Clinical Problems: Hepatitis in Dialysis Units in the United Kingdom

A prospective study of hepatitis in 20 dialysis units in the United Kingdom showed that the number of units with outbreaks increased from one in 1968 to three in 1969 and the overall attack rate rose from 1·7 to 5·3% in patients and from 0·5 to 1·3% in staff.In July 1969 a pilot study of patients'' sera showed that all of the outbreaks were associated with Australia (Au) antigen. Au antigen was not detected in the unaffected units or in one unit in which there were several patients with abnormal liver function.In January 1970 systematic prospective testing for Au antigen was begun. Au antigen was detected in single patients in five more of the 20 units. The transfer of the affected patients to isolation for dialysis seemed to prevent the spread of infection in the units. The incidence of hepatitis in 1970 was 5·6% in patients and 0·4% in staff.     

Malignant Lymphomas of Waldeyer's Ring: Natural History and Survival after Radiotherapy

The natural history of 292 consecutive cases of reticulum cell sarcoma and lymphosarcoma of Waldeyer''s ring and the survival rate after radiotherapy are reported. In our institute since 1928 from 30 to 35% of pharyngeal neoplasms have been lymphomas, and of these 55% have been reticulum cell sarcomas, 21% lymphosarcomas, and 1% Hodgkin''s disease. This high incidence may probably be ascribed to the fact that in all malignant lymphomas, irrespective of the clinical presentation, a systematic biopsy of the whole Waldeyer''s ring was carried out. Pharyngeal lymphomas were confined to Waldeyer''s ring in 19·6% of cases, with initial spread to contiguous cervical nodes in 43·8%, to distant nodes in 24·2%, and to extranodal tissues in 12·4%. Lymphography showed abnormal retroperitoneal lymph nodes in 38·3% of cases. There was gastrointestinal involvement either initially or later in 17·6% of cases. High-energy radiation therapy to both sides of the neck was the treatment of choice for local and regional disease. It achieved a five-year survival rate of 41·9% in the group of 97 patients treated during the past decade. The incidence of relapse (recurrence and new manifestations) was highest in the first year after treatment.     

Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging and electrophysiological study

Introduction

The aim was to investigate the frequency of neurological adverse events in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA) treated with tumor necrosis factor (TNF) α antagonists.

Methods

Seventy-seven patients eligible for anti-TNFα therapy were evaluated. There were 36 patients with RA, 41 with SpA [24 psoriatic arthritis (PsA) and 17 with ankylosing spondylitis (AS)]. All patients had a complete physical and neurological examination. Brain and cervical spine magnetic resonance imaging (MRI) and neurophysiological tests were performed in all patients before the initiation of anti-TNFα therapy and after a mean of 18 months or when clinical symptoms and signs indicated a neurological disease. Exclusion criteria included hypertension, diabetes mellitus, dyslipidemia, heart arrhythmias, atherothrombotic events, vitamin B12 and iron deficiency, head and neck trauma and neurological surgeries.

Results

Two patients did not receive anti-TNFα therapy because brain MRIs at baseline revealed lesions compatible with demyelinating diseases. Thus, 75 patients received anti-TNFα (38 infliximab, 19 adalimumab and 18 etanercept). Three patients developed neurological adverse events. A 35-year-old man with PsA after 8 months of infliximab therapy presented with paresis of the left facial nerve and brain MRI showed demyelinating lesions. Infliximab was discontinued and he was treated with pulses of corticosteroids recovering completely after two months. The second patient was a 45-year-old woman with RA who after 6 months of adalimumab therapy presented with optic neuritis. The third patient was a 50-year-old woman with AS, whom after 25 months of infliximab therapy, presented with tingling and numbness of the lower extremities and neurophysiological tests revealed peripheral neuropathy. In both patients anti-TNF were discontinued and they improved without treatment after 2 months. The rest of our patients showed no symptoms and MRIs showed no abnormalities. The estimated rate of neurological adverse events in patients treated with anti-TNF therapy is 4% (3/75).

Conclusions

Neurological adverse events after anti-TNFα therapy were observed in our patient. Brain MRI and neurophysiological tests are essential tools to discriminate neurological diseases.     

