Accelera Srl

Nerviano, Italy

Accelera Srl

Nerviano, Italy
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Longo M.,Accelera S.r.l. | Zanoncelli S.,Accelera S.r.l. | Colombo P.A.,Accelera S.r.l. | Harhay M.O.,University of Pennsylvania | And 5 more authors.
Reproductive Toxicology | Year: 2013

Filarial diseases affect millions of people in poverty-stricken areas. In 2011, an investigation of the potential of flubendazole as a safe, highly efficacious, and field-usable macrofilaricidal drug was begun by DND. i.As part of the preclinical development program, whole embryo culture was used to investigate the potential embryotoxicity of flubendazole and its metabolites, reduced and hydrolyzed flubendazole. Albendazole was included as a comparator.Flubendazole and albendazole showed similar potency in affecting rat embryonic development in vitro, inducing retardation of growth and dysmorphogenic effects at concentrations ≥0.5. μg/mL. The head, optic and otic systems, branchial arches and posterior body portion were affected. Diffuse areas of cell death were seen in various embryonic districts. The No Observed Effect Level (NOEL) was 0.25. μg/mL for both drugs.Reduced and hydrolyzed flubendazole were less embryotoxic than the parent compound, with NOELs 4-fold and >40-fold higher than that of flubendazole, respectively. © 2013 Elsevier Inc.

Longo M.,Accelera S.r.l. | Zanoncelli S.,Accelera S.r.l. | Messina M.,Accelera S.r.l. | Scandale I.,DND Drug for Neglected Diseases | And 5 more authors.
Reproductive Toxicology | Year: 2014

Flubendazole, in a new formulation with high systemic bioavailability, has been proposed as a macrofilaricide against filarial diseases.To investigate embryotoxic activity, the new flubendazole formulation was administered orally to Sprague Dawley rats at 2, 3.46, 6.32. mg/kg/day on gestation day (GD) 9.5 and 10.5. Embryos/fetuses were evaluated on GD 11.5, 12.5 or 20.At 6.32mg/kg/day (Cmax=0.801μg/mL after single administration), flubendazole initially induced an arrest of embryonic development followed by a generalized cell death that led to 100% embryolethality by GD 12.5.At 3.46mg/kg/day (Cmax=0.539μg/mL after single administration), flubendazole markedly reduced embryonic development by GD 12.5 without causing cell death. On GD 20, 80% of fetuses showed malformations.At 2mg/kg/day (Cmax=0.389μg/mL after single administration), it did not interfere with rat embryofetal development. © 2014 Elsevier Inc.

Repetto-Llamazares A.H.V.,Nordic Nanovector AS | Repetto-Llamazares A.H.V.,University of Oslo | Larsen R.H.,Sciencons Ltd. | Giusti A.M.,Accelera Srl | And 4 more authors.
PLoS ONE | Year: 2014

Background: CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA- HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studieswith 177Lu-HH1. Methodology/Principal Findings: Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group. Conclusions/Significance: 177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients. © 2014 Repetto-Llamazares et al.

Germani M.,Accelera S.r.l. | Del Bene F.,Accelera S.r.l. | Poggesi I.,Janssen Pharmaceutical | Magni P.,University of Pavia | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: Pharmacokinetic-pharmacodynamic (PK-PD) models able to predict the action of anticancer compounds in tumor xenografts have an important impact on drug development. In case of anti-angiogenic compounds, many of the available models show difficulties in their applications, as they are based on a cell kill hypothesis, while these drugs act on the tumor vascularization, without a direct tumor cell kill effect. For this reason, a PK-PD model able to describe the tumor growth modulation following treatment with a cytostatic therapy, as opposed to a cytotoxic treatment, is proposed here. Methods: Untreated tumor growth was described using an exponential growth phase followed by a linear one. The effect of anti-angiogenic compounds was implemented using an inhibitory effect on the growth function. The model was tested on a number of experiments in tumor-bearing mice given the anti-angiogenic drug bevacizumab either alone or in combination with another investigational compound. Nonlinear regression techniques were used for estimating the model parameters. Results: The model successfully captured the tumor growth data following different bevacizumab dosing regimens, allowing to estimate experiment-independent parameters. A combination model was also developed under a 'no-interaction' assumption to assess the effect of the combination of bevacizumab with a target-oriented agent. The observation of a significant difference between model-predicted and observed tumor growth curves was suggestive of the presence of a pharmacological interaction that was further accommodated into the model. Conclusions: This approach can be used for optimizing the design of preclinical experiments. With all the inherent limitations, the estimated experiment-independent model parameters can be used to provide useful indications for the single-agent and combination regimens to be explored in the subsequent development phases. © 2013 Springer-Verlag Berlin Heidelberg.

Consalvi S.,IRCCS Fondazione Santa Lucia | Mozzetta C.,IRCCS Fondazione Santa Lucia | Bettica P.,Italfarmaco SpA | Germani M.,Accelera SpA | And 9 more authors.
Molecular Medicine | Year: 2013

Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice-the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.

