Vitamin D and lactoferrin attenuate stress-induced colitis in Wistar rats via enhancing AMPK expression with inhibiting mTOR-STAT3 signaling and modulating autophagy.

Irritable bowel syndrome (IBS) is a global gastrointestinal disorder closely related to psychological stress exposure and local colonic inflammation. Herein, we investigated the effect of wrap-restraint stress (WRS) on rat behavior, on adenosine monophosphate-activated protein kinase-mammalian/mechanistic target of rapamycin-signal transducer and activator of transcription 3 (AMPK-mTOR-STAT3) signaling, and autophagy in colonic mucosa. The impact of chronic administration of vitamin D3 and lactoferrin was compared. Twenty-four male Wistar rats were randomly divided into four groups. Chronic WRS protocol was applied as a rodent model of IBS. Group I: naïve animals, Group II: WRS animals, Group III: WRS-exposed and treated with vitamin D3 (500 IU/kg/day), and Group IV: WRS-exposed and treated with lactoferrin (300 mg/kg/day). In this study, we found that chronic administration of each of vitamin D3 and lactoferrin resulted in a significant increase in social interaction test, interleukin-10, AMPK, optical density of LC3B, goblet cell count and marked decrease in serum cortisol level, STAT3, inflammatory cell count, and optical density of mTOR in comparison to the WRS rats. Our findings suggest that both vitamin D3 and Lactoferrin could augment colonic autophagy through enhanced AMPK expression and inhibition of mTOR-STAT3 signaling, which offers practical insights into their clinical use in the prevention and therapy of IBS. However, lactoferrin intake as a nutritional supplement could be more helpful for stress-induced colitis treatment than vitamin D3.

Adverse drug reactions associated with off-label use of ketorolac, with particular focus on elderly patients. An analysis of the Italian pharmacovigilance database and a population based study.

OBJECTIVE: This study aims to evaluate the frequency of off-label use of ketorolac in Italy and the related suspected adverse drug reactions (ADRs) reported. METHODS: All the suspected cases associated with ketorolac recorded in the Italian Pharmacovigilance database were retrieved. Case evaluations were carried out in order to identify the off-label use of ketorolac. Moreover, an analysis of the inappropriate use of ketorolac was conducted using the 'Arianna' database of Caserta local health unit. RESULTS: Up to December 2014, 822 reports of suspected ADRs related to ketorolac were retrieved in the database. The use of ketorolac was classified as off-label for 553 reports and on-label for 269. Among the off-label cases, 58.6% were serious compared to 39.0% of on-label cases. Gastrointestinal events were more frequently reported with off-label use. The analysis of Arianna database showed that 37,729 out of 61,910 patients, were treated off-label. CONCLUSIONS: The off-label use of ketorolac is widespread in Italy. This use increases the risk of serious ADR, especially in in case of prolonged duration of treatment and in elderly patients. The Italian Medicine Agency has decided to accurately monitor the appropriate use of the drug in Italy and, if necessary, take measures in order to minimize the risks.

Effect of an educational program in primary care: the case of lipid control in cardio-cerebrovascular prevention.

Lowering blood cholesterol levels reduces the risk of coronary heart disease. However, the effect of interventions depends on the patients' adherence to treatment. Primary care plays an important role in the detection, treatment and monitoring of disease, therefore different educational programs (EP) have been implemented to improve disease management in general practice. The present study is aimed to assess whether a general practitioner auditing and feedback EP may improve dyslipidaemia management in a primary care setting and to evaluate patients' adherence to prescribed lipid-lowering treatment. The quality of cardiovascular and cerebrovascular disease prevention before and after the implementation of an EP offered to 25 general practitioners (GPs), was evaluated. Clinical and prescription data on patients receiving at least one lipid-lowering treatment was collected. To evaluate the quality of the healthcare service provided, clinical and biochemical outcomes, and drug-utilization, process indicators were set up. Adherence was evaluated before and after the EP as the "Medication Possession Ratio" (MPR). A correlation analysis was carried out to estimate the effect of the MPR in achieving pre-defined clinical end-points. Prescription data for lipid-lowering drugs was collected in a sample of 839 patients. While no differences in the achievement of blood lipid targets were observed, a slight but significant improvement of the MPR was registered after the EP (MPR >0.8=64.2% vs 60.6%, p=0.0426). Moreover, high levels of statin adherence were associated with the achievement of total blood cholesterol target (OR=3.3 for MPR >0.8 vs MPR <0.5, 95% CI:1.7-6.7) or LDL therapeutic goal (OR=3.3 for MPR >0.8 vs MPR <0.5, 95% CI:1.5-7.2). The EP partially improved the defined clinical targets; probably, a more patient-based approach could be more appropriate to achieve the defined target. Further studies are needed to identify how healthcare services can be improved.

Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts.

Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.

Immunotherapy with an alum-adsorbed Parietaria-pollen allergoid: a 2-year, double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was performed in order to confirm the safety, suitability, and efficacy of an alum-adsorbed Parietaria judaica-pollen allergoid, Allergovit, for allergen-specific immunotherapy. Parietaria pollen is an important cause of pollinosis, particularly in the Mediterranean zone, where it may be encountered for up to 8-9 months of the year. It is an aggressive allergen, and the doses tolerated during immunotherapy are less than those achieved with grass pollen. This factor increases the desirability of using therapeutic preparations with minimal IgE-binding activity, such as allergoids, in order to reduce the risk of side-effects and enable patients to tolerate a higher dose of allergen, thereby increasing the chances of successful specific immunotherapy. Forty patients with rhinitis and/or asthma were allocated at random to active- or placebo-treatment groups at the beginning of the study. All patients received the active preparation during the second year of the study. Immunotherapy was well tolerated by all patients and the incidence of side-effects was low. Treatment resulted in significant reductions in specific cutaneous reactivity and increases in nasal tolerance. A progressive improvement in nasal inspiratory peak flow in association with the immunotherapy indicated a reduction in nasal inflammation. These objective assessments of efficacy endorsed the results from the patients' diary cards, which indicated significant improvements in symptoms and reductions in the use of medication. The immunologic activity of the therapeutic preparation was demonstrated by the induction of a significant specific-IgG antibody response, with increases in IgG4 during the second year of treatment. We conclude that the safety and efficacy of immunotherapy with the Parietaria allergoid make it suitable for consideration in the treatment of patients with Parietaria-pollen-induced rhinitis or asthma.

Immunologic evaluation of 24 month course of sublingual immunotherapy.

58 patients under 12 years of age, positive to mites (Dermatophagoides pteronyssinus and D. farinae) according to prick, in vitro specific IgE and challenge tests, suffering from asthma and rhinitis, have been randomly assigned on a double blind basis to receive per os either a biologically standardized extract of mites (active therapy TA = 30 patients) or a saline buffered solution (placebo TP = 28 patients). The serologic results are interesting. The specific IgE level differences of significance are, in comparison with the placebo group. In particular, we did observe the increase of the specific IgE level in the placebo group during the autumn, whereas after 12 months and after 24 months of active treatment there was a clear (p < 0.01) decline in serum specific IgE antibody. In the active group, there was a significant increase in IgG antibodies level after 12 and 24 months and a significant increase in IgG4 level after 24 months. In the placebo group, the level of IgG antibodies was unchanged. In the actively treated patients, a significant increase of CD8+ values and a significant reduction of the ratio CD4+/CD8+ was observed.

Immunotherapy by inhalation of allergen in powder in house dust allergic asthma--a double-blind study.

The authors report the analysis of clinical and immunological parameters during local immunotherapy (LI) by inhalation of an extract in powder in patients with allergic asthma due to D. pteronyssinus (DP). The study was double-blind and lasted 24 months. Twenty-four patients were randomly assigned on a double-blind basis to receive by inhalation increasing doses of a micronized, freeze-dried DP extract in powder (14 patients, active therapy) or capsules of lactose (10 patients, placebo group). Results showed a statistically lower symptom score, a significant increase in bronchial tolerance to the allergen and significant levels of DP-specific IgG in actively treated patients compared to those treated with placebo.

Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double-blind study.