High-Resolution Imaging of Parafoveal Cones in Different Stages of Diabetic Retinopathy Using Adaptive Optics Fundus Camera

PurposeTo assess cone density as a marker of early signs of retinopathy in patients with type II diabetes mellitus.MethodsAn adaptive optics (AO) retinal camera (rtx1^™; Imagine Eyes, Orsay, France) was used to acquire images of parafoveal cones from patients with type II diabetes mellitus with or without retinopathy and from healthy controls with no known systemic or ocular disease. Cone mosaic was captured at 0° and 2°eccentricities along the horizontal and vertical meridians. The density of the parafoveal cones was calculated within 100×100-μm squares located at 500-μm from the foveal center along the orthogonal meridians. Manual corrections of the automated counting were then performed by 2 masked graders. Cone density measurements were evaluated with ANOVA that consisted of one between-subjects factor, stage of retinopathy and the within-subject factors. The ANOVA model included a complex covariance structure to account for correlations between the levels of the within-subject factors.ResultsTen healthy participants (20 eyes) and 25 patients (29 eyes) with type II diabetes mellitus were recruited in the study. The mean (± standard deviation [SD]) age of the healthy participants (Control group), patients with diabetes without retinopathy (No DR group), and patients with diabetic retinopathy (DR group) was 55 ± 8, 53 ± 8, and 52 ± 9 years, respectively. The cone density was significantly lower in the moderate nonproliferative diabetic retinopathy (NPDR) and severe NPDR/proliferative DR groups compared to the Control, No DR, and mild NPDR groups (P < 0.05). No correlation was found between cone density and the level of hemoglobin A_1c (HbA_1c) or the duration of diabetes.ConclusionsThe extent of photoreceptor loss on AO imaging may correlate positively with severity of DR in patients with type II diabetes mellitus. Photoreceptor loss may be more pronounced among patients with advanced stages of DR due to higher risk of macular edema and its sequelae.     

Restless Legs Syndrome in Chronic Pulmonary Disease

Eight consecutive patients referred for neurological opinion because of very severe “restless legs” all suffered from chronic pulmonary disease. It was considered that the restless legs syndrome was not a metabolic consequence of respiratory failure but a nervous manifestation of their invalidism.     

Streptokinase in Recent Myocardial Infarction: A Controlled Multicentre Trial

In this controlled multicentre trial treatment with either streptokinase or heparin was allocated at random to patients suffering from myocardial infarction of less than 24 hours'' duration. Treatment with either drug was standardized and lasted for 24 hours. A total of 764 patients entered the trial; 34 patient charts were rejected (including all 28 charts from one centre) because of data failure. On retrospective analysis of the 730 remaining patients the two groups were found to have been comparable at the start.The total hospital mortality was 18·5% of 373 patients allotted to streptokinase treatment and 26·3% of 357 given herapin. The mortality after infusion (24 hours) was 10·6% of 340 patients treated with streptokinase and 17·8% of 320 given herapin (P=0·011). Reinfarction in hospital after the 24-hour period of infusion occurred significantly less often in patients treated with streptokinase (P=0·036). Bleeding from puncture sites and pyrexia occurred more frequently during streptokinase treatment.After exclusion of those patients whose diagnosis was unconfirmed on retrospective assessment, the total hospital mortality rate was 19·0% of 357 patients treated with streptokinase and 27·4% of 339 treated with heparin (P=0·011). These results indicate that in recent myocardial infarction streptokinase was superior to heparin in reducing mortality and reinfarction rate during an average period of six weeks in hospital.     

Surgical Treatment of Severe Attacks of Ulcerative Colitis,with Special Reference to the Advantages of Early Operation

The management and outcome of 258 severe attacks of ulcerative colitis from 1952 to 1969 has been reviewed. If remission did not occur during an initial course of intensive medical treatment, including administration of corticosteroids, operation (generally ileostomy with proctocolectomy or subtotal colectomy) was performed. This took place some 12 to 17 days after admission as a rule during the years 1952-63, but usually within five to seven days from 1964 to 1969.Roughly half the attacks underwent spontaneous remission during the two periods, but the medical mortality was 4·8% in the former and 0·7% in the latter, the operative mortality 20·0 and 7·0%, and the overall mortality 11·3 and 4.5% respectively. The lowering of the mortality was particularly striking in severe first attacks and in severe attacks in patients over 60 years of age.Perforation of the colon was found in 21 cases, or nearly 20% of 112 patients coming to operation during attacks, being commoner in the first period (32·5%) than in the second (11·1%). The immediate mortality of all such operations was 11·6%; in cases with perforation it was 28·6%.Acute colonic dilatation was observed in 28 cases. All but one were treated by emergency colectomy, at which the colon was noted to be perforated in 11. The mortality of these operations was 18·5%.Follow-up of the 140 patients who survived without coming to operation during their attacks shows that 52 (37·1%) subsequently underwent surgical treatment either during further attacks or electively.Though all 258 attacks were thought at the time to be due to ordinary ulcerative colitis, subsequent pathological examination of operative specimens derived from 98 patients who came to urgent or subsequent operation during the 1964-9 period revealed that the lesion in the large bowel was Crohn''s disease in 17 instances.     

