Effect of PTX3 and voriconazole combination in a rat model of invasive pulmonary aspergillosis.

This study evaluated the pharmacological activity of PTX3, administered in combination with voriconazole, in a rat model of pulmonary aspergillosis. The data indicated additive therapeutic activities of these compounds, as demonstrated by the amelioration of respiratory function changes, reduction of lung fungal burden, and increased survival. Overall, we provide clear evidence that the combination of PTX3 with a suboptimal dose of voriconazole might represent a therapeutic option under those clinical conditions where the use of voriconazole alone is not warranted for efficacy and tolerability reasons.

Chronic istaroxime improves cardiac function and heart rate variability in cardiomyopathic hamsters.

PURPOSE: Istaroxime is a new luso-inotropic compound. It exerts inotropic action by reducing Na+/K+-ATPase activity, and simultaneously it stimulates sarcoplasmic reticulum Ca(2+)-ATPase function, thus also inducing lusitropic action. The aim of present study is to assess the effect of chronic istaroxime treatment on cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure. METHODS: Bio TO.2 hamsters were daily treated, from 12 to 28 weeks of age, with 30 mg/kg/day oral istaroxime. Age-matched Bio TO.2 and Bio F1B hamsters were treated with vehicle and used as diseased and healthy controls. At the end of treatment, hearts function and autonomic cardiac control were evaluated. RESULTS: Hearts from vehicle-treated Bio TO.2 when compared with hearts from Bio F1B showed higher heart/body weight ratio, and lower left ventricular systolic pressure (LVSP), positive and negative derivative of LV pressure (dP/dT), coronary flow rate (CFR). Hearts from istaroxime-treated when compared with those of vehicle-treated hamsters, showed the reduction of heart/body weight ratio, and the increase of LVSP, of both positive and negative dP/dT, and of CFR. Autonomic cardiac control, evaluated by HRV analysis, indicated in vehicle-treated Bio TO.2 hamsters, when compared to healthy, a shift towards increased sympathetic and decreased parasympathetic activities. Istaroxime-treatment preserved parasympathetic activity. CONCLUSIONS: Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.

Efficacy of PTX3 in a rat model of invasive aspergillosis.

Pentraxin 3 (PTX3) is an acute-phase glycoprotein with a nonredundant function in the host resistance to Aspergillus fumigatus. PTX3 activity was evaluated against pulmonary aspergillosis in rats immunosuppressed with cortisone acetate. PTX3 enhanced the survival rate and reduced the lung fungal burden of infected rats in both therapeutic and prophylactic modalities. Thus, we extended the protective activity of PTX3 in pulmonary aspergillosis to corticosteroid-induced immunodeficiency, which is a relevant clinical condition in graft-versus-host disease and in solid organ transplant.

Istaroxime: a new luso-inotropic agent for heart failure.

Istaroxime is a new luso-inotropic compound selected for the treatment of acute heart failure syndromes, which reduces sodium-potassium adenosine triphosphatase (ATPase) activity and stimulates the sarcoplasmic calcium ATPase isoform 2 reuptake function. The aim of this study was to evaluate the safety profile of istaroxime. For this purpose, istaroxime was administered during a 24-hour infusion to conscious dogs with chronic heart failure and to genetically cardiomyopathic BIO TO.2 hamsters for 34 weeks orally. The parameters recorded were arrhythmic events and hemodynamic effects in dogs and mortality in hamsters. In dogs, istaroxime at 1, 3, and 4 microg/kg per min did not trigger arrhythmic events or magnify preexisting events. It increased left ventricular (LV) dP/dtmax (about 50% at 3 microg/kg per min) and LV-dP/dtmax (about 20% at 3 microg/kg per min) without changing heart rate, blood pressure, or double product. At 4 microg/kg per min, istaroxime increased dP/dtmax>100% but induced intense emesis in all animals. In cardiomyopathic hamsters, the dose of 30 mg/kg prolonged the survival rate to 32%. In conclusion, istaroxime seems to be a promising and safe new drug for improving cardiac performance in the failing heart.

Acetyl-L-Carnitine prevents and reverts experimental chronic neurotoxicity induced by oxaliplatin, without altering its antitumor properties.

BACKGROUND: Oxaliplatin (OHP) is severely neurotoxic and induces the onset of a disabling sensory peripheral neuropathy. Acetyl-L-carnitine (ALC), a natural compound with neuroprotective action, was tested to determine whether it plays a protective role in OHP-induced neuropathy. MATERIALS AND METHODS: Peripheral neuropathy was induced in Wistar rats, and the effect of OHP alone or in combination with ALC was assessed, using behavioral and neurophysiological methods. Moreover, ALC interference on OHP antitumor activity was investigated using several in vitro and in vivo models. RESULTS: ALC-co-treatment reduced the neurotoxicity of OHP when it was coadministered. Furthermore, the administration-of OHP, once OHP-induced neuropathy was established, significantly mitigated its severity. Finally, experiments in different tumor systems indicated that ALC does not interfere with the antitumor effects of OHP. CONCLUSION: ALC is effective in the prevention and treatment of chronic OHP-induced peripheral neurotoxicity in an experimental rat model.

Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine.

