Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin.

AIMS: To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin). METHODS: In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c). RESULTS: The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%). CONCLUSIONS: Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.

Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459.

BACKGROUND: The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. A study was conducted to determine the effect of lower once daily doses of OC000459 and to define the phenotype of subjects most responsive to treatment. METHODS: Adult subjects (percentage of predicted forced expiratory volume in 1 s (FEV1 ) 60-85%) were randomized to OC000459 at three dose levels (25 mg once daily, 200 mg once daily or 100 mg twice daily) or placebo for 12 weeks (n = 117-125 per group, full analysis set). The primary endpoint was the change from baseline in prebronchodilator FEV1 , and secondary endpoints included Asthma Control Questionnaire (ACQ) and Standardised Asthma Quality of Life Questionnaire [AQLQ(S)], and incidence of exacerbations and respiratory tract infections. RESULTS: OC459 caused a significant improvement in FEV1 compared with placebo at a dose of 25 mg once daily (P = 0.028). A similar increase was observed in the other dose groups, and the mean change in FEV1 in the pooled dose groups at endpoint was 95 ml greater than placebo (P = 0.024). In a post hoc analysis of atopic eosinophilic subjects with uncontrolled asthma, a mean increase in FEV1 of 220 ml was observed compared with placebo (P = 0.005). The mean increase in FEV1 was more marked in younger subjects in this group: for subjects aged ≤40 years, there was a mean increase of 355 ml compared with placebo (P = 0.007). Improvements in ACQ and AQLQ(S) were observed in both the full analysis set and the atopic eosinophilic subgroup. There was a lower incidence of exacerbations and respiratory infections in subjects treated with OC000459. There were no drug-related serious adverse events. CONCLUSIONS: OC000459 is a safe and effective oral anti-inflammatory agent, which achieved clinically meaningful improvements in lung function and asthma control in allergic asthmatics with an eosinophil-dominant form of the disease. A dose of 25 mg given once daily was as effective as the higher doses studied.

The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo-controlled, double-blind trial.

BACKGROUND: CRTH2 mediates activation of Th2 cells, eosinophils and basophils in response to prostaglandin D(2). The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. The objective of the present study was to determine the involvement of CRTH2 in promoting nasal and ocular symptoms in allergic subjects exposed to grass pollen. METHODS: A single centre, randomised, double-blind, placebo-controlled, two-way crossover study was conducted in 35 male subjects allergic to grass pollen comparing OC000459 200 mg bid with placebo for 8 days. Subjects were exposed to grass pollen (≥ 1400 grains/m(3)) for 6 h on the 2nd and 8th days of treatment and assessed for nasal symptoms, ocular symptoms, other symptoms, nasal secretion weight and rhinomanometry over the 6-h period. After a washout period of 3 weeks, subjects were switched to the alternative treatment for a further 8 days. The trial was registered on the clinical trials.gov database (Identifier NCT01448902). RESULTS: During the first treatment period, treatment with OC000459 significantly reduced both nasal and ocular symptoms in allergic subjects compared with placebo after challenge with grass pollen. A significant effect was observed on the 2nd day of dosing which was increased on the 8th day of dosing. The therapeutic effects of OC000459 persisted into the second treatment period despite a 3-week washout phase. The safety profile of OC000459 was similar to that of placebo. CONCLUSION: Treatment with OC000459 was well tolerated and led to a significant and persistent reduction in the symptoms of rhinoconjunctivitis.

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma.

BACKGROUND: CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma. OBJECTIVE: To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma. METHODS: Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927). RESULTS: Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment. CONCLUSION AND CLINICAL RELEVANCE: This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.

Biodegradation of [S,S], [R,R] and mixed stereoisomers of ethylene diamine disuccinic acid (EDDS), a transition metal chelator.

