance which are associated with Type 1 diabetes and nephropathy.
Adult↗
Basal and saline-stimulated plasma atrial natriuretic hormone in Cushing's syndrome.
The pathogenesis of hypertension associated with Cushing's syndrome is incompletely understood. We have studied basal and saline-stimulated levels of plasma atrial natriuretic hormone in 10 subjects with active Cushing's syndrome (8 F: 2 M), aged 43 +/- 4 years (mean +/- SEM). Ten age- and sex-matched normal control subjects were also studied. Subjects fasted from 22.00 h, rose at 07.45 h, and remained ambulant until 09.45 h when blood was taken for plasma ANH, plasma renin activity and serum aldosterone. Subjects then rested supine until 10.00 h when blood was again taken, and blood pressure recorded. Then, while subjects remained supine, 21 of 0.9% NaCl were infused between 10.00 and 14.00 h. Blood was taken hourly. Basal plasma ANH was 8.0 +/- 0.9 pmol/l in Cushing's subjects and 6.9 +/- 2.5 pmol/l in controls. Levels increased in response to saline in both groups, and became significantly higher in the group of patients with Cushing's syndrome (14.00 h level 21.3 +/- 3.9 vs 10.4 +/- 1.9 pmol/l; p less than 0.05). Serum aldosterone and plasma renin activity were not different between groups. Mean blood pressure was higher in patients (114 +/- 4 vs 91 +/- 7 mmHg; p less than 0.05). Urinary sodium excretion was not different between groups before saline, but during the four hours of saline was higher in Cushing's subjects (133 +/- 12 vs 67 +/- 11 mmols; N = 6; p less than 0.05). Our results suggest that during salt loading the exaggerated natriuresis seen in the Cushing's group may have been caused by ANH.
Adult↗
Basal and stimulated plasma atrial natriuretic factor in type 2 diabetes.
Subjects with Type 2 diabetes have been reported to have elevated total exchangeable sodium when compared with normal subjects. Sodium retention may contribute to the development of hypertension in these subjects. Atrial natriuretic factor may play a role in sodium and blood pressure homeostasis in Type 2 diabetes. We have studied plasma atrial natriuretic factor in 17 subjects with Type 2 diabetes (9M:8F; aged 49 +/- 2 years) (mean +/- SE) and in 17 age- (49 +/- 2 years) and sex-matched controls. Mean fasting blood sugar was 8.3 +/- 0.6 mmol l-1 in the diabetic subjects. After fasting from 2200h, subjects remained upright from 0745h until 0945h when blood was taken for plasma atrial natriuretic factor, plasma renin activity and serum aldosterone. Two litres of 0.15 mmol l-1 NaCl was infused intravenously between 1000h and 1400h while the subjects remained supine. Blood was taken hourly. At 0945h plasma atrial natriuretic factor was 3.8 +/- 0.4 pmol l-1 in diabetic subjects and 6.1 +/- 1.6 pmol l-1 in controls (NS), at 1000h after 15 mins supine 3.5 +/- 0.3 and 7.9 +/- 2.3 pmol l-1 respectively (p < 0.05) and increased to 9.4 +/- 1.5 and 9.4 +/- 1.2 pmol l-1 in diabetic subjects and controls at 1400h (NS; both p < 0.01 vs basal values). Serum aldosterone, plasma renin activity, blood pressure and urinary sodium output for 12h before, 4h during and 8h after the NaCl infusion were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldosterone↗
Underestimation of glucose turnover determined using [6-3H]glucose tracer in non-steady state. The role of a tritiated tracer impurity.