Australia (Hepatitis-Associated) Antigen in Patients Attending a Venereal Disease Clinic

A total of 1,650 patients attending the venereal disease department at St. Mary''s Hospital, London, have been tested for Australia antigen. Twenty-three positive results were obtained, or 1·39%, which is more than 10 times the rate noted by others in blood donor populations in the U.K. and U.S.A. The positive rates among female patients and European male heterosexual patients were 0·36% and 0·19% respectively. High rates were obtained for homosexual patients (3·8%) and non-European heterosexual patients (3·1%). The reasons for the higher rates found in these groups merit further study.     

Glycaemic threshold for changes in electroencephalograms during hypoglycaemia in patients with insulin dependent diabetes

The relation between blood glucose concentration, the symptoms and signs of hypoglycaemia, and electroencephalographic changes in diabetic patients is not known. The effect of hypoglycaemia on brain function was studied in 13 patients with insulin dependent diabetes. During a gradual fall in blood glucose concentration induced by a bolus injection of insulin followed by an intravenous infusion of insulin, during 60 minutes of biochemical hypoglycaemia, and after restoration of normoglycaemia with intravenous glucose electroencephalograms were evaluated continuously by period-amplitude analysis; blood samples were taken every 10 minutes throughout. No changes were seen in electroencephalograms when the blood glucose concentration was above 3 mmol/l. At a median blood glucose concentration of 2·0 (95% confidence interval 1·7 to 2·3) mmol/l alpha activity decreased abruptly in the electroencephalograms concomitant with an increase in theta activity, reflecting neuronal dysfunction in the cortex. When the blood glucose concentration was further lowered changes were observed in the electroencephalograms indicating that deeper brain structures were affected. A normal electroencephalogram was re-established at a blood glucose concentration of 2·0 (1·8 to 2·1) mmol/l. There was no significant correlation between the blood glucose concentration at the onset of changes in the electroencephalograms and age, duration of diabetes, insulin dose, haemoglobin A_1c concentration, initial blood glucose concentration, rate of fall in blood glucose concentration, and appearance of symptoms and signs of hypoglycaemia.Changes in electroencephalograms during hypoglycaemia appear and disappear at such a narrow range of blood glucose concentrations that the term threshold blood glucose concentration for the onset of such changes seems justified.     

Fat Embolism in Patients with Fractured Hips

Fat embolism was assessed at necropsy and correlated with clinical findings in the patients who died among 854 with fractured hips admitted to hospital between 1967 and August 1971. Sixteen cases of clinical importance were found, eight of which were judged to have been fatal or to have seriously contributed to death. Frequencies were as follows: 2·4 to 3·3% among 424 patients with subcapital fractures; 0·7 to 0·8% in the 405 with trochanteric fractures; 4·1 to 7% among subjects treated without operation, representing 30% of those who died within seven days; and 0·9 to 1·1% among patients treated by pinning, nailing, or nail-plating. The higher frequency in the conservatively treated group is probably related to selection of poor-risk subjects. Fat embolism was found in 6·8 to 8·0% of those with subcapital fractures treated by primary Thompson''s arthroplasty which utilizes acrylic cement, and in none of those given Moore''s prostheses for which cement is not used. Study of a larger group after Moore''s prosthesis is required to establish its lack of special risk. Fat embolism accounted for all the deaths within seven days of Thompson''s arthroplasty and for most within 14 days; it was clearly related to surgery in some cases.A possible explanation of the hazard of Thompson''s arthroplasty is that fat globule entry is enhanced by a rise of intramedullary pressure due to proximal occlusion of the reamed marrow cavity. A controlled trial of the effect of venting the marrow cavity on the frequency of fat embolism is warranted. It is possible that the acrylic monomer may also contribute to venous entry of medullary fat. The higher-age group of those with subcapital fractures and associated chronic cardiac and pulmonary disease might make them more susceptible to fat embolization than those in whom arthroplasty is also carried out for chronic hip disease.     

