Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes.

OBJECTIVE: Insulin in pancreatic ß-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment. RESEARCH DESIGN AND METHODS: We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin. RESULTS: ß-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin. CONCLUSIONS: Although nasal insulin did not retard loss of residual ß-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals.

Antibiotic resistance: how it arises, the current position and strategies for the future.

After 70 years of antibiotic therapy, the threat of untreatable infections is again a reality with resistance to antibiotics increasing in both Gram positive and Gram negative bacteria. Antibiotic-resistant bacteria cause both community and healthcare associated infections, presenting challenges in treatment and management. The development of new and novel antibiotics, particularly for Gram negative bacteria, is worryingly lacking. This article reviews the current situation and examines future strategies to tackle the continued threat of bacterial resistance.

Exploring the evidence for screening staff for MRSA.

Christine Perry reviews the current evidence for screening staff for MRSA and the issues to be considered when screening identifies positive members of staff.

A clinical screening tool identifies autoimmune diabetes in adults.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS: Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA-) (aged 30-75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a "LADA clinical risk score," based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS: In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset <50 years (P < 0.0001), 2) acute symptoms (P < 0.0001), 3) BMI <25 kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score > or =2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score < or =1 of 99%. CONCLUSIONS: At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.

Chemical kinetics and aqueous degradation pathways of a new class of synthetic ozonide antimalarials.

Chemical stability of a new class of ozonide (1,2,4 trioxolanes) antimalarial compounds was investigated. The effects of pH, ionic strength, dielectric constant and cyclodextrin-complexation on the chemical stability and degradation product formation of selected compounds were examined. The mechanism of degradation in aqueous solution was probed using (18)O-labelled water and kinetic solvent isotope effect studies. The effect of stereochemistry was investigated using selected pairs of stereoisomers. The degradation of the ozonides in aqueous solution followed apparent first-order kinetics, with no effect of ionic strength and no indication of any direct involvement of water in the degradation mechanism. All major degradation products were identified and mass balance was confirmed. Stereochemistry had a significant effect on degradation rate; trans isomers degrading approximately four-fold faster than the corresponding cis isomers. The degradation rates were essentially independent of pH above pH 2; however, an additional specific acid catalysed pathway was dominant below pH 2. Solvent dielectric constant had a significant effect on the degradation rate. It is proposed that the degradation observed in aqueous solution occurred through a concerted heterolytic scission of the central ozonide ring, with chemical substituents on the cyclohexyl ring having only a minor influence on degradation rate.

Alteration of the intravenous pharmacokinetics of a synthetic ozonide antimalarial in the presence of a modified cyclodextrin.

The pharmacokinetic profile and renal clearance of a novel synthetic ozonide antimalarial (1) was found to be significantly altered when intravenously administered to rats as a cyclodextrin-based formulation (0.1 M Captisol, a sulfobutylether beta-cyclodextrin derivative (SBE(7)-beta-CD)) compared to a cyclodextrin-free isotonic buffered glucose formulation. There was an 8.5-fold decrease in the steady-state blood volume of distribution, a 6.6-fold decrease in the mean residence time and a greater than 200-fold increase in renal clearance of 1 when administered in the cyclodextrin formulation. Analysis of the whole blood and plasma concentration profiles revealed an essentially constant blood to plasma ratio when 1 was administered in the cyclodextrin-free formulation, whereas this ratio changed as a function of time when administered in the presence of the cyclodextrin derivative. It is postulated that the observed differences were due to a very strong complexation interaction between 1 and the cyclodextrin, resulting in a slow dissociation of the complex in vivo, and altered distribution and excretion profiles. Preliminary studies using isothermal titration calorimetry (ITC) indicated that the association constant for the 1/Captisol complex was approximately two orders of magnitude higher than reported for typical drug/cyclodextrin complexes.

The binding interaction of synthetic ozonide antimalarials with natural and modified beta-cyclodextrins.

