On-line monitoring of chemical reactions by using bench-top nuclear magnetic resonance spectroscopy.

Real-time nuclear magnetic resonance (NMR) spectroscopy measurements carried out with a bench-top system installed next to the reactor inside the fume hood of the chemistry laboratory are presented. To test the system for on-line monitoring, a transfer hydrogenation reaction was studied by continuously pumping the reaction mixture from the reactor to the magnet and back in a closed loop. In addition to improving the time resolution provided by standard sampling methods, the use of such a flow setup eliminates the need for sample preparation. Owing to the progress in terms of field homogeneity and sensitivity now available with compact NMR spectrometers, small molecules dissolved at concentrations on the order of 1 mmol L(-1) can be characterized in single-scan measurements with 1 Hz resolution. Owing to the reduced field strength of compact low-field systems compared to that of conventional high-field magnets, the overlap in the spectrum of different NMR signals is a typical situation. The data processing required to obtain concentrations in the presence of signal overlap are discussed in detail, methods such as plain integration and line-fitting approaches are compared, and the accuracy of each method is determined. The kinetic rates measured for different catalytic concentrations show good agreement with those obtained with gas chromatography as a reference analytical method. Finally, as the measurements are performed under continuous flow conditions, the experimental setup and the flow parameters are optimized to maximize time resolution and signal-to-noise ratio.

Highly stable and finely tuned magnetic fields generated by permanent magnet assemblies.

Permanent magnetic materials are the only magnetic source that can be used to generate magnetic fields without power consumption or maintenance. Such stand-alone magnets are very attractive for many scientific and engineering areas, but they suffer from poor temporal field stability, which arises from the strong sensitivity of the magnetic materials and mechanical support to temperature variation. In this work, we describe a highly efficient method useful to cancel the temperature coefficient of permanent magnet assemblies in a passive and accurate way. It is based on the combination of at least two units made of magnetic materials with different temperature coefficients arranged in such a way that the ratio of the fields generated by each unit matches the ratio of their effective temperature coefficients defined by both the magnetic and mechanical contributions. Although typically available magnetic materials have negative temperature coefficients, the cancellation is achieved by aligning the fields generated by each unit in the opposite direction. We demonstrate the performance of this approach by stabilizing the field generated by a dipolar Halbach magnet, recently proposed to achieve high field homogeneity. Both the field drift and the homogeneity are monitored via nuclear magnetic resonance spectroscopy experiments. The results demonstrate the compatibility of the thermal compensation approach with existing strategies useful to fine-tune the spatial dependence of the field generated by permanent magnet arrays.

Cyclic DGR-peptidomimetic containing a bicyclic reverse turn inducer as a selective alpha(v)beta (5) integrin ligand.

3-Aza-6,8-dioxabicyclo[3.2.1]octane-based amino acids as reverse turn inducers have been introduced into cyclic peptidomimetics containing the RGD or DGR retro-sequence, in order to achieve a stereochemical scanning of the binding capability of the resulting molecules towards alpha(v)beta(3) and alpha(v)beta(5) integrins, resulting in retro-inverso DGR peptides as micromolar ligands. A comparative analysis between the conformational preferences of 4 and of its isomer 3, having the opposite RGD sequence, was reported with respect to the binding activity, giving insight into the factors affecting the preferential binding of 4 to the alpha(v)beta(5) integrin.

[Long-term effects of cyclic therapy with iloprost in systemic sclerosis]. / Effetti a lungo termine della terapia ciclica con iloprost nella sclerosi sistemica.

OBJECTIVE: To assess the long-term effects of cyclic infusion of iloprost, a derivative of prostacyclin, on Raynaud's phenomenon-related symptoms and ischemic ulcers in patients with Systemic Sclerosis (SSc). METHODS: A retrospective analysis of prospectively collected parameters in 59 consecutive SSc patients, followed at one institution, who were treated for a median time of 52 months with iloprost for severe Raynaud's phenomenon and ischemic ulcers. RESULTS: Among the 50 patients with ischemic ulcers at the start of therapy, 35 (70%) did not show lesions at the last observation. Despite therapy, four patients underwent amputations (two of forefoot, two of finger distal phalanges). Compared to the pre-treatment point, we observed: decrease of the Raynaud's phenomenon VAS (p<0.001), and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score (p=0.002). The Health Assessment Questionnaire was not significantly improved. CONCLUSION: Treatment with cyclic iloprost can control Raynaud's phenomenon-related symptoms and ischemic ulcers in the large majority of patients with SSc. However, a disease-modifying effect of this therapy could not be demonstrated.

