Comparison of depot tetracosactrin and corticotrophin gel

Depot tetracosactrin has been compared with corticotrophin gel in 12 inpatients of a rheumatic diseases unit Every patient received one subcutaneous infection each of the synthetic and the animal preparation, with serial measurements of plasma 11-hydroxycorticosteroids, 12-hourly urinary 11-hydroxycorticosteroids, and 17-oxogenic steroids. The duration of action of the depot tetracosactrin was virtually twice that of corticotrophin gel, the dose relationship being about 0·25 mg. of depot tetracosactrin to 50 units of gel. Local reaction to the injection of depot tetracosactrin was relatively frequent.     

Controlled Trial of Azathioprine and Prednisone in Chronic Renal Disease

Patients with various forms of glomerulonephritis, but excluding those with minimal glomerular changes, were admitted to a controlled trial of a regimen which combined azathioprine in a dosage of 2·5 mg/kg/day with prednisone in a dosage of 20 mg/day (adults) or 0·5 mg/kg/day (children). Of 149 patients included, 32 of them under the age of 15, 72 were randomly allocated to the “treatment” group and 77 to the “control” group. There was no evidence of benefit from the treatment group as a whole; and the mortality was in fact higher in the treated group.     

Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus

A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 μmol/l (100 μg/ml)), yet the variation in dosage was only sixfold (0·5-3·9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 μmol/l (244 μg/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5·4%) of the tolbutamide-treated patients and 10 (16·7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5·5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8·0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.     

Continuous Intravenous Infusion of Small Doses of Insulin in Treatment of Diabetic Ketoacidosis

Continuous intravenous infusion of small amounts of insulin has been used in the management of a series of patients with diabetic ketoacidosis. In 13 patients with a plasma glucose level on admission of 725 mg/100 ml (± 80 S.E. of mean) and an arterial pH of 7·07 ± 0·05 a mean loading dose of 6·5 ± 0·82 units of soluble insulin was administered intravenously, and thereafter a sustaining infusion of 6·5 ± 0·82 U/hr was continued until ketosis was corrected and the plasma glucose fell below 300 mg/100 ml. The total insulin dose needed to achieve this was 39·2 ± 6·6 units given over a 3 to 10-hour period. Plasma insulin was measured in patients who had not previously received insulin and the mean level at an infusion rate of 4 U/hr was 75·6 ± 8·0 μU/ml. Plasma glucose fell at a regular rate of 101 ± 11 mg/100 ml/hr, and ketosis improved in parallel. Plasma potassium was well maintained throughout treatment. This regimen of treatment was clinically effective and simple to follow.     

Relation between Plasma Lignocaine Levels and Induced Haemodynamic Changes

Intravenous lignocaine (1 mg./kg. body weight) was found to produce insignificant haemodynamic changes, and in particular no reduction in myocardial contractility. A rate of 2 mg./minute infused intravenously is suggested for therapeutic purposes.In anaesthetized dogs an infusion of 13·5 mg./minute caused moderate haemodynamic depression and a maximum plasma level of 7 μg./ml. Massive injections of 200 and 400 mg. of lignocaine produced a maximum plasma level of 13·8 and 27·8 μg./ml., respectively, and in the latter failure of myocardial contraction in the presence of a normal E.C.G. ensued (“pump failure”). Lignocaine appears to alter the uptake of calcium by myocardial sarcoplasmic reticulum, and this may explain the negative inotropic effect of large doses.     

Prolonged Corticotrophic Action of a Synthetic Substituted α1-18 ACTH

The adrenocorticotrophic effects of a synthetic corticotrophin analogue, α^1-18 ACTH with D-serine¹, lysine¹⁷, and lysine amide¹⁸ substitutions has been studied. It is effective after both intramuscular and subcutaneous administration and compared with tetracosactrin depot (Synacthen depot, Cortrosyn depot) it has a similarly prolonged time course of action—about 24 hours after 0·5 mg and 30 hours after 1 mg. Unlike tetracosactrin depot, however, it is well absorbed when given intranasally and does not produce painful reactions at the site of injection. Its prolonged time course of action does not depend on a formulation designed to delay its release from the injection site but most probably on a decreased rate of degradation in the circulation.     

