Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome.

BACKGROUND: Haemolytic uraemic syndrome (HUS) is a common cause of acquired kidney failure in children and rarely in adults. The most important risk factor for development of HUS is a gastrointestinal infection by Shiga toxin-producing Escherichia coli (STEC). This review addressed the interventions aimed at secondary prevention of HUS in patients with diarrhoea who were infected with a bacteria that increase the risk of HUS. OBJECTIVES: Our objective was to evaluate evidence regarding secondary preventative strategies for HUS associated with STEC infections. In doing so, we sought to assess the effectiveness and safety of interventions as well as their potential to impact the morbidity and death associated with this condition. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Studies were considered based on the methods, participants, and research goals. Only randomised controlled trials were considered eligible for inclusion. The participants of the studies were paediatric and adult patients with diarrhoeal illnesses due to STEC. The primary outcome of interest was incidence of HUS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified four studies (536 participants) for inclusion that investigated four different interventions including antibiotics (trimethoprim-sulfamethoxazole), anti-Shiga toxin antibody-containing bovine colostrum, Shiga toxin binding agent (Synsorb Pk: a silicon dioxide-based agent), and a monoclonal antibody against Shiga toxin (urtoxazumab). The overall risk of bias was unclear for selection, performance and detection bias and low for attrition, reporting and other sources of bias. It was uncertain if trimethoprim-sulfamethoxazole reduced the incidence of HUS compared to no treatment (47 participants: RR 0.57, 95% CI 0.11-2.81, very low certainty evidence). Adverse events relative to this review, need for acute dialysis, neurological complication and death were not reported. There were no incidences of HUS in either the bovine colostrum group or the placebo group. It was uncertain if bovine colostrum caused more adverse events (27 participants: RR 0.92, 95% CI 0.42 to 2.03; very low certainty evidence). The need for acute dialysis, neurological complications or death were not reported. It is uncertain whether Synsorb Pk reduces the incidence of HUS compared to placebo (353 participants: RR 0.93, 95% CI 0.39 to 2.22; very low certainty evidence). Adverse events relevant to this review, need for acute dialysis, neurological complications or death were not reported. One study compared two doses of urtoxazumab (3.0 mg/kg and 1.0 mg/kg) to placebo. It is uncertain if either 3.0 mg/kg urtoxazumab (71 participants: RR 0.34, 95% CI 0.01 to 8.14) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) reduced the incidence of HUS compared to placebo (very low certainty evidence). Low certainty evidence showed there may be little or no difference in the number of treatment-emergent adverse events with either 3.0 mg/kg urtoxazumab (71 participants: RR 1.00, 95% CI 0.84 to 1.18) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) compared to placebo. There were 25 serious adverse events reported in 18 patients: 10 in the placebo group, and 9 and 6 serious adverse events in the 1.0 mg/kg and 3.0 mg/kg urtoxazumab groups, respectively. It is unclear how many patients experienced these adverse events in each group, and how many patients experienced more than one event. It is uncertain if either dose of urtoxazumab increased the risk of neurological complications or death (very low certainty evidence). Need for acute dialysis was not reported. AUTHORS' CONCLUSIONS: The included studies assessed antibiotics, bovine milk, and Shiga toxin inhibitor (Synsorb Pk) and monoclonal antibodies (Urtoxazumab) against Shiga toxin for secondary prevention of HUS in patients with diarrhoea due to STEC. However, no firm conclusions about the efficacy of these interventions can be drawn given the small number of included studies and the small sample sizes of those included studies. Additional studies, including larger multicentre studies, are needed to assess the efficacy of interventions to prevent development of HUS in patients with diarrhoea due to STEC infection.

Human Milk Oligosaccharides Support Normal Bowel Function and Improve Symptoms of Irritable Bowel Syndrome: A Multicenter, Open-Label Trial.