Synthesis of a bicyclic delta-amino acid as a constrained Gly-Asn dipeptide isostere.

Delta-amino acids are very attractive in drug discovery, especially in the peptidomimetic area, because of their capability to act as dipeptide isosteres and reverse turn mimetics. Herein we report the synthesis of a rigid delta-amino acid constrained by a 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffold, which can be considered as a Gly-Asn dipeptide mimetic. Key steps are the condensation of glycidol and tartaric acid derivatives, and the intramolecular trans-acetalization of the oxidized adduct to give the bicyclic delta-amino acid. Starting from L-tartaric acid derivative, it was achieved the corresponding Gly-D-Asn isostere, whereas from the enantiomeric D-tartaric acid derivative the corresponding Gly-L-Asn isostere could be obtained, thus giving access to both enantiomeric dipeptide sequences.

Disease-modifying effects of long-term cyclic iloprost therapy in systemic sclerosis. A retrospective analysis and comparison with a control group.

OBJECTIVE: To evaluate the role of iloprost, a derivative of prostacyclin, as a possible disease-modifying agent for systemic sclerosis (SSc). METHODS: Fifty-six consecutive SSc patients treated for a median period of 4 years with cyclic infusions of iloprost for severe Raynaud's phenomenon and ischemic ulcers were compared with 56 control patients matched for age, sex, disease subset and duration. Control patients were also similar to the iloprost group with regard to autoantibody status, the presence of major disease-related organ manifestations at baseline, and the use of other treatments. The evolution of lung function test results, the frequency of major disease-specific complications and the survival of the cohorts were the objects of this analysis. RESULTS: No significant difference was observed between the two groups with regard to changes in lung function tests over time, or the number of patients who presented with the onset of active interstitial lung disease, pulmonary arterial hypertension or scleroderma renal crisis. Survival did not differ between the two groups. CONCLUSION: The evolution of lung function test results, the frequency of major disease-specific complications, and survival did not differ significantly between SSc patients treated with cyclic iloprost and a group of patients matched for sex, age, and disease subset and duration. However, no cases of severe pulmonary arterial hypertension were observed in the patients treated with iloprost, suggesting that studies focusing on the possible preventive action of iloprost on the progression of SSc- associated mild pulmonary arterial hypertension would be warranted.

Intravenous cyclophosphamide for interstitial lung disease associated to systemic sclerosis: results with an 18-month long protocol including a maintenance phase.

OBJECTIVE: Cyclophosphamide (CYC) is generally considered the most promising agent available today for systemic sclerosis (SSc)-related interstitial lung disease (ILD). However, the optimal dosage and length of treatment are still undetermined. Our objective was to evaluate the effect of an 18-month long protocol with intravenous (iv) CYC. METHODS: In a single-centre, prospective, observational study, 13 patients with SSc and active alveolitis were given 8 iv pulses in a 6-months period (CYC 750 mg + 6-methylprednisolone 125 mg every three weeks), as an induction therapy. Patients received maintenance therapy with further cycles at 4 (3 pulses), 6 (3 pulses) and 9 weeks (3 pulses) interval. Total CYC dosage was 12.75 g in an 18-month period. End-points were modifications of lung function test (LFT). RESULTS: During the first 6 months of treatment with CYC an increase in Forced Vital Capacity (FVC; p = 0.005) and in diffusion lung capacity for carbon monoxide (DLCO; p = 0.10) was observed; during the maintenance therapy, there was a stabilization in FVC and a mild, non significant decline in DLCO. Treatment was well tolerated. CONCLUSION: iv CYC can induce an initial improvement in LFT (particularly, in FVC) in the first six months, but no further improvement was observed during the maintenance phase.

Response to tetanus vaccination in infants exposed in utero to immunosuppressants for maternal autoimmune disorders.

Immunosuppressive drugs given during pregnancy to mothers suffering from a systemic autoimmune disease (AID) can cross the placenta, thus being potentially able to affect the offspring immune system. Aim of our study was to evaluate the in vivo immune function of a series of these newborns. Twenty-two babies born from mothers suffering from autoimmune diseases (AID) who had been taking immunosuppressive drugs during pregnancy were evaluated for their response to vaccination with C. Tetani toxoid. Six babies born from mothers receiving low-dose aspirin only were used as controls. The immune response to C. Tetani vaccination was evaluated with an ELISA to detect circulating antibodies. Five children out of 28 (17%) did not achieve a protective titer of anti C. Tetani toxoid IgG. No clear relationship was found between specific drug exposure and antibody response. Our findings suggest that maternal immunosuppressive treatment given for a systemic AID can affect the response to an active immunization, without specificities for drug types used.