Plasma TSH and Serum T-4 Levels in Long-term Follow-up of Patients Treated with 131I for Thyrotoxicosis

In February 1972 58% of patients euthyroid after iodine-131 therapy given for thyrotoxicosis between 1954 and 1966 had a high plasma TSH (>7·4 μU/ml) and 42% a normal plasma TSH level. A group of 69 of the euthyroid patients with high plasma TSH levels (25·0±2·0 μU/ml) in 1972 were re-examined 15 and 24 months later. The mean plasma TSH in the 66 patients remaining euthyroid at 15 months was 22·6±1·8 μU/ml, while three patients had become hypothyroid. At 24 months 64 of the patients were still available for study, of whom 61 remained euthyroid with a mean plasma TSH of 21·6±2·0 μU/ml, and a further three had become hypothyroid.All of a group of 61 of the euthyroid patients with normal plasma TSH levels (4·0±0·2 μU/ml) in 1972 remained euthyroid at 24 months with a mean plasma TSH of 4·1±0·3 μU/ml, though the plasma TSH level had become slightly raised in three.The mean serum T-4 level in the euthyroid patients with a high plasma TSH was significantly lower, though still in the normal range, than that in the euthyroid patients with a normal plasma TSH both in 1972 and in 1974.Since no patient with a normal plasma TSH level after iodine-131 treatment six to 18 years earlier for thyrotoxicosis developed hypothyroidism over a two-year period, the follow-up of such patients need not be so rigorous as that of similarly treated euthyroid patients with raised plasma TSH levels in whom hypothyroidism developed at the rate of 5% per year.     

Treatment of Hypothyroidism: A Reappraisal of Thyroxine Therapy

Twenty-two subjects with hypothyroidism have been studied in detail before and during replacement therapy with L-thyroxine (T-4). All subjects were stabilized on the minimum dose of T-4 which was necessary to suppress their serum thyroid-stimulating hormone (TSH) concentration to normal, and on this dose most subjects had a normal or impaired TSH response to thyrotrophin-releasing hormone (TRH). The daily dose of T-4 required to suppress TSH was 0·1 mg (13 subjects), 0·15 mg (six subjects), and 0·2 mg (three subjects). It was shown that all subjects were euthyroid on these doses and, using a range of thyroid function tests, that they were normal in all respects when compared with a group of euthyroid controls, with the exception of a small group who had a marginally raised serum triiodo-L-thyronine (T-3) concentration. It has been shown that those subjects who required the larger doses of T-4 had a more advanced degree of thyroid failure than those who were stabilized on 0·1 mg T-4 daily. It is concluded that conventional doses of T-4 (0·2-0·4 mg daily) are often associated with subclinical hyperthyroidism.     

Comparative Study of the Absorption,Plasma Levels,and Urinary Excretion of the “New” and the “Old” Lanoxin

A comparative study was performed of the absorption, the plasma level at equilibrium, and the urinary excretion of digoxin using two types of Lanoxin tablets, those produced before and after the 1972 alteration of the tablet manufacture.After a single dose the absorption rate of the new tablets was about twice as great as the old, both in young subjects and in the elderly patients. There were no significant differences in the plasma levels of digoxin for the two tablets 15 hours after the last administration in patients on an equal maintenance dose. The urinary excretion of digoxin increased about 40% when the “old” Lanoxin was replaced by the “new.” In elderly patients a daily dose of 0·125 mg twice daily of the new tablets should be sufficient to reach the therapeutic range. Young people need a higher dosage. If the kidney function is reduced by as much as 50% the dose should be reduced.     

