Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial

Background: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids.  Methods: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994.  Findings: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060–2810] in the metformin group vs 1770 mg [1020–2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI −0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (−3835 mm 2, 95% CI −6781 to −888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima–media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01).  Interpretation: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation.  Funding: Barts Charity and Merck Serono

Instrumental nuclear activation techniques and applications to biomedical problems.

The principles and practice of instrumental neutron activation analysis (INAA) which serves as the basis of this work is described. The various irradiation and counting conditions used are also described. As sampling and sample preparation has a large effect on the accuracy of analytical techniques for trace element work, some of the problems faced by the analyst during these processes are identified and ways of minimising these problems are described. A method of obtaining the representative mass for various elements in standard material, Bowen's Kale is described and values for a number of elements in this material have been determined. The application of INAA in the determination of the concentrations of a range of elements in hair and blood samples, whole blood, erythrocytes and plasma obtained from two groups of women, senile demented and depressives and their respective controls is described. The results suggest that the senile dements have significantly higher concentrations of Na, Al, Cl, I and Hg in blood and hair relative to that of the controls whereas, V, Fe, Zn, Cu, Se and Rb were found at higher concentrations in the controls. In the depressives, Na, Al, S, Cl, K, V, Mn, Br, Sc, Ag, I and Hg were found to be significantly elevated in their blood and hair relative to that of controls while Mg, Ca, Zn, Cu, Se, Sb and Au were found at higher concentrations in the controls. The statistical methods used in the interpretation of these results are also described. The effect of Se supplementation on the concentration of Se in whole blood and blood components, collected from three groups of healthy adults given as a supplement to their usual diet, is described. The results indicate that the level of selenium in whole blood and its components increases with dose and time and the concentration of the element is maintained for at least 45 days following cessation of supplementation. The influence of the supplement on some electrolytes was also investigated. The usefulness of the K[0] factor in multielemental analysis is demonstrated by application to a standard material. The method employed for the determination of the parameters needed for accurate determination of the K[0] factor is described

Instrumental nuclear activation techniques and applications to biomedical problems.

The principles and practice of instrumental neutron activation analysis (INAA) which serves as the basis of this work is described. The various irradiation and counting conditions used are also described. As sampling and sample preparation has a large effect on the accuracy of analytical techniques for trace element work, some of the problems faced by the analyst during these processes are identified and ways of minimising these problems are described. A method of obtaining the representative mass for various elements in standard material, Bowen's Kale is described and values for a number of elements in this material have been determined. The application of INAA in the determination of the concentrations of a range of elements in hair and blood samples, whole blood, erythrocytes and plasma obtained from two groups of women, senile demented and depressives and their respective controls is described. The results suggest that the senile dements have significantly higher concentrations of Na, Al, Cl, I and Hg in blood and hair relative to that of the controls whereas, V, Fe, Zn, Cu, Se and Rb were found at higher concentrations in the controls. In the depressives, Na, Al, S, Cl, K, V, Mn, Br, Sc, Ag, I and Hg were found to be significantly elevated in their blood and hair relative to that of controls while Mg, Ca, Zn, Cu, Se, Sb and Au were found at higher concentrations in the controls. The statistical methods used in the interpretation of these results are also described. The effect of Se supplementation on the concentration of Se in whole blood and blood components, collected from three groups of healthy adults given as a supplement to their usual diet, is described. The results indicate that the level of selenium in whole blood and its components increases with dose and time and the concentration of the element is maintained for at least 45 days following cessation of supplementation. The influence of the supplement on some electrolytes was also investigated. The usefulness of the K[0] factor in multielemental analysis is demonstrated by application to a standard material. The method employed for the determination of the parameters needed for accurate determination of the K[0] factor is described

Worldviews on erectile dysfunction: perspectives in knowledge systems and development

Abstract: In a bid to achieve sustainable development, there is a need for a connection and integration of knowledge system and western knowledge (medicine). More specifically is in the area of health care for sustainable development. In a bid to achieve sustainable development in the health care system, there is a need for deeper understanding of diseases in terms of its worldview by key actors especially in indigenous settings based on peoples’ contextual knowledge. It is against this background that erectile dysfunction, known as Idakole in Yoruba indigenous knowledge systems was examined. This article investigates the knowledge gap relative to worldviews of erectile dysfunction in Ibadan metropolis, Oyo State, Nigeria. The interpretation of Idakole in western medicine is erectile dysfunction. The research that informed this article was conducted in 2018 and it adopted quantitative methodology. Very useful findings were made with implications for policy and scholarship