The current studies were undertaken to explore the potential basis for a significant difference in the pharmacokinetic parameters after intravenous administration of a synthetic ozonide (OZ) antimalarial drug candidate (1) to rats when formulated in either Captisol (a sulfobutylether substituted beta-cyclodextrin derivative ((SBE)(7)-beta-CD)) or a buffered aqueous vehicle. It was suspected that the differences may have been due to failure of 1 to rapidly dissociate from the cyclodextrin complex in vivo, perhaps due to an unusually tight binding within the cyclodextrin cavity. To address this hypothesis, the binding of representative synthetic OZ antimalarial drug candidates (including 1) with beta-cyclodextrin and (SBE)(7)-beta-CD was investigated by isothermal titration calorimetry and phase solubility analysis. It was found that each of the OZ compounds exhibited an exceptionally high binding constant ( approximately 10(6)/M) with both Cyclodextrins (CD). The nature of the complexation was investigated by molecular dynamics simulations and NMR to explore the mechanisms, which generated such high binding constants. The data suggested that the most probable cause of the unusually high binding constants was a very close fit within the cyclodextrin cavity that resulted in more favourable changes in both the enthalpy and entropy of the binding interaction, compared to published data for other drugs.

Epidemiology and cost of nosocomial gastroenteritis, Avon, England, 2002-2003.

Healthcare-associated outbreaks of gastroenteritis are an increasingly recognized problem, but detailed knowledge of the epidemiology of these events is lacking. We actively monitored three hospital systems in England for outbreaks of gastroenteritis in 2002 to 2003. A total of 2,154 patients (2.21 cases/1,000-hospital-days) and 1,360 healthcare staff (0.47 cases/1,000-hospital-days) were affected in 227 unit outbreaks (1.33 outbreaks/unit-year). Norovirus, detected in 63% of outbreaks, was the predominant etiologic agent. Restricting new admissions to affected units resulted in 5,443 lost bed-days. The cost of bed-days lost plus staff absence was calculated to be 635,000 pounds sterling (US. 1.01 million dollars) per 1,000 beds. By our extrapolation, gastroenteritis outbreaks likely cost the English National Health Service 115 million pounds sterling (US 184 million dollars) in 2002 to 2003. Outbreaks were contained faster (7.9 vs. 15.4 days, p = 0.0023) when units were rapidly closed to new admissions (<4 days). Implementing control measures rapidly may be effective in controlling outbreaks.

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant.

Recent studies in a conscious dog model demonstrated intestinal lymphatic transport to be a significant contributor to the bioavailability of the highly lipid-soluble free-base of halofantrine (Hf), and surprisingly, also the poorly lipid-soluble hydrochloride salt (Hf. HCl). Partial conversion of solubilized Hf. HCl to Hf base within the intestinal lumen prior to the lymphatic uptake seemed to be the most likely explanation for these results. This hypothesis was supported by studies exploring the partitioning behavior of Hf. HCl between soybean oil (SBO) and aqueous micellar solutions containing different ionic and nonionic surfactants. Mixed micelles prepared from sodium taurodeoxycholate (NaTC) and lecithin (PC) were chosen to represent fed-state intestinal fluids. The apparent ionization constants derived from the partitioning versus pH profiles showed marked shifts when compared with the likely aqueous pK(a) value. In the present paper, the apparent pK(a) values of Hf in aqueous micellar phases, without a coexisting oil phase, were investigated to further probe the mechanisms underlying the effect of micellar media on the apparent ionization equilibrium, and subsequently, on its partitioning behavior in the triphasic systems. Another aim of this study was to further evaluate the aqueous pK(a) value of Hf. The results indicate that the aqueous pK(a) of Hf is most probably in the range approximately 8-9, and that the ionization equilibrium is highly dependent on the solution environment. For example, marked pK(a) shifts of several units were observed for Hf in the presence of different micellar species and SBO. The apparent ionization equilibrium depends not only on interaction of Hf with the micelles, but also on its partitioning into the oil phase.