PURPOSE: Antineoplastic drugs belonging to platinum or taxane families are severely neurotoxic, inducing the onset of disabling peripheral neuropathies with different clinical signs. Acetyl-L-carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. In this study we have tested the hypothesis that ALC may have a protective role on cisplatin and paclitaxel-induced neuropathy. EXPERIMENTAL DESIGN: Sensory nerve conduction velocity (SNCV) was measured in rats before, at end, and after an additional follow-up period from treatments with cisplatin, paclitaxel, or with the respective combination with ALC. In addition, serum from treated animals was collected to measure the levels of circulating NGF, and left sciatic nerves were processed for light and electron microscope observations. ALC interference on cisplatin and paclitaxel antitumor activity and protective mechanisms were investigated using several in vitro and in vivo models. RESULTS: ALC cotreatment was able to significantly reduce the neurotoxicity of both cisplatin and paclitaxel in rat models, and this effect was correlated with a modulation of the plasma levels of NGF in the cisplatin-treated animals. Moreover, experiments in different tumor systems indicated the lack of interference of ALC in the antitumor effects of cisplatin and paclitaxel. The transcriptional profile of gene expression in PC12 cells indicated that ALC, in the presence of NGF, was able to positively modulate NGFI-A expression, a gene relevant in the rescue from tissue-specific toxicity. Finally, the transcriptionally ALC-mediated effects were correlated to increase histone acetylation. CONCLUSION: In conclusion, our results indicate that ALC is a specific protective agent for chemotherapy-induced neuropathy after cisplatin or paclitaxel treatment without showing any interference with the antitumor activity of the drugs.

Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction.

BACKGROUND: Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery. METHODS AND RESULTS: We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial ß-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of ß-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction. CONCLUSION: PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial ß-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. Antioxidant therapy and pharmacological targeting of endothelial dysfunction may represent a promising tool for the treatment of delayed wound healing or chronic ulcers.

Autonomic neuropathy in streptozotocin diabetic rats: effect of acetyl-L-carnitine.

The present study was designed to characterize cardiac autonomic neuropathy in streptozotocin-induced (45 mg/kg i.v.) diabetic rat by analysis of heart rate variability (HRV), and to assess, in this model, the effects of treatment with acetyl-L-carnitine (ALC). Heart rate was reduced in diabetic rats (332+/-22 vs. 411+/-35 beat per min; P<0.0001). This bradycardia was partly reversed with ALC (369+/-52 beat per min; P<0.05 vs. untreated). Both time- and frequency-domain parameters of HRV were significantly reduced in diabetic rats. The reduction of spectral power was around 50% at high frequencies and about 70% at low frequencies, suggesting a decrease of parasympathetic activity. Low/high frequency ratio was significantly decreased in diabetic rats suggesting decreased sympathetic tone, while nonlinear analysis indicated a reduction of the chaotic complexity of heart rate dynamics in diabetic rats. Standard deviation of heart rate in ALC-treated rats was significantly higher than in untreated diabetic rats (P<0.0001). ALC counteracts the reduction of the power spectrum observed in diabetic animals (P<0.0005) normalizing the spectra profile. ALC restored chaotic complexity of heart rate dynamics. These results on the whole indicate that both sympathetic and parasympathetic cardiac tone were reduced significantly in diabetic rats and that ALC treatment prevents the development of autonomic neuropathy in streptozotocin-induced diabetes in rats.

Preclinical thalassemic cardiopathy: a study by acoustic densitometry.

BACKGROUND: The cardiac function in thalassemia major has never been studied at ultrasonic backscatter techniques. We assessed the utility of acoustic densitometry in thalassemic patients without clinical or echocardiographic signs of heart failure. METHODS: Three groups of subjects with comparable age, sex and body surface area were analyzed: 25 with beta-thalassemia major (group A), 14 with thalassemia intermedia (group B) and 10 healthy subjects (group C). All patients were asymptomatic and without conventional echocardiographic signs of systo-diastolic dysfunction. The left ventricular mass and volumes were echocardiographically evaluated. The ultrasonic myocardial integrated backscatter signal (IBS) was recorded and analyzed by means of acoustic densitometry in the parasternal long-axis view at the septum and posterior wall, both at the basal and intermediate levels. Both the average image intensity and the systo-diastolic variations of the IBS (cyclic variation index-CVIibs and peak-to-peak intensity-PPI), respectively related to the structure and contractility of the myocardium, were calculated. The serum ferritin and liver iron concentrations were also measured, as markers of tissue iron storage. RESULTS: The CVIibs was significantly lower in groups A and B than in group C at basal (22.7 +/- 8.4 vs 22.1 +/- 7.8 vs 31.8 +/- 10.2%; p = 0.001) and intermediate septum (24.4 +/- 7.6 vs 25.3 +/- 8.1 vs 30 +/- 9.8%; p = 0.03) and at basal (25.9 +/- 7.6 vs 24.5 +/- 6.1 vs 31.1 +/- 10.6%; p = 0.02) and intermediate posterior wall (25.1 +/- 5.1 vs 24.3 +/- 6.2 vs 30.2 +/- 6.6%; p = 0.02). The PPI was also significantly lower in groups A and B than in group C. Both CVIibs and PPI were comparable in groups A and B. The average image intensity and left ventricular mass and volumes were not significantly different in the three groups. No correlation was found between the densitometric findings and markers of tissue iron storage. CONCLUSIONS: In asymptomatic patients with thalassemia major with normal conventional indexes of systo-diastolic cardiac function, acoustic densitometry may show a reduced cyclic variation of the IBS as a possible marker of initial myocardial contractile deficiency. On the contrary, neither structural alterations nor the extent of myocardial iron stores are detectable by this technique in this type of patients.