The use of tritiated glucose tracers may result in underestimation of glucose turnover during hyperinsulinaemic clamps giving paradoxical negative endogenous glucose production rates. While mathematical modelling errors in the analysis of tracer data are major determinants of this underestimate in the non-steady state, the relative importance of tracer contamination under these conditions remains in doubt. We have used high performance liquid chromatography to assess the possible contribution to this problem of a labelled tracer impurity found in [6-3H]glucose. In conventional 4 h hyperinsulinaemic clamps performed in six normal subjects, labelled impurity increased as a percentage of the neutral plasma radioactivity fraction from 5.3 +/- 0.9% after a 2 h equilibration period (0 min) to 13.5 +/- 2.2% at 120 min and 15.4 +/- 2.4% at 240 min, as plasma glucose specific activities fell following the infusion of insulin. Negative endogenous glucose production rates were observed both at 90-120 min (-8.8 +/- 1.6 mumol.kg-1min-1) and at 210-240 min (-8.5 +/- 1.4 mumol.kg-1min-1) implying a persistent underestimate in isotopically determined glucose appearance rate. Using chromatography data to correct for impurity increased glucose appearance rates by 7.9 +/- 2.1% at 120 min and 11.0 +/- 2.5% at 240 min. Purified tracer was then used for a further six clamps. When the conventional protocol was used with unlabelled glucose infusion an obvious negative error persisted only at 90-120 min. In contrast, labelled infusions gave exclusively positive values for endogenous glucose production.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The growth hormone response to growth hormone releasing hormone in patients previously treated with bilateral adrenalectomy alone for Cushing's disease.
Human growth hormone releasing hormone (GHRH) fails to stimulate human growth hormone (GH) in hypercortisolism. In order to study whether the responsiveness to GHRH stimulation returns after cure of the hypercortisolism, the GH response to GHRH was examined in 8 patients at least 5 yr after they had undergone bilateral adrenalectomy as their sole treatment for Cushing's disease. None had current evidence of a pituitary macroadenoma. A group of 8 healthy subjects matched for age and sex formed the control group. All patients and subjects received an iv injection of GHRH 1 microgram/kg, after an overnight fast, blood samples were taken before and at 15, 30, 45, 60, 90 and 120 min. There was no statistical difference between the peak GH or area under curve (AUC) response (median, range) in the two groups studied (adrenalectomized peak GH 9.2 (4.6-32.0) vs 16.5 (7.5-63) mU/l, adrenalectomized AUC response 647.5 (344.2-1489.5) vs 1103.5 (339.7-5188.5) mU/l. Patients with Cushing's disease once cured of hypercortisolism, have a GH response to GHRH.
Adrenalectomy↗
The effect of cyproheptadine and/or bromocriptine on plasma ACTH levels in patients cured of Cushing's disease by bilateral adrenalectomy.
Cyproheptadine and bromocriptine have been reported to be therapeutic in suppressing ACTH levels in Cushing's disease and Nelson's syndrome. However, there have been only scattered reports of their effect in suppressing raised ACTH levels found in patients cured of Cushing's disease by bilateral adrenalectomy. In order to assess whether these agents could prove beneficial in such patients we studied 12 patients previously treated with bilateral adrenalectomy alone for Cushing's disease before and after 3 weeks of cyproheptadine and/or bromocroptine therapy. All had raised plasma ACTH values but no patient had evidence of a pituitary macroadenoma. Plasma ACTH and cortisol were sampled 2-hourly for 24 h. Neither drug regime led to any change in plasma levels of cortisol for 24 h after a 20 mg dose of oral hydrocortisone. Plasma ACTH (mean +/- SEM) showed a small but significant overall reduction (523 +/- 45 vs 392 +/- 34 ng/l; P less than 0.05) while on bromocriptine alone (5 mg given at 0800 and 1800 h, n = 5). When each time point was analysed individually this reduction was significant at only five out of 13 time points. At 0400 h plasma ACTH (mean +/- SEM) was 758.4 +/- 298.1 vs 380.2 +/- 166.6; 0600 h, 795 +/- 288.7 vs 477.8 +/- 191.7; 1200 h, 266.8 +/- 106.2 vs 187.0 +/- 80.3; 1400 h, 470.0 +/- 239.0 vs 302.0 +/- 135.9; 1600 h, 548.6 +/- 262.5 vs 394.2 +/- 178.5 ng/l (P less than 0.05). There was no significant change in plasma ACTH during treatment with the combination of bromocriptine and cyproheptadine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenalectomy↗
Plasma atrial natriuretic factor levels during normal pregnancy and pregnancy complicated by diabetes mellitus and hypertension.