INTRODUCTION: Treatment options for irritable bowel syndrome (IBS) are limited, causing many patients to remain symptomatic. This study assessed the potential of human milk oligosaccharides (HMOs) to normalize bowel habits. Secondary outcomes included IBS severity and health-related quality of life. METHODS: This multicenter, open-label trial recruited patients with IBS from 17 sites across the United States. Patients received daily orally administrated 5-g intervention of the HMOs 2'-fucosyllactose and lacto-N-neotetraose in a 4:1 mix. Bowel habits, IBS symptoms, and quality of life were assessed at baseline and every 4 weeks during the 12-week intervention. RESULTS: A total of 317 patients (70.7% women; mean age of 44.0 years, range 18-93 years) received the trial product, and 245 patients completed the trial according to protocol. Patients had a significant improvement from baseline to 12 weeks in total percentage of bowel movements with abnormal stool consistency (mean and [95% confidence interval]: 90.7 [88.9-92.9] vs 57.2% [53.9-60.5], P < 0.0001), overall IBS Symptom Severity Score (323 [314-332] vs 144 [133-155], P < 0.0001) and health-rela,ted quality of life (50.4 [48.0-52.8] vs 74.6 [72.3-76.9], P < 0.0001). Improvement was similar across IBS subtypes. Symptoms improved most in the first 4 weeks of intervention. The most common side effects were mild gastrointestinal symptoms such as flatulence, abdominal pain and discomfort, and distension. DISCUSSION: Supplementation with 2 selected HMOs improves IBS symptoms and quality of life without substantial side effects. These promising results suggest that this novel approach to IBS should be confirmed in a randomized, placebo-controlled trial.

Confirmed Hypoallergenicity of a Novel Whey-Based Extensively Hydrolyzed Infant Formula Containing Two Human Milk Oligosaccharides.

BACKGROUND: We sought to determine whether an extensively hydrolyzed formula (EHF) supplemented with two human milk oligosaccharides (HMO) was tolerated by infants with cow's milk protein allergy (CMPA). METHODS: A whey-based EHF (Test formula) containing 2'fucosyl-lactose (2'FL) and lacto-N-neotetraose (LNnT) was assessed for clinical hypoallergenicity and safety. The Control formula was a currently marketed EHF without HMO. Children with CMPA, aged 2 months to 4 years, were assessed by double-blind, placebo-controlled food challenges (DBPCFC) to both formulas, in randomized order. If both DBPCFC were negative, subjects participated in a one-week, open food challenge (OFC) with the Test formula. Symptoms and adverse events were recorded. Hypoallergenicity was accepted if at least 90% (with 95% confidence intervals) of subjects tolerated the Test formula. RESULTS: Of the 82 children with CMPA that were screened, 67 (intention-to-treat [ITT] cohort-mean age 24.5 ± 13.6 months; range 2-57; 45 [67.2%] male) were randomized to receive either the Test or the Control formula during the first DBPCFC. Of these, 64 children completed at least one DBPCFC (modified intention-to-treat [mITT] cohort). Three children were excluded due to protocol deviations (per protocol [PP] cohort; n = 61). There was one allergic reaction to the Test, and one to the Control formula. On the mITT analysis, 63 out of 64 (98.4%; 95% CI lower bound 92.8%), and on the PP analysis 60 out of 61 (98.4%; 95% CI lower bound 92.5%) participants tolerated the Test formula, confirming hypoallergenicity. CONCLUSION: The whey-based EHF supplemented with 2'FL and LNnT met the clinical hypoallergenicity criteria and can be recommended for the management of CMPA in infants and young children.

Effects of kestose on gut mucosal immunity in an atopic dermatitis mouse model.

BACKGROUND: Atopic dermatitis (AD) is recently increasing among populations, but the underlying mechanisms remain controversial. Interactions between the gut microbiota and mucosal immunity are considered to be a crucial etiology. Fructooligosaccharide (FOS), prebiotics have been reported as activators of the gut microbiota. OBJECTIVE: The aim of this study was to investigate the effects of kestose, the smallest FOS and FOS on atopic dermatitis in mice. METHODS: An AD mouse model was developed by (ovalbumin) epidermal sensitization using BALB/c mice. Kestose (1%, 5%, and 10%) or FOS (5%, positive control) was orally administered throughout the study. RESULTS: In comparison with the values observed for the control AD mice, transepidermal water loss (TEWL), clinical score, and skin inflammation on histopathology were significantly decreased by the oral administration of kestose. Total IgE, thymic stromal lymphopoietin (TSLP) in skin, and IL-4 were also suppressed by this administration. In addition, the population of CD4+Foxp3+ cells in mesenteric lymph nodes (MLNs) and acetate concentrations in feces were significantly increased by kestose treatment. CONCLUSIONS: These findings suggest that kestose activates the gut immune system to induce the tolerance against allergic skin inflammations in AD.