Regulation of Nitric Oxide Production by δ-Opioid Receptors during Glaucomatous Injury

To determine the roles of nitric oxide in glaucomatous injury and its regulation by δ-opioid-receptor activation, animals were treated with: 1) a selective inducible nitric oxide synthase (iNOS) inhibitor (aminoguanidine; AG; 25 mg/kg, i.p.); 2) δ-opioid-receptor agonist (SNC-121; 1 mg/kg, i.p.); or 3) with both drugs simultaneously for 7 days, once daily. The loss in retinal ganglion cell (RGC) numbers and their function in glaucomatous eyes were significantly improved in the presence of AG or SNC-121; however, we did not see any significant additive or synergistic effects when animals were treated with both drugs simultaneously. The levels of nitrate-nitrite were significantly increased in the glaucomatous retina when compared with normal retina (normal retina 86±9 vs. glaucomatous retina 174±10 mM/mg protein), which was reduced significantly when animals were treated either with SNC-121 (121±7 mM/mg protein; P<0.05) or AG (128±10 mM/mg protein; P<0.05). Additionally, SNC-121-mediated reduction in nitrate-nitrite levels was not only blocked by naltrindole (a δ-opioid-receptor antagonist), but naltrindole treatment potentiated the nitrate-nitrite production in glaucomatous retina (235±4 mM/mg protein; P<0.001). As expected, naltrindole treatment also fully-blocked SNC-121-mediated retina neuroprotection. The nitrotyrosine level in the glaucomatous retina was also increased, which was significantly reduced in the SNC-121-treated animals. Additionally, the expression level of iNOS was clearly increased over the control levels in the glaucomatous retina and optic nerves, which was also reduced by SNC-121 treatment. In conclusion, our data support the notion that nitric oxide plays a detrimental role during glaucomatous injury and inhibition of nitric oxide production provided RGC neuroprotection. Furthermore, δ-opioid receptor activation regulates the production of nitric oxide via inhibiting the activity of iNOS in the retina and optic nerve.     

Weight loss in obese subjects on a restricted diet given BRL 26830A,a new atypical β adrenoceptor agonist

A double blind placebo controlled study was carried out in 40 subjects newly referred for treatment for obesity to determine the effects of the new thermogenic β adrenoceptor agonist BRL 26830A. The subjects were randomised to receive either BRL 26830A, 200 mg daily for two weeks then 400 mg daily, or placebo for 18 weeks, and all were instructed to follow a 3·35 MJ diet that was low in fat and high in fibre. Weight loss was 15·4 (SD 6·6) kg in subjects given BRL 26830A compared with 10·0 (5·9) kg in those given placebo (p=0·02). The relative weight loss was 0·93 (0·39)% a week with BRL 26830A and 0·61 (0·38)% with placebo (p=0·02). Urinary excretion of nitrogen was similar in both groups, whereas measurements of skinfold thickness indicated a 4·1 kg difference in the amount of fat lost, suggesting that weight loss with BRL 26830A was mainly from adipose and not lean tissue. BRL 26830A had no effect on resting pulse rate or pressor effects on either diastolic or systolic blood pressure. No significant differences were found between the two groups in serum cholesterol concentration, percentage of high density lipoprotein cholesterol, plasma concentrations of glucose and insulin, the ratio of glucose to insulin, serum concentrations of triiodothyronine and thyroxine, and creatinine clearance. Short term administration of BRL 26830A to six subjects who had taken the drug for 18 weeks showed that the expenditure of energy increased by 11·6% during the second hour after administration, which suggests that BRL 26830A may enhance weight loss thermogenically.BRL 26830A may be a useful drug in the treatment of obesity.     

Failure of Glucagon Release in Infants of Diabetic Mothers

Two hours after birth 30 normal infants had a fall in blood glucose of 20·6 mg/100 ml and a rise of plasma pancreatic glucagon of 50·7 pg/ml. Fifteen infants of diabetic mothers treated with insulin had a much greater fall in blood glucose of 77·5 mg/100 ml and a smaller rise of glucagon of 20·9 pg/ml. By comparison 14 small-for-dates infants, who are also prone to hypoglycaemia, had a blood glucose fall of 32·8 mg/100 ml and a larger rise of pancreatic glucagon of 96·0 pg/ml. It is suggested that the impaired pancreatic glucagon rise in the infants of diabetic mothers may be a significant factor in their hypoglycaemia.     