An in-depth biodegradation test program was executed on the hexadentate ligand Ethylene Diamine Di Succinate (EDDS). The EDDS structure contains two chiral carbon atoms, and has three stereoisomers ([R,R], [R,S]/[S,R], [S,S]). Our research has focused on the isomer mixture (i.e. 25%[S,S]; 25%[R,R]; 50%[S,R]/[R,S], as produced from the reaction of ethylene diamine with maleic anhydride) and on the single [S,S]- and [R,R]-isomers. Biodegradation screening of the 14C-labelled EDDS isomer mixture in a Batch Activated Sludge (BAS) test with various inocula revealed incomplete mineralization, up to ca. 65% after 28 days. N-(2-aminoethyl) aspartic acid (AEAA), probably the d-isomer, was identified as the major portion of the 14C-material remaining in solution. Further testing revealed that the [S,S]-isomer is rapidly and completely mineralized in all test systems. By contrast, [R,R]-EDDS remained undegraded in a Sturm (OECD 301B) test, but was very slowly biotransformed into the recalcitrant metabolite AEAA in a BAS test. The [S,R]/[R,S] form undergoes biotransformation to AEAA in both high and low biomass systems. In a sewage treatment simulation test (OECD 303) the steady state DOC removal of mixture-EDDS in a CAS test was limited to 25-35%, even after extensive pre-acclimation, while the [S,S]-isomer achieved nearly complete removal (96%). This study illustrates the importance stereospecificity may have on the biodegradation and metabolite formation of a chemical. A biodegradation scheme for the different EDDS stereoisomers is proposed.

The effect of aldose reductase inhibition on erythrocyte polyols and galactitol accumulation in diabetic patients.

Erythrocyte sorbitol level has previously been used as a measure of the efficacy of aldose reductase inhibitors, but its value is limited by fluctuations related to variations in blood glucose concentration. The aim of the study was to compare sorbitol content with the ability to accumulate galactitol during ex vivo incubation with galactose, of erythrocytes taken from diabetic patients following administration of a single 600 mg dose of the aldose reductase inhibitor, ponalrestat. Twelve patients were studied in a placebo-controlled crossover trial. Blood glucose levels were not statistically different during the placebo and ponalrestat treatment periods except at 1 h after the dose was taken (10.6 +/- 6.7 vs 7.7 +/- 4.6 mmol l-1 (+/- SD), p less than 0.05). Ponalrestat reduced erythrocyte sorbitol concentrations compared with placebo at 3, 5 and 7 h (0.82 +/- 0.36, 0.69 +/- 0.23, and 0.83 +/- 0.35 mg l-1 vs 1.79 +/- 0.67, 1.68 +/- 0.65, and 1.57 +/- 0.59 mg l-1 respectively, p less than 0.005) and 24 h post-dose (1.57 + 0.45 vs 2.01 + 0.73 mg l-1, p less than 0.05). Ponalrestat also reduced erythrocyte galactitol accumulation at 3, 5 and 24 h post-dose from 5.53 +/- 2.41, 5.43 +/- 1.89, and 5.42 +/- 1.96 mg l-1 2-h-1 to 1.47 +/- 0.30, 1.76 +/- 0.41, and 4.12 +/- 0.72 mg l-1 2-h-1 respectively, p less than 0.01. Galactitol accumulation rate appeared to be a less variable parameter than erythrocyte sorbitol and was not influenced by fluctuations in blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldose reductase in the etiology of diabetic complications. 3. Neuropathy.

Aldose reductase has been shown to be present in both autonomic and somatic nerves. Activation of this enzyme and the polyol pathway has been demonstrated in diabetic animal models to cause a range of biochemical, functional, and structural consequences that include the accumulation of sorbitol and fructose; axoglial dysjunction; paranodal demyelination; abnormalities in axonal transport, blood flow, and vascular permeability; and resistance to ischemic transmission of action potentials. These data provide an insight into the range of processes that if activated may either singly or in combination result in altered patterns of nerve function and structural alterations in diabetic neuropathy. In animal models of diabetes, it has been shown that inhibition of aldose reductase can modify these diabetes-induced changes. It is hoped that the results of large-scale controlled trials will provide clinical evidence to support these data.

Peripheral nerve concentrations of glucose, fructose, sorbitol and myoinositol in diabetic and non-diabetic patients.