Prevalence of microalbuminuria,arterial hypertension,retinopathy, and neuropathy in patients with insulin dependent diabetes

Diabetic nephropathy is the main cause of the increased morbidity and mortality in patients with insulin dependent diabetes. The prevalence of microalbuminuria was determined in adults with insulin dependent diabetes of five or more years'' duration that had started before the age of 41. All eligible patients (n=982) attending a diabetes clinic were asked to collect a 24 hour urine sample for analysis of albumin excretion by radio-immunoassay; 957 patients complied. Normoalbuminuria was defined as urinary albumin excretion of ≤30 mg/24 h (n=562), microalbuminuria as 31-299 mg/24 h (n=215), and macroalbuminuria as ≥300 mg/24 h (n=180). The prevalence of microalbuminuria and macroalbuminuria was significantly higher in patients whose diabetes had developed before rather than after the age of 20. The prevalence of arterial hypertension increased with increased albuminuria, being 19%, 30%, and 65% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. The prevalence of proliferative retinopathy and blindness rose with increasing albuminuria, being 12% and 1·4%, respectively, in patients with normoalbuminuria, 28% and 5·6% in those with microalbuminuria and 58% and 10·6% in those with macroalbuminuria. An abnormal vibratory perception threshold was more common in patients with microalbuminuria (31%) and macroalbuminuria (50%) than in those with normoalbuminuria (21%).This study found a high prevalence (22%) of microalbuminuria, which is predictive of the later development of diabetic nephropathy. Microalbuminuria is also characterised by an increased prevalence of arterial hypertension, proliferative retinopathy, blindness, and peripheral neuropathy. Thus, urinary excretion of albumin should be monitored routinely in patients with insulin dependent diabetes.     

Raised plasma intact parathyroid hormone concentrations in young people with mildly raised blood pressure

To study the role of parathyroid gland activity in early primary hypertension plasma concentrations of intact parathyroid hormone were measured in 90 untreated young subjects, aged 16-29, with stable mildly raised blood pressure and in 40 normotensive control subjects selected from the same population in Zoetermeer, The Netherlands. Intact parathyroid hormone concentration was significantly higher in the hypertensive than the normotensive group (2.34 (SE 0.11) pmol/l v 1·47 (0·13)pmol/l, respectively; difference 0·87 pmol/l; 95% confidence interval 0·55 to 1·21; p<0·0001). Serum total calcium concentration was 2·36 (0·01) mmol/l in the hypertensive group and 2·42 (0·01) mmol/l in the normotensive group (difference 0·06 mmol/l; 95% confidence interval 0·02 to 0·09; p=0·02). Urinary calcium excretion over 24 hours did not differ significantly between the two groups (4·17 (0·28) mmol/24 h in the hypertensive group and 3·89 (0·39) mmol/24 h in the normotensive group; difference 0·28 mmol/24 h; 95% confidence interval -0·66 to 1·22). In the hypertensive group both systolic and diastolic blood pressures increased slightly though significantly with intact parathyroid hormone concentrations. No obvious associations between serum calcium concentration and blood pressure were observed.These findings support the view that enhanced activity of the parathyroid gland may play a part in the early stage of primary hypertension.     

Concentrations of the Stress Hormone Copeptin Increase upon Hypoglycaemia in Patients with Type 1 Diabetes Dependent of Hypoglycaemia Awareness

Objective

Copeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness.

Materials and Methods

In this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min.

Results

During insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p<0.001). Copeptin concentrations increased from 3.2 (±1.7) to 3.8 (±1.9) pmol/L (p = 0.03). Mood and Symptoms Questionnaire scores increased from 14 (±3.0) to 18 (±5.8), (p = 0.006). Patients with good hypoglycaemia awareness had an increase in copeptin from 3.0 (±1.8) to 4.2 (±2.4) pmol/L (p = 0.03) in contrast to patients more unaware of hypoglycaemia who only showed an increase in copeptin from 3.3 (±1.6) to 3.6 (±1.4) pmol/L (p = 0.4). There was a trend to a larger copeptin increase in patients aware of hypoglycemia compared to patients unaware of hypoglycemia (p = 0.074).

Conclusion

Copeptin increases in patients with type 1 diabetes upon insulin induced hypoglycaemia. Interestingly, the copeptin increase seems associated with the degree of hypoglycaemia awareness. This hypothesis warrants further verification.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00515801","term_id":"NCT00515801"}}NCT00515801     

The Restless Leg Syndrome

The author reviews and provides examples of the restless leg syndrome (Ekbom''s syndrome), emphasizing the frequency of the disorder and its distressing symptoms. The syndrome is characterized by a creeping, crawling sensation in the lower legs, usually at night. It is accompanied by an irresistible urge to move the legs, and this movement eventually relieves the symptoms. It is found in 5% of the general population, with a higher incidence in pregnant women and people with anemia, but no vascular, neurological or other abnormalities are found on examination. Patients are treated empirically with vasodilators or intravenous iron. The etiology is unknown.     