Fifty eight patients under 12 years of age, positive to mites (Dermatophagoides pteronyssinus and D. farinae) according to prick, "in vitro" specific IgE and challenge tests, suffering from asthma and rhinitis, were randomly assigned on a double blind basis to receive per os either a biologically standardized extract of mites (active therapy TA = 30 patients) or a saline buffered solution (placebo = 28 patients). Patients took sublingually increasing doses of the solution, followed by maintenance therapy consisting of 15 drops 3 times a week. The results of the trial were assessed after 12 an 18 months, according to the following parameters: symptom scores recorded in diary cards, total and specific IgE levels, total IgG level, IgG1 and IgG4 levels, lymphocytes underpopulations, nasal challenge test, side effects. During the first 18 months, the patients on active therapy had significantly lower scores (p less than 0.001) and clear variations of rhinomanometric parameters (p less than 0.01); IgG also significantly increased. After 12 months, bronchial specific and specific challenge tests showed significantly higher threshold values in comparison to initial values (p less than 0.05). No statistically significative variation was registered in the placebo group.

Immunotherapy with alginate-conjugated two grass pollen extract in patients with allergic rhinoconjunctivitis.

The aim of the present study was to evaluate the clinical and immunological effects of specific immunotherapy with alginate-conjugated two grass pollen extract in patients with rhinoconjunctivitis. A total of 52 patients were admitted to the study. Before and after 3 years of immunotherapy quantitative skin test (QST) to Dactylis glomerata (Dg) and to Phleum pratense (Php), variation of grass specific IgE and IgG4 and nasal challenge with the aqueous extract of the two grasses were compared. Each patient kept a daily record of symptoms and medication required during pollen season. In all patients a significant decrease in QST and a significant increase in grass specific IgG4 was observed. In 47 patients a significant decrease in nasal symptom scores and drug consumption was observed. In 5 patients no significant decrease in nasal symptom scores was observed.

Intropic effects of several antiarrhythmic drugs.

The effects of intravenous administration of several quinidine-like antiarrhythmic drugs (bunaftine, monochloroacetyl ajmaline, lidocaine, mexiletine, disopyramide, aprindine, diphenylhydantoin, procainamide) on left ventricular performance, evaluated by systolic time intervals (STI), were studied in 100 patients with atherosclerotic heart disease. The STI were measured: the pre-ejection period (PEP), the isometric contraction time (ICT), the left ventricular ejection time (LVET), corrected LVET (LVETc), and the PEP/LVET ratio. The degree of impairment of left ventricular performance was maximal after aprindine and disopyramide administration. This was demonstrated by significant increases in the PEP, ICT, and PEP/LVET and by significant decreases in LVET and LVETc, in patients in both III-IV and I-II NYHA classes. Bunaftine, monochloroacetyl ajmaline, and lidocaine induced a less marked impairment of myocardial performance, since the PEP, ICT, and PEP/LVET increases were not significant compared to controls in patients in NYHA class I-II, and since no variation of LVET and LVETc were observed. Mexiletine effects on myocardial performance appear to be intermediate between these groups of drugs. Diphenylhydantoin and procainamide, considered separately because of their effects on heart rate and blood pressure which are not possessed by the other drugs, induced significant increases of PEP in NYHA class III-IV patients. However, the effects of these 2 drugs on myocardial performance may have been underestimated, due to the concomitant hemodynamic effect of these drugs.

Non-invasive evaluation by thermistor plethysmography of left ventricular performance during dynamic exercise. Comparison with echocardiography.

The purpose of this study was to evaluate the reliability of two non-invasive techniques (STI and echocardiography) in assessing cardiovascular response during exercise. STI were obtained using a new carotid pulse transducer (thermistor pulse) proved to be reliable in exercise recording. The study population included 12 male rowers (age 15-20 years), who performed supine bicycle exercise; STI and echocardiographic recording of left ventricle were simultaneously obtained at rest and continuously throughout the exercise period. A negative linear correlation (r=-0.782; p less than 0.001) was found between PEP (pre-ejection period) and %LVID (fractional shortening of left ventricle), reliable indexes of cardiac contractility measured by the two techniques. A lower, but significant correlation (r=0.643; p less than 0.001) was present between ETI (left ventricular ejection time corrected by heart rate) and SV (stroke volume) indexes of pump function. The present study shows that STI measured with this new technique, can be employed in evaluating left ventricular function in those patients in whom a good echocardiogram is difficult to record during exercise.