Glucose, fructose, sorbitol and myoinositol concentrations were measured in biopsies of peripheral nerve obtained at above-knee or below-knee amputation. In diabetic patients nerve glucose (median [range]) (5.09 [1.62-12.82] vs 3.12 [1.81-4.01]) p less than 0.001, fructose (0.245 [0.060-1.280] vs 0.150 [0.053-0.385]) p less than 0.05, and sorbitol (0.028 [0.012-0.496] vs 0.016 [0.007-0.059] p less than 0.02, mumol/g wet weight) were significantly higher than in non-diabetic patients. No significant difference was found in myoinositol concentration (1.95 [1.00-3.55] vs 2.09 [1.27-5.40] mumol/g wet weight). Concentrations differed markedly from previously reported values in human nerve obtained at post-mortem.

Diagnosis and treatment of heart failure in different European countries: a young AEMIE questionnaire.

To compare diagnosis and treatment of heart failure among different European countries, an anonymous questionnaire was developed and sent to young AEMIE members all over Europe. 159 filled-in questionnaires were received: 30 p. 100 from France (F), 25 p. 100 from Great Britain (GB), 21 p. 100 from the Benelux countries (NL), 13 p. 100 from Italy (I) and 11 p. 100 from West-Germany (D). Baseline characteristics of the participating physicians (age, years of hospital training, available equipment, etc.) were comparable among the different countries. There was good agreement in the value of history, clinical examination, ECG and chest X-ray for the diagnosis of heart failure. In all countries breathlessness, basal crepitations and gallop rhythm were counted among the most important signs of left heart failure. Whereas the value of gated-blood-pool scanning and Holter monitoring as a first diagnostic approach was unanimously denied, the value of 2D-echocardiography in heart failure was discussed controversially: in I, F and D 50-80 p. 100 of the physicians thought echocardiography a first-hand diagnostic tool, whereas only 20-30 p. 100 of the physicians in GB and NL recommended echocardiography in the first place. Diuretics, sodium reduced diet and afterload reduction (in GB only) are the first therapeutic measures in GB, NL and F. However, in I and D digitalis is still the cornerstone of therapy (greater than or equal to 50 p. 100!). Physicians of all European countries with the exception of the physicians in D prefer pure digoxin as the first digitalis preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell volume and metabolic dependence of NEM-activated K+-Cl- flux in human red blood cells.

The effects of incubation in anisosmotic media and of metabolic depletion on ouabain-resistant (OR) Cl--dependent K+ influxes stimulated by N-ethylmaleimide (NEM) were studied in human red blood cells using Rb+ as K+ analogue. The NEM-stimulated but not the basal Rb+-Cl- influx measured in phosphate-buffered anisosmotic media was found to be cell volume dependent. When cellular ATP, [ATP]c, was lowered to less than 0.10 of its initial level by exposure to nonmetabolizable 2-deoxy-D-glucose, the NEM-stimulated but not the basal Cl--dependent Rb+ influxes were abolished. Metabolically depleted red blood cells subsequently repleted by incubation in glucose plus inosine regained the NEM-inducible Rb+ (K+) transport activity. The difference in the time course of ATP breakdown and Rb+ influx inhibition suggests that energization of the NEM-stimulated Rb+ flux by metabolism may involve factors additional to ATP.

A sensitive high-temperature electrothermal atomic absorption analysis for Rb+ in erythrocytes and plasma of normal and hypertensive persons.

This method for determination of Rb+ in human plasma and erythrocytes by graphite-furnace atomic absorption spectrophotometry has a sensitivity of 29 nmol/L for plasma, 12 nmol/L for erythrocytes. The detection limit is 24 nmol/L for plasma, 4.8 nmol/L for erythrocytes. This assay is approximately 30-fold more sensitive than previously reported techniques involving atomic absorption spectrophotometry, enabling use of smaller samples. The rubidium signal is linear with concentration up to 1.2 mumol/L, and addition of other cations to the matrix produces only minor alterations in the Rb+ signal. We measured plasma and erythrocytic Rb+ concentrations in healthy subjects and in patients with untreated essential hypertension. In both, our values are similar to those previously reported for healthy individuals.