Longo M.,Accelera S.r.l. | Torre P.D.,Accelera S.r.l. | Allievi C.,CTI Expert Consultant | Morisetti A.,CTI Expert Consultant | And 2 more authors.
Reproductive Toxicology | Year: 2014

The tolerability of pixantrone dimaleate (Pixuvri®), an aza-anthracenedione for non-Hodgkin lymphoma, was assessed in juvenile mice after intraperitoneal injection. Twenty animals/sex/dose received pixantrone 15 or 27. mg/kg/day on Post-Natal-Days (PND) 10, 13, 17, 20, 35, 39 and 42 in comparison with doxorubicin, 3. mg/kg/day. Animals were sacrificed on PND 42, 73 and 96.All pixantrone animals survived, while doxorubicin induced 52.5% mortality and the surviving animals were sacrificed early due to severe toxicity. Recoverable bone marrow toxicity (pixantrone), and toxicity to thymus and reproductive organs (pixantrone, doxorubicin) were observed without nephro- or hepatotoxicity. Pixantrone was measurable in plasma up to 2h (occasionally 6h) post-dose. At PND 42, mean Cmax and AUC values increased proportionally with dose, without gender difference or accumulation.Pixantrone showed minimal cardiotoxicity in males and negligible in females at PND 96. Doxorubicin induced significant heart weight reduction at PND 42, however early sacrifice impeded further cardiac assessments. © 2014 Elsevier Inc.

Palmieri C.,University of Queensland | Riccardi E.,Accelera S.r.l.
Journal of Comparative Pathology | Year: 2013

Homeobox genes are known to be examples of the intimate relationship between embryogenesis and tumourigenesis. Specifically, the HOXA13 gene plays a fundamental role in the development of the urogenital tract and external genitalia and in prostate organogenesis. There are no reports on the expression of HOXA13 in normal, hyperplastic or neoplastic canine prostate tissue or in other types of tumours. Six normal, 16 hyperplastic and 12 neoplastic canine prostates were examined microscopically and immunohistochemically with a polyclonal antibody specific for human HOXA13. An immunohistochemical score was generated. HOXA13 was expressed in the cytoplasm of epithelial cells in normal, hyperplastic and neoplastic prostates. The percentage of immunolabelled cells in all prostatic carcinomas (PCs) was greatly increased, with a score of 85.3 (±5.25) compared with normal (2±0.71) and hyperplastic prostates (6.08±2.21). The increase in HOXA13 expression in canine PCs suggests the involvement of this transcription factor in carcinogenesis and promotion of tumour growth. © 2013 Elsevier Ltd.

Breda M.,Accelera S.r.l. | Baratte S.,Accelera S.r.l.
Analytical and Bioanalytical Chemistry | Year: 2010

5-Fluorouracil (5-FU) is a cytostatic agent that has been widely used in the treatment of various solid tumours for more than 20 years, and is still considered to be among the most active antineoplastic agents in advanced colorectal cancer and malignancies of the head and neck. A large number of non-chromatographic and chromatographic methods for the quantitation of 5-FU, related prodrugs and their metabolites in biological matrices have been developed in the last 30 years to support preclinical and clinical studies. However, 5-FU monitoring has not been widely used, at least not in the USA, and certainly not outside the clinical research setting, given the absence of simple, fast and inexpensive testing methods for 5-FU monitoring. Recent developments with testing based on liquid chromatography-tandem mass spectrometry and a nanoparticle antibody-based immunoassay may facilitate routine monitoring of 5-FU in daily clinical practice. In this review the advantages and disadvantages of the bioanalytical methods developed and used for 5-FU, its metabolites and related prodrugs are discussed. © Springer-Verlag 2010.

Germani M.,Accelera S.r.l. | Del Bene F.,Accelera S.r.l. | Rocchetti M.,Accelera S.r.l. | Van Der Graaf P.H.,Pfizer
Computer Methods and Programs in Biomedicine | Year: 2013

Effective communication of PK/PD principles and results in a biomedical research environment remains a significant challenge which can result in lack of buy-in and engagement from scientists outside the modeling and simulation communities. In our view, one of the barriers in this area is a lack of user-friendly tools which allow " non experts" to use PK/PD models without the need to develop technical skills and expertise in advanced mathematical principles and specialist software. The costs of commercial software may also prevent large-scale distribution. One attempt to address this issue internally in our research organizations has resulted in the development of the A4S (" Accelera for Sandwich" ) software, which is a simple-to-use, menu-drive Matlab-based PK/PD simulator targeted at biomedical researchers with little PK/PD experience. © 2012 Elsevier Ireland Ltd.

Magni P.,University of Pavia | Terranova N.,University of Pavia | Del Bene F.,Accelera Srl | Germani M.,Accelera Srl | De Nicolao G.,University of Pavia
IEEE Transactions on Biomedical Engineering | Year: 2012

One important issue in the preclinical development of an anticancer drug is the assessment of the compound under investigation when administered in combination with other drugs. Several experiments are routinely conducted in xenograft mice to evaluate if drugs interact or not. Experimental data are generally qualitatively analyzed on empirical basis. The ability of deriving from single drug experiments a reference response to the joint administrations, assuming no interaction, and comparing it to real responses would be key to recognize synergic and antagonist compounds. Therefore, in this paper, the minimal model of tumor growth inhibition (TGI), previously developed for a single drug, is reformulated to account for the effects of noninteracting drugs and simulate, under this hypothesis, combination regimens. The model is derived from a minimal set of basic assumptions that include and extend those formulated at cellular level for the single drug administration. The tumor growth dynamics is well approximated by the deterministic evolution of its expected value that is obtained through the solution of an ordinary and several partial differential equations. Under suitable assumptions on the cell death process, the model reduces to a lumped parameter model that represents the extension of the very popular Simeoni TGI model to the combined administration of noninteracting drugs. © 2012 IEEE.

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