Metabolic Effects of Oestrogen Treatment in Patients with Carcinoma of Prostate: A Comparison of Stilboestrol and Conjugated Equine Oestrogens

Serum cholesterol and triglyceride levels were estimated and oral glucose tolerance tests performed on 16 patients with carcinoma of the prostate before treatment and while receiving stilboestrol in doses of 1 mg, 7·5 mg, and 15 mg daily and conjugated equine oestrogens (Premarin) 15 mg daily. Serum triglyceride levels were greater than 170 mg/100 ml in nearly all the patients while receiving Premarin or stilboestrol 7·5 mg and 15 mg daily. In six out of 10 patients who were given stilboestrol 1 mg daily the serum triglycerides remained within the normal range. No significant effects on serum cholesterol levels or glucose tolerance tests were observed with the various oestrogen regimens. The results support previous suggestions that a daily dose of 1 mg of stilboestrol should be regularly used in the treatment of carcinoma of the prostate.     

Salt-poor Human Albumin in Management of Nephrotic Syndrome

Thirteen patients with the nephrotic syndrome were treated with a high-protein diet, a 0·5 g sodium intake (equivalent to 1·3 g sodium chloride), and frusemide in increasing dosage. One became oedema-free with frusemide 240 mg daily, three became oedema-free with frusemide 500 mg daily, and two required a combination of high-dose frusemide and spironolactone. In three there was an appreciable increase in the blood urea, one patient developed hyponatraemia, and in two there was no weight loss. In these six patients infusions of human salt-poor albumin produced a prompt diuresis, loss of weight, and correction of the abnormal biochemical findings. In the seventh severely oedematous patient combined albumin and diuretic therapy led to a loss of 27 kg in 14 days.     

Kinetics of the Daily Rate of Photosynthesis at Low Temperatures for two Conifers

The daily course of photosynthesis at low temperatures in 2 coniferous species, Pinus ponderosa Laws., and Pseudotsuga menziesii (Mirb.) Franco, were studied using controlled environment facilities. After having been grown at a 23° day, and 19° night for a year, seedlings were acclimatized for 4 months to either a 3°, 7° or 11° day all under 1200 ft-c of light and followed by a 16-hour night at 3°. Measurement of photosynthesis at 1200 ft-c revealed 3 separate responses. First, the rapidity at which the plants attained their maximum photosynthesis when the lights were turned on depended upon the species, the current temperature, and the previous temperature condition to which the plants had become acclimatized. The warmer the day temperature the sooner the daily maximum was reached. Second, fluctuations in the rate of photosynthesis during the day varied with the species and the day temperature. Photosynthesis in both fir and pine kept at an 11° day and pines kept at a 7° day attained a daily peak rate followed by a decline. This decline occurred even though temperature and light were kept constant, the CO₂ level was returned to 320 ppm from 290 ppm, and the plants were kept well watered. At a 3° day neither species showed this decline. Third, a plant transferred to another temperature acquired a new stable daily photosynthetic pattern. The number of days required for stabilization depended upon the previous temperature history of the plant. The adjustment rate was faster when the temperature was raised than when it was lowered.     

Impaired renal functional reserve and albuminuria in essential hypertension

The stimulatory effects of an infusion of amino acids on glomerular filtration rate has previously been used to measure renal functional reserve and detect glomerular hyperfiltration. Thirty four patients with mild to moderate essential hypertension and seemingly normal renal function and 22 healthy controls were given infusions of amino acids to investigate whether renal functional reserve is reduced in essential hypertension and to detect patients at risk of renal damage. Although basal creatinine clearance increased after the infusion of amino acids in the controls (mean 27·9 ml/min; 95% confidence interval 18·2 to 37·6), the overall change was lower in the patients (mean 13·4 ml/min; 8·3 to 18·5), 11 of the 34 showing no increase at all. In these 11 non-responders the mean systolic blood pressure was higher than that in the 23 others (178·5 mm Hg v 157 mm Hg, respectively). Mean urinary albumin excretion was abnormal in the patients (93·3 mg/24 h; 44·2 to 142·4); eight of the 11 non-responders had an albumin excretion above the normal range (>20 mg/24 h). In the 11 patients without renal functional reserve a positive correlation was found between basal creatinine clearance and albumin excretion (r=0·695).As consumed renal reserve and albuminuria are markers of glomerular hyperfiltration studying renal function before and after infusion of amino acids can detect hypertensive patients at risk of progressive renal damage.     