Effects of two different glutamine-containing enteral supplements on stool frequency and density in elderly patients recovering from acute critical illness.

AIM: Glutamine has various beneficial functions in the gastrointestinal tract. The present study was designed to investigate the effect of two different glutamine supplements on bowel movement at the start of enteral feeding in elderly inpatients. METHODS: This was a double-blind, prospective, randomized comparison study. A total of 25 patients aged >75 years recovering from a critical illness in a non-intensive care unit and scheduled for tube feeding were recruited. Of them, 22 consenting patients were randomly assigned to two groups: glutamine-fiber-oligosaccharide treatment group (n = 11) and glutamine F treatment group (n = 11). They were given glutamine three times daily at a dosage of 9 g/day. Enteral nutrition was given at the same dosage to both groups for the duration of the study. The end-points were stool frequency, Bristol Scale Form Score, bowel function index (Bristol Scale Form Score × stool frequency), the percentage of patients with stool frequency over three per day and those with a BSFS of 6 or 7 in each group. RESULTS: There were no significant differences between the two groups in terms of patient characteristics before the study. All the end-points in the glutamine F group were significantly lower than those in the glutamine-fiber-oligosaccharide group. CONCLUSIONS: Compared with glutamine-fiber-oligosaccharide, glutamine F administration resulted in stool hardening and reduced stool frequency in elderly inpatients recovering from acute critical illness in non-intensive care units. The effects might be caused by the different additive components of glutamine supplements. Geriatr Gerontol Int 2017; 17: 2514-2519.

Oral supplementation of healthy adults with 2'-O-fucosyllactose and lacto-N-neotetraose is well tolerated and shifts the intestinal microbiota.

The gut microbiota has been established as an important player influencing many aspects of human physiology. Breast milk, the first diet for an infant, contains human milk oligosaccharides (HMO) that shape the infant's gut microbiota by selectively stimulating the growth of specific bacteria, especially bifidobacteria. In addition to their bifidogenic activity, the ability of HMO to modulate immune function and the gut barrier makes them prime candidates to restore a beneficial microbiota in dysbiotic adults and provide health benefits. We conducted a parallel, double-blind, randomised, placebo-controlled, HMO-supplementation study in 100 healthy, adult volunteers, consuming chemically produced 2'-O-fucosyllactose (2'FL) and/or lacto-N-neotetraose (LNnT) at various daily doses and mixes or placebo for 2 weeks. All participants completed the study without premature discontinuation. Supplementation of 2'FL and LNnT at daily doses up to 20 g was shown to be safe and well tolerated, as assessed using the gastrointestinal symptoms rating scale. 16S rRNA sequencing analysis showed that HMO supplementation specifically modified the adult gut microbiota with the primary impact being substantial increases in relative abundance of Actinobacteria and Bifidobacterium in particular and a reduction in relative abundance of Firmicutes and Proteobacteria. This study provides the first set of data on safety, tolerance and impact of HMO on the adult gut microbiota. Collectively, the results from this study show that supplementing the diet with HMO is a valuable strategy to shape the human gut microbiota and specifically promote the growth of beneficial bifidobacteria.

Cynatratoside-C efficacy against theronts of Ichthyophthirius multifiliis, and toxicity tests on grass carp and mammal blood cells.