Blood Muramidase Activity in Colorectal Cancer

The serum muramidase levels were measured in 128 patients with primary or metastatic colorectal cancer, 166 tumour-free patients after resection of a colorectal cancer, and 172 controls. Muramidase levels over 10 μg/ml were detected in 30%-39% of the tumour-bearing patients, in 8·2% of the tumour free, and in only 1·7% of the controls (normal level 6·68 ± 1·42 μg/ml). Long-term follow up indicated that raised levels may occur as a transient phenomenon in recurrent or metastatic disease. The likely relation of abnormal serum muramidase activity and stimulation of the reticuloendothelial system is discussed.     

Measles Virus-Specific IgG in Cerebrospinal Fluid in Multiple Sclerosis

The prevalence of measles virus-specific IgG in cerebrospinal fluid (C.S.F.) of patients with multiple sclerosis (M.S.) has been compared with that in fluids from patients with other neurological diseases and from normal control subjects. The prevalence in the three groups was 58·1%, 24·1%, and 0% respectively. Fivefold concentration of the specimens increased the prevalence in the first two groups to 80·6% and 34·5% respectively, while measles IgG was not detected in any fluids of the normal control group, even after concentration.     

Use of 4% Chlorhexidine Detergent Solution (Hibiscrub) and Other Methods of Skin Disinfection

In a comparison of three antiseptic detergent preparations for hand washing, Hibiscrub, a 4% chlorhexidine detergent solution, caused a significantly greater estimated immediate reduction of skin flora (86·7% ± 3·0) than was obtained with Dermofax, a 0·75% chlorhexidine detergent solution (55·5% ± 5·1), or with Disadine scrub, a povidone iodine detergent preparation (68% ± 6·8). After six applications the mean estimated reductions of skin flora were 99·2% ± 0·2 for Hibiscrub, 97·7% ± 0·7 for povidone iodine, and 91·8% ± 1·6 for Dermofax.After a series of hand washings with Hibiscrub, as with a hexachlorophane detergent preparation, a further large reduction of skin flora, shown by bacterial counts of hand sampling, was obtained by a second phase of disinfection consisting of two minutes'' application on gauze swabs of 0·5% chlorhexidine digluconate in 70% ethanol; a further wash with Hibiscrub, in place of alcoholic chlorhexidine, for the second phase of disinfection caused an increase rather than a reduction in the yield of bacteria on skin sampling. Unlike this “two-phase” disinfection, the application for 30 minutes of compresses soaked in 10% aqueous povidone iodine or in 0·5% aqueous chlorhexidine digluconate did not cause a greater reduction in skin flora than that obtained by the conventional two minutes'' application on gauze of 0·5% chlorhexidine in 70% ethanol.Chlorocresol (0·3%) liquid soap (the base used for Ster-Zac liquid hexachlorophane soap) caused a mean reduction of skin flora when used for hand washing of 29% after one application and 72% after six applications spread over two days. This formulation, though less active and more variable as a detergent skin antiseptic than chlorhexidine, hexachlorophane, or povidone iodine detergent preparations, is an inexpensive disinfectant soap which could be useful in catering establishments. Alcoholic cetrimide applied as for disinfection of an operation site caused a reduction of skin flora greater than that shown by aqueous cetrimide but comparable to that shown by 70% ethyl alcohol in previous experiments.     

Incidence of Dumping after Truncal and Selective Vagotomy with Pyloroplasty and Highly Selective Vagotomy without Drainage Procedure

The incidence of dumping after truncal or selective vagotomy with pyloroplasty and highly selective vagotomy without a drainage procedure was assessed both clinically and experimentally. At a gastric follow-up clinic dumping was found to be significantly less frequent in patients who had undergone highly selective vagotomy without a drainage procedure than in patients who had undergone truncal or selective vagotomy with pyloroplasty (P < 0·05 or < 0·001, respectively). Hypertonic glucose given by mouth provoked the onset of dumping in 20% of patients with duodenal ulcer before operation, in 73% after truncal vagotomy and pyloroplasty, in 80% after selective vagotomy and pyloroplasty, and in 47% after highly selective vagotomy. The test meal also produced significantly greater decreases in blood pressure and increases in pulse rate in patients who had undergone vagotomy with pyloroplasty than in patients who had undergone highly selective vagotomy.     

Improved Glycaemia Correlates with Liver Fat Reduction in Obese,Type 2 Diabetes,Patients Given Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months’ GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA₁c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m² (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA₁c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy (¹H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA_1c reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (−59.3, −16.5%). The relative reduction in IHL correlated with that in HbA₁c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.     

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.