Electronegative Low-Density Lipoprotein Increases C-Reactive Protein Expression in Vascular Endothelial Cells through the LOX-1 Receptor

Objectives

Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1.

Methods and Results

Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5]  =  L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine.

Conclusions

Our results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5.     

Metabolism of propionate by sheep liver. Stimulation of the mitochondrial rate by factors from the cell sap

1. The rate of metabolism of propionate by aged sheep-liver mitochondria in the presence of oxygen + carbon dioxide (95:5) was 5·0 (± s.e.m. 0·8) μmoles/mg. of mitochondrial N/hr. 2. When aged in the presence of the mitochondrial supernatant the rate was increased. Mitochondria from 0·33g. of liver, when combined with the corresponding mitochondrial supernatant from 0·08g. of liver, metabolized propionate at a rate of 11·4 (± s.e.m. 1·2) μmoles/mg. of mitochondrial N/hr. This rate is comparable with rates previously obtained with aged nuclear-free homogenates. 3. Two factors in the mitochondrial supernatant were detected, which when combined reproduced the effect of the fresh supernatant and prevented loss of activity on aging. One of these was non-diffusible and was recovered by fractionation of the dialysed mitochondrial supernatant with ammonium sulphate. The second factor was present in an ultrafiltrate of fresh mitochondrial supernatant and in boiled mitochondrial supernatant; it was isolated and identified as l(+)-glutamate. 4. The effect of the non-diffusible factor was due to protection of the mitochondria from the aging process, whereas glutamate served both in this capacity and as a direct stimulant of propionate metabolism at low concentration.     

Endocrine Changes in Premature Labour

Plasma oestradiol and progesterone levels in peripheral blood have been studied before and during premature labour of unknown aetiology. Hormones were measured by radio-immunoassay using specific antisera. Levels in patients who delivered prematurely were compared with levels measured serially in 33 primigravidae during normal pregnancy and labour.In 19 out of 25 patients admitted in progressive premature labour the plasma oestradiol level was two standard deviations or more above the mean for the control patients of similar gestational age. The mean (± S.E. of mean) plasma oestradiol in premature labour was 19·1 ± 1·1 ng/ml, similar to levels found in labour at term (18·5 ± 1·4 ng/ml). In contrast, in over 50% of cases levels of plasma progesterone during premature labour lay below the mean for gestation though within the normal range. In six patients studied serially oestradiol levels rose dramatically, high values being detected one to 10 days before the onset of premature labour. Serial progesterone levels gave no consistent trend though one patient showed steadily decreasing values.These studies suggest that the onset of premature labour is preceded by a marked increase in peripheral plasma oestradiol levels, which may be of value not only in the prediction of premature labour but also in its prevention by suppression of the premature oestradiol surge.     

Neonatal plasma lipids as measured in cord blood

The status of cord blood screening of plasma lipids is reviewed, emphasizing the problems associated with the diagnosis of familial hyperlipoproteinemia (HLP), particularly type II (hyperbetalipoproteinemia), in the neonate. For 2937 neonates in this study the mean ± standard deviation (SD) of plasma cholesterol was 70.3 ± 16.9 mg/dl. The mean triglyceride level of 1805 neonates was 39.6 ± 19.3 mg/dl. The mean level of β-cholesterol in 240 neonates was 34.3 ± 10.9 mg/dl and the correlation between total and β-cholesterol was high (r=0.89). By convention, the upper limit of normal was defined as the mean + 2 SD, and these levels for total cholesterol, triglyceride and β-cholesterol were 100, 80 and 55 mg/dl respectively. Only by careful follow-up of hyperlipidemic neonates can the incidence of HLP and the worth of early diagnosis be assessed.