Infection by Ichthyophthirius multifiliis, a ciliated protozoan parasite, results in high fish mortality and causes severe economic losses in aquaculture. To find new, efficient anti-I. multifiliis agents, cynatratoside-C was isolated from Cynanchum atratum by bioassay-guided fractionation in a previous study. The present study investigated the anti-theront activity, determined the toxicity of cynatratoside-C to grass carp Ctenopharyngodon idellus and mammalian blood cells, and evaluated the protection of cynatratoside-C against I. multifiliis theront infection in grass carp. Results showed that all theronts were killed by 0.25 mg l-1 of cynatratoside-C in 186.7 ± 5.8 min. Cynatratoside-C at 0.25 mg l-1 was effective in treating infected grass carp and protecting naive fish from I. multifiliis infestation. The 96 h median lethal concentration (LC50) of cynatratoside-C to grass carp and 4 h median effective concentration (EC50) of cynatratoside-C to theront were 46.8 and 0.088 mg l-1, respectively. In addition, the hemolysis assay demonstrated that cynatratoside-C had no cytotoxicity to rabbit red blood cells. Therefore, cynatratoside-C could be a safe and effective potential parasiticide for controlling I. multifiliis.

Selective proliferation of intestinal Barnesiella under fucosyllactose supplementation in mice.

The oligosaccharides 2-fucosyllactose and 3-fucosyllactose are major constituents of human breast milk but are not found in mouse milk. Milk oligosaccharides have a prebiotic action, thus affecting the colonisation of the infant intestine by microbiota. To determine the specific effect of fucosyllactose exposure on intestinal microbiota in mice, in the present study, we orally supplemented newborn mice with pure 2-fucosyllactose and 3-fucosyllactose. Exposure to 2-fucosyllactose and 3-fucosyllactose increased the levels of bacteria of the Porphyromonadaceae family in the intestinal gut, more precisely members of the genus Barnesiella as analysed by 16S pyrosequencing. The ability of Barnesiella to utilise fucosyllactose as energy source was confirmed in bacterial cultures. Whereas B. intestinihominis and B. viscericola did not grow on fucose alone, they proliferated in the presence of 2-fucosyllactose and 3-fucosyllactose following the secretion of linkage-specific fucosidase enzymes that liberated lactose. The change in the composition of intestinal microbiota mediated by fucosyllactose supplementation affected the susceptibility of mice to dextran sulphate sodium-induced colitis, as indicated by increased resistance of mice subjected to 2-fucosyllactose supplementation for 6 weeks. The present study underlines the ability of specific milk oligosaccharides to change the composition of intestinal microbiota and thereby to shape an intestinal milieu resilient to inflammatory diseases.

Select human milk oligosaccharides directly modulate peripheral blood mononuclear cells isolated from 10-d-old pigs.

Infant formulas lack the complex mixture of oligosaccharides found in human milk. These human milk oligosaccharides (HMO) may be pivotal to the development of the neonatal immune system. Few comprehensive analyses of the effects of HMO on immune cells from neonates have been undertaken. Herein, the direct effects of HMO on immune cells were analysed ex vivo. Peripheral blood mononuclear cells (PBMC) isolated from 10-d-old sow-reared (SR) or colostrum-deprived formula-fed (FF) pigs were stimulated for 72 h with single HMO, mixtures of single HMO or a complex mixture of HMO isolated from human milk (iHMO). T-cell phenotype, cytokine production and proliferation were measured by flow cytometry, immunoassay and [³H]thymidine incorporation, respectively. Stimulation with HMO had direct effects on PBMC. For instance, cells stimulated with iHMO produced more IL-10 than unstimulated cells, and cells stimulated with fucosylated HMO tended to proliferate less than unstimulated cells. Additionally, co-stimulation with HMO mixtures or single HMO altered PBMC responses to phytohaemagglutinin (PHA) or lipopolysaccharide (LPS) stimulation. Compared with PBMC stimulated with PHA alone, cells co-stimulated with iHMO and PHA proliferated more and had fewer detectable CD4⁺CD8⁺ T cells. Compared with PBMC stimulated by LPS alone, cells co-stimulated with a mixture of sialylated HMO and LPS proliferated more and tended to have fewer detectable CD4⁺ T cells. Differences in the baseline responses of PBMC isolated from the SR or FF pigs were observed. In summary, HMO directly affected PBMC populations and functions. Additionally, ex vivo measurements of PBMC phenotype, cytokine production and proliferation were influenced by the neonate's diet.

Improving lactose digestion and symptoms of lactose intolerance with a novel galacto-oligosaccharide (RP-G28): a randomized, double-blind clinical trial.