Atrial natriuretic factor (ANF) may play a role in the regulation of the changes of blood volume and vascular reactivity during pregnancy and when pregnancy is complicated by hypertension. Reports of plasma ANF levels during pregnancy are conflicting. We have prospectively studied plasma ANF levels during pregnancy in 25 women, and compared these with 20 age-matched non-pregnant women. Five women developed hypertension during pregnancy and a further five who remained normotensive had insulin-dependent diabetes mellitus. Plasma ANF was 6.8 +/- 1.2 (mean +/- SEM) and 6.3 +/- 0.9 pmol/l during weeks 8-15 and 24-31 of normal pregnancy (n = 15; vs non-pregnant levels (4.0 +/- 0.6 pmol/l) P less than 0.05, n = 20). Levels were 4.3 +/- 0.8 and 3.9 +/- 0.4 pmol/l during weeks 16-23 and 32-39. In the diabetic patients and in the group who developed hypertension levels were at no time different from the uncomplicated pregnancy group. Serum aldosterone increased as pregnancy progressed, but plasma renin activity remained unchanged. As plasma ANF was not different between those who did, and those who did not develop hypertension, early measurement of it will not predict who will and who will not develop hypertension during pregnancy.
Adult↗
Studies on the pathogenesis of hypertension in Cushing's disease and acromegaly.
The pathogenesis of the hypertension associated with Cushing's syndrome and with acromegaly is poorly understood. We have investigated the possible roles of sodium retention, activation of the renin-angiotensin system and increased sympathetic nervous system activity in untreated patients. In 11 patients with Cushing's disease, seven of whom were hypertensive, total exchangeable sodium was normal despite increased levels of the mineralocorticoid hormones, 11-deoxy-corticosterone and corticosterone. The renin-angiotensin system was also normal. Cardiac sensitivity to the beta-receptor agonist isoprenaline was increased, but this was not due to an increase in beta-adrenoceptor density. Hypertension in Cushing's disease is neither sodium-dependent nor angiotensin II-mediated, but increased cardiac sensitivity to catecholamines, by increasing cardiac output, may contribute to the pathogenesis of hypertension. In nine patients with acromegaly (three of whom were hypertensive) total exchangeable sodium was elevated. Although no correlation between blood pressure and exchangeable sodium was found, hypertension in acromegaly is probably sodium dependent. No evidence was found for a pathogenetic role for either the renin-angiotensin-aldosterone or the sympathetic nervous system.
Acromegaly↗
Selective toxicity of purine nucleosides to human leukaemic cells.
The in vitro cytotoxicity of various purine nucleosides and purine enzyme inhibitors, alone or in combination, and of the alkylating agent mafosfamide (Asta Z7557), incubated for 4 and 24 h have been studied in 17 leukaemic cell lines and normal bone marrow (BM). The purine nucleosides and their analogues included: 2'chlorodeoxyadenosine (CdA), 2'deoxyadenosine (AdR), 3'deoxyadenosine (3'AdR) (cordycepin), adenosine (AR), adenine arabinoside (Ara-A), deoxyguanosine (GdR) and guanine arabinoside (Ara-G). Purine enzyme inhibitors included 2-deoxycoformycin (dCF) and 8-aminoguanosine (8-AG). Cytotoxicity was based on inhibition of (i) incorporation of 3H-leucine into cell proteins and (ii) colony forming units--granulocytic/monocytic (CFU-GM) and for mixed cell colonies (CFU-GEMM). Marked and selective inhibition of T-cell growth was shown by the combinations dCF with either AdR or Ara-A, 8-AG and GdR and by CdA or Ara-G alone; these compounds even at high concentrations produced only partial inhibition of the growth of normal bone marrow CFU-GM and CFU-GEMM except for CdA which completely inhibited the formation of CFU-GEMM colonies. The combination dCF + cordycepin and alkylating agent mafosfamide were, however, toxic to all the cell lines at the concentrations employed, as well as to CFU-GM and CFU-GEMM. The high therapeutic index of some of the purine nucleosides with a relatively short exposure time makes them candidates for selective in vitro removal of residual neoplastic cells in autologous bone marrow transplantation (ABMT) for T-ALL.
Adenosine Deaminase Inhibitors↗