Relationship between systolic time intervals and heart rate during atrial or ventricular pacing in normal subjects.

Systolic time intervals (STI) are regarded as good indices of cardiac performance in many heart diseases. It must be considered, however, that they are temporally related to the cardiac contraction cycle and, therefore, may be modified by heart rate changes. Thus, it is necessary to define the possible relationship between STI and heart rate changes. In this study, changes in heart rate were induced by atrial and ventricular pacing. Tachycardia caused a proportional decrease of left ventricular ejection time (LVET) (y=275.142-1.0025 x, r=0.76, p less than 0.001 for atrial pacing and y=298.28-0.691 x, r=-0.75, p less than 0.001 for ventricular pacing, respectively), but did not modify the pre-ejection period (PEP) and the isometric contraction time (ICT) and the electromechanical interval (QS1). These results demonstrate that while LVET must be corrected for the changes in heart rate, no correction of PEP and ICT is necessary.

Effects of intravenous disopyramide on myocardial function in patients with different degrees of cardiac failure.

The effects of intravenous disopyramide phosphate on myocardial function were evaluated by non-invasive indices of cardiac performance (systolic time intervals, STI) in 15 patients with atherosclerotic heart disease and different degrees of cardiac failure. Disopyramide (1.5 mg/Kg) was given intravenously over a period of 5 min. This drug induced in patients in I-II classes of NYHA a significant decrease of LVETc, while PEP, ICT, and PEP/LVET ratio rose significantly. STI were affected much more markedly in patients in III-IV classes of NYHA. Particularly affected were contractility indices (PEP, ICT, PEP/LVET), which were reduced significantly more in patients in III-IV classes as compares to patient in I-II classes. In contrast, LVETc, which correlates to stroke volume and cardiac output, was similarly worsened by the drug in the 2 groups of patients. Therefore, this study shows that disopyramide has relevant depressant effects on myocardial performance, simultaneously reducing stroke volume and contractility, and that the effect on contractility is more marked in patients with severe left ventricular impairment.

[Correlations between polygraphic and hemodynamic parameter changes induced by high concentrated oxygen administration in patients with mitral valvulopathy (author's transl)]. / Correlazioni tra le variazioni dei parametri poligrafici ed emodinamici indotte dalla somministrazione di ossigeno ad elevata concentrazione in soggetti con valvulopatia mitralica.

The goal of this study was to identify, utilizing apexcardiogram, other noninvasive parameters useful to evaluate the functional condition of the pulmonary vascular bed in patients with mitral stenosis and insufficiency. The patients of both sexes with mitral stenosis and insufficiency underwent left and right heart catetherization and simultaneously a polygraphic study was performed. Recordings of polygraphic as well as hemodynamic parameters were performed under control condition and after 5 min breathing of 100% Oxygen administered by facial mask. These results indicate that changes in rapid filling angle have a close relationship with changes in pulmonary capillary wedge pressure and variation of rapid filling interval are correlated with changes in pulmonary capillary wedge pressure and variation of rapid filling interval are correlated with changes in cardiac output.

[Effects of metoprolol on myocardial performance in hypertensive patients during exercise (author's transl)]. / Effetti del metoprololo sulla funzione miocardica durante lo sforzo in soggetti ipertesi.

In this study the effects of metoprolol administration (200 mg daily per os) to 20 hypertensive subjects (WHO stage I and II), as a 20-days course, on heart rate (HR), systolic blood pressure (BP) and myocardial performance evaluated by systolic time intervals, were studied both at rest and during exercise. This treatment was able to reduce significantly HR and BP in all the patients, both at rest and during exercise. After the 20 days treatment, the left ventricular ejection time corrected for HR (LVETc) did not show any significant change both at rest and during exercise. On the other hand, the pre-ejection period (PEP) changed at rest in all the subjects studied after metoprolol treatment, but increased significantly during exercise only in patients in the I WHO class and only at the highest work load (at 70 watts, from 63 +/- 2 to 78 +/- 7 msec, P ¿ 0.05). Furthermore, in the same group of patients the maximal work load increased significantly after metoprolol treatment (from 67.5 +/- 6 to 85 +/- 8 watts, P < 0.05).