BACKGROUND: Lactose intolerance (LI) is a common medical problem with limited treatment options. The primary symptoms are abdominal pain, diarrhea, bloating, flatulence, and cramping. Limiting dairy foods to reduce symptoms contributes to low calcium intake and the risk for chronic disease. Adaptation of the colon bacteria to effectively metabolize lactose is a novel and potentially useful approach to improve lactose digestion and tolerance. RP-G28 is novel galacto-oligosaccharide (GOS) being investigated to improve lactose digestion and the symptoms of lactose intolerance in affected patients. METHODS: A randomized, double-blind, parallel group, placebo-controlled study was conducted at 2 sites in the United States. RP-G28 or placebo was administered to 85 patients with LI for 35 days. Post-treatment, subjects reintroduced dairy into their daily diets and were followed for 30 additional days to evaluate lactose digestion as measured by hydrogen production and symptom improvements via a patient-reported symptom assessment instrument. RESULTS: Lactose digestion and symptoms of LI trended toward improvement on RP-G28 at the end of treatment and 30 days post-treatment. A reduction in abdominal pain was also demonstrated in the study results. Fifty percent of RP-G28 subjects with abdominal pain at baseline reported no abdominal pain at the end of treatment and 30 days post treatment (p = 0.0190). RP-G28 subjects were also six times more likely to claim lactose tolerance post-treatment once dairy foods had been re-introduced into their diets (p = 0.0389). CONCLUSIONS: Efficacy trends and favorable safety/tolerability findings suggest that RP-G28 appears to be a potentially useful approach for improving lactose digestion and LI symptoms. The concurrent reduction in abdominal pain and improved overall tolerance could be a meaningful benefit to lactose intolerant individuals.

Chitinase inhibition promotes atherosclerosis in hyperlipidemic mice.

Chitinase 1 (CHIT1) is secreted by activated macrophages. Chitinase activity is raised in atherosclerotic patient sera and is present in atherosclerotic plaque. However, the role of CHIT1 in atherosclerosis is unknown. Preliminary studies of atherosclerosis in cynomolgous monkeys revealed CHIT1 to be closely correlated with areas of macrophage infiltration. Thus, we investigated the effects of a chitinase inhibitor, allosamidin, on macrophage function in vitro and on atherosclerotic development in vivo. In RAW264.7 cells, allosamidin elevated monocyte chemoattractant protein 1 and tumor necrosis factor alpha expression, and increased activator protein 1 and nuclear factor-κB transcriptional activity. Although inducible nitric oxide synthase, IL-6, and IL-1ß expression were increased, Arg1 expression was decreased by chitinase inhibition, suggesting that suppression of CHIT1 activity polarizes macrophages into a M1 phenotype. Allosamidin decreased scavenger receptor AI, CD36, ABCA1, and ABCG1 expression which led to suppression of cholesterol uptake and apolipoprotein AI-mediated cholesterol efflux in macrophages. These effects were confirmed with CHIT1 siRNA transfection and CHIT1 plasmid transfection experiments in primary macrophages. Apolipoprotein E-deficient hyperlipidemic mice treated for 6 weeks with constant administration of allosamidin and fed an atherogenic diet showed aggravated atherosclerotic lesion formation. These data suggest that CHIT1 exerts protective effects against atherosclerosis by suppressing inflammatory responses and polarizing macrophages toward an M2 phenotype, and promoting lipid uptake and cholesterol efflux in macrophages.

Bullous skin reaction seen after extravasation of calcium gluconate.

Intravenous (IV) calcium is usually given to temporarily treat the effects of hyperkalaemia on muscle and heart. When extravasation of a calcium gluconate infusion occurs, there may be rapid and marked swelling and erythema, with signs of soft-tissue necrosis or infection, and ensuing extensive local calcification, called calcinosis cutis. We report a 26-year-old woman who was hospitalized for exacerbation of acute intermittent porphyria. She had a history of hypertension and chronic renal failure. On the second day of her hospitalization, she developed hyperpotassaemia (6.7 mEq/L potassium; normal range 3.5-5 mEq/L). She was given an IV infusion of 10 mL calcium gluconate into the left dorsal pedal vein. Bullous skin reactions occurred in the infusion area nearly 2 h after administration. The patient's leg was elevated and the lesions cleaned with 0.9% saline. By day 9 of hospitalization, the lesions had markedly regressed. Several drugs have been associated with dermoepidermal blistering as an adverse drug reaction, but there is only one existing report in the literature about this side-effect associated with calcium gluconate. Clinicians should be alert to the possibility of bullous skin reactions, which may be a predictor of extravasation and necrosis, when treating patients with IV calcium gluconate.

Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study.

BACKGROUND: Despite continued investigation, limited progress has been made in the adjuvant treatment of resected pancreatic cancer. Novel or targeted therapies are needed. METHODS: Multi-institutional, open-label, dose-finding, phase 2 trial evaluating the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA) immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant setting for resected pancreatic cancer (ClinicalTrials.gov identifier, NCT00569387). The primary outcome was 12-month disease-free survival. Secondary outcomes included overall survival and toxicity. RESULTS: Seventy patients were treated with gemcitabine and 5-fluorouracil-based chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1-14). After a median follow-up of 21 months, the 12-month disease-free survival was 62 %, and the 12-month overall survival was 86 %. The most common adverse events were injection site pain and induration. CONCLUSIONS: The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A multi-institutional, phase 3 study is ongoing (ClinicalTrials.gov identifier, NCT01072981).

Cancer immunotherapy by intratumoral injection of α-gal glycolipids.

UNLABELLED: AIM/ BACKGROUND: To determine the feasibility and safety of intratumoral α-gal glycolipids injection for conversion of human tumors into autologous Tumor Associated Antigens (TAA) vaccine. α-Gal glycolipids bind anti-Gal--the most abundant antibody in humans. Pre-clinical studies indicated that injected α-gal glycolipids insert into tumor cell membranes, bind anti-Gal and target tumor cells to Antigen Presenting Cells, thereby converting tumors into autologous TAA vaccines. We hypothesized that α-gal glycolipids might have similar utility in humans. PATIENTS AND METHODS: Eleven patients with advanced solid tumors received one intratumoral injection of 0.1 mg, 1 mg, or 10 mg α-gal glycolipids. The primary endpoint was dose-limiting toxicity (DLT) within 4 weeks. Secondary endpoints included long-term toxicity, autoimmunity, radiological tumor response and survival. RESULTS: There were no DLT and no clinical or laboratory evidence of autoimmunity, or any other toxicity. Few patients had an unexpectedly long survival. CONCLUSION: Intratumoral injection of α-gal glycolipids is feasible and safe for inducing a protective anti-tumor immune response.

[Oral anti-diabetes medicines, an update]. / Antidiabéticos orales. Actualización.

The use of oral anti-diabetes medicines should be considered when nutritional control methods and physical exercise programs have failed. These medicines have several types of active mechanisms: to stimulate pancreatic secretion of insulin, to delay the absorption of carbohydrates in the intestines, to sensitize tissues to the action of insulin. Sulfonylureas are the pharmaceutical group most commonly utilized in the treatment of type 2 diabetes mellitus.

Acarbose-induced generalised erythema multiforme.

A 58-year-old man with diabetes mellitus was treated with acarbose 300 mg daily. 13 days after the start of treatment with acarbose, generalised erythema multiforme developed with blood eosinophilia. Tissue eosinophilia was also found histologically. A challenge test for acarbose confirmed allergic reaction clinically and histologically.

The effectiveness, safety and epidemiology of the use of acarbose in the treatment of patients with type II diabetes mellitus. A model of medicine-based evidence.