Furosemide-sensitive Na+-K+ cotransport and cellular metabolism in human erythrocytes.

Metabolic depletion of human red cells with 2-deoxy-D-glucose in the presence of EGTA decreased ATP to about 4% of the initial value and increased total ouabain- and furosemide-resistant Na+ and K+ effluxes by 20% and 100%, respectively, and furosemide-sensitive Na+ and K+ effluxes by 100% and 60%, respectively. When ATP was restored, all the components of Na+ and K+ fluxes measured returned to baseline levels suggesting a metabolic dependence.

A paradoxical fall in urine dopamine output when patients with essential hypertension are given added dietary salt.

The effect of dietary sodium on the urine dopamine excretion of eight hypertensive patients and six matched controls was studied under metabolic balance conditions over a 2 week period during which dietary sodium intake was increased from 20 to 220 mmol/day. The control group showed the expected increase in dopamine excretion in response to sodium but the hypertensive patients showed an initial fall followed by a return to baseline values. Neither group showed a rise in blood pressure but the hypertensive patients showed a greater weight gain on salt loading, although this change was not significant. The cumulative sodium balance was greater and more prolonged in the hypertensive patients, although this difference also did not attain statistical significance. This defect in dopamine mobilization may be important in relation to renal sodium handling by patients with essential hypertension.

The Measurement of Haemoglobin A1c by isoelectric focussing in diabetic patients.

Incubation in vitro of human red cells in increasing glucose concentrations results in a rise in both haemoglobin A1c levels and an intermediate band when measured by an isoelectric focussing method. There are strong correlations between blood glucose levels, levels of haemoglobin A1c and the intermediate band both in vitro and in blood samples taken from diabetic patients. As the intermediate band is also included in the measurement of haemoglobin A1c by the usual analytical methods, this may lead to inaccurate results.

Urine dopamine in normal and hypertensive pregnancies.

Dopamine output in urine was determined in two groups of women with hypertension in pregnancy. A highly significant elevation of urine dopamine was detected in those women with pre-eclampsia compared with that in matched control subjects. In contrast, no difference in urine dopamine output was detected between a group of multigravidae with hypertension in pregnancy and matched control subjects.

Urine free dopamine in normal primigravid pregnancy and women taking oral contraceptives.

1. Urine free dopamine was estimated at predetermined points of the menstrual cycle in normal volunteer subjects and in women taking a combined oral contraceptive. 2. There was no alteration in 24 h urine dopamine during the normal menstrual cycle but, in contrast, combined oral contraceptives produced a fall which recovered premenstrually. 3. In 19 primigravid subjects 24 h urine free dopamine was estimated at monthly intervals throughout pregnancy and at the time of the postnatal examination. 4. Urine dopamine was elevated throughout pregnancy when compared with postnatal values. Women receiving an oral progestogen contraceptive at the time of the postnatal examination showed a further fall in urine dopamine.

The treatment of idiopathic orthostatic hypotension: a combined fludrocortisone and flurbiprofen regime.

We report our experience in the management of idiopathic orthostatic hypotension using the prostaglandin synthetase inhibitor, flurbiprofen. In five subjects with proven autonomic failure the effect on blood pressure of the addition of flurbiprofen (or fludrocortisone) to the previous drug regime was assessed. Both lying and standing blood pressure were seen to rise with fludrocortisone treatment although the change in standing blood pressure was not statistically significant. Flurbiprofen, in contrast, produced no change in lying blood pressure but a significant rise in standing blood pressure. Digital blood flow measurements were made on three subjects before and after flurbiprofen and a dose-related reduction in post-occlusive reactive hyperaemia was demonstrated suggesting an effect of this drug on precapillary smooth muscle tonus. Two patients failed to maintain a long-term response to treatment with flurbiprofen and fludrocortisone but have been helped by the addition of I) ephedrine or II) tyramine an monoamine oxidase inhibitor (phenelzine). We recommend a stepwise approach to treatment in this condition commencing with flurbiprofen and adding fludrocortisone later if necessary. This approach would appear to offer the maximum benefit with a minimum of side effects.