OBJECTIVE: To assess the efficacy, safety and extent of perceived indications of acarbose, a new antidiabetic agent, under routine clinical practice conditions in an unselected Northern Italian population of type II diabetic patients. METHODS: The study population was assigned to three different groups according to the physician's clinical judgement: group A (acarbose considered as an elective treatment); group B (acarbose considered to be of uncertain benefit): group C (acarbose deemed not to be appropriate). Group B patients were randomized either to continue their standard treatment or to add acarbose to it. Patients with type II diabetes mellitus were recruited from 17 diabetes outpatient clinics from one Italian region (Lombardy). A total of 1027 patients were recruited (group A: 283; group C: 494; group B: 250, of whom 124 were randomly assigned to standard treatment + acarbose and 126 to standard treatment alone). Acarbose was administered for 1 year at a median dose of 100 mg 3 times daily. Drug efficacy was evaluated in terms of mean HbAlc, pre- and post-prandial glycaemic values. Additional endpoints were the proportion of patients with HbA1c levels below 8% at the end of the study period and the proportion of subjects who needed a modification in the standard treatment. The safety and tolerability profiles of the drug were also investigated. Data on HbA1c, fasting and post-prandial blood glucose levels were analysed over time using repeated-measures analysis [Generalized Estimating Equation (GEE) models]. RESULTS: The analysis of Group B showed that, after treatment for 1 year, the mean reduction in HbA1c levels in the acarbose group with respect to the control group was 0.30% (95% confidence limits -0.60 +0.02; P = 0.07), while the mean reduction in post-prandial glycaemia was 17 mg-dl(-1) (95% c.l. -33.5 -0.8; P = 0.04). No difference resulted for fasting blood glucose levels. When looking at the baseline HbA1c levels, it emerged that the mean benefit associated with the use of acarbose was 0.14% (95% c.l. -0.6 +0.28; P = 0.5) in patients with HbAlc levels below 8%, 0.28% (95% c.l. -0.6 +0.05; P = 0.09) in those with values between 8% and 9.9% and 0.65% (95% c.l. -1.36 +0.06; P = 0.07) in those with values > or =10%. Only patients treated with diet+/-oral anti-diabetic agents (OAA) benefited from acarbose treatment (mean benefit = 0.37%, 95% c.l. -0.65 -0.08), while no effect was shown for insulin-treated subjects. The proportion of patients with HbA1c below 8% increased from 31% to 44% in the acarbose group and from 40% to 45% in the control group (absolute difference between baseline and end-of-study values = 8.0% in favour of acarbose-treated patients; P = 0.058). Patients treated with acarbose were significantly more likely to undergo a dose reduction in concomitant diabetic treatments compared with the control group; they were also less likely to require an increase in the dose of standard treatment and to start insulin during the study period. One third of the patients could not assume the drug for the whole study period, mainly due to gastrointestinal side-effects. CONCLUSIONS: The design adopted in this study allowed an integrated evaluation of the overall effectiveness of acarbose in clinical practice. The benefits of the drug in an unselected population of non-insulin-dependent diabetes mellitus (NIDDM) patients are significant but of marginal clinical relevance. Only a better definition of the subgroups of patients who are more likely to benefit from long-term treatment, particularly through possible postponement of secondary OAA failure, will allow a reliable definition of the cost-effectiveness of this complementary component of anti-diabetic strategy.

Efficacy and safety of acarbose in the treatment of Type 1 diabetes mellitus: a placebo-controlled, double-blind, multicentre study.

AIMS: The aim of the study was to evaluate the efficacy and safety of acarbose in patients with Type 1 diabetes mellitus (DM). METHODS: A multicentre double-blind, randomized, placebo-controlled study was performed. After a 6-week run-in, 121 patients were randomized to acarbose or placebo and to high- or low-fibre diet for 24 weeks. Acarbose dose was 50 mg t.d.s. for the first 2 weeks and 100 mg t.d.s. for the subsequent weeks. RESULTS: At the end of 24 weeks of treatment the intention to treat analysis showed that acarbose compared with placebo decreased 2 h postprandial plasma glucose levels (12.23 +/- 0.83 vs. 14.93 +/- 0.87 mmol/l; F = 6.1, P < 0.02) (least square means +/- SEM). No significant effect of acarbose was recorded on HbA1c or on the number of hypoglycaemic episodes. The effect of acarbose on blood glucose control was not influenced by the amount of carbohydrate and/or fibre intake. The incidence of adverse events were 75% and 39% in acarbose and placebo groups, respectively; they were mild and confined to the gastrointestinal tract. CONCLUSIONS: The use of acarbose in combination with insulin reduces postprandial plasma glucose levels in Type 1 diabetic patients who are not satisfactorily controlled with insulin alone but without significant effect on HbA1c.