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Hu J.,Johnnie chran Jr Brain Tumor Center | Wen P.Y.,Dana-Farber Cancer Institute | Abrey L.E.,University of Zurich | Fadul C.E.,Dartmouth Hitchcock Medical Center | And 4 more authors.
Journal of Neuro-Oncology | Year: 2013

Gimatecan is a lipophilic oral camptothecin analogue with preclinical activity in glioma models. We conducted a multicenter phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, Eastern Cooperative Oncology Group performance status 0-1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m2 was given orally once daily for 5 consecutive days during each 28-day cycle. The primary endpoint was progression-free survival at 6 months. A Simon 2-stage optimal design was used in which 19 patients were evaluated in the 1st stage, with an additional 36 patients accrued if >4 patients in stage 1 achieved PFS at 6 months. 29 patients were enrolled in the study, with median age of 58 years (range, 25-77 years); 58.6 % female. All patients received prior surgery, radiation therapy, and at least one chemotherapy regimen. The daily dose was reduced to 1.0 mg/m2 after four of the first 10 patients experienced grade 4 hematologic toxicity. Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2 %), leukopenia (17.2 %) and neutropenia (10.3 %). None of the 19 patients treated at 1.0 mg/m2/day experienced grade 4 hematologic toxicity. One patient had a partial radiographic response by modified Macdonald criteria. Only 3 patients (12 %) were progression-free at 6 months. Median time to progression was 12.0 weeks (7.0, 17.0).Treatment with gimatecan 1.0 mg/m2/day for 5 days, repeated every 28-days showed minimal efficacy. © 2012 Springer Science+Business Media New York.

Virmani A.,Sigma-Tau Pharmaceuticals | Ali S.F.,Neurochemistry Laboratory | Binienda Z.K.,U.S. Food and Drug Administration
Annals of the New York Academy of Sciences | Year: 2010

Encephalopathy is evidenced as an altered mental state with various neurological symptoms, such as memory and cognitive problems. The type of a substance-evoked encephalopathy will depend on the drug, substance, or combination being abused. The categories into which we could place the various abused substances could be tentatively divided into stimulants, amphetamines, hallucinogens, narcotics, inhalants, anesthetics, anabolic steroids, and antipsychoticsantidepressants. Other factors that may underlie encephalopathy, such as infectious agents, environmental, and other factors have also to be taken into account. Drugs of abuse can be highly toxic to the CNS following acute, but more so in chronic exposure, and can produce significant damage to other organs, such as the heart, lungs, liver, and kidneys. The damage to these organs may be at least partially reversible when drug abuse is stopped but CNS damage from repeated or prolonged abuse is often irreversible. The major pathways for the organ and CNS toxicity could be related to ischemic events as well as increased cell damage due to metabolic or mitochondrial dysfunction resulting in increased excitotoxicity, reduced energy production, and lowered antioxidant potential. These susceptibilities could be strengthened by the use of antioxidants to combat free radicals (e.g., vitamin E, lipoic acid); trying to improve energy generation by using mitochondriotropicmetabolic compounds (e.g., thiamine, coenzyme Q10, carnitine, riboflavin); by reducing excitotoxicity (e.g., glutamate antagonists) and other possible strategies, such as robust gene response, need to be investigated further. The drug-abuse-evoked encephalopathy still needs to be studied further to enable better preventative and protective strategies. © 2010 New York Academy of Sciences.

Palermo V.,University of Rome La Sapienza | Falcone C.,University of Rome La Sapienza | Calvani M.,Sigma-Tau Pharmaceuticals | Mazzoni C.,University of Rome La Sapienza
Aging Cell | Year: 2010

In this work we report that carnitines, in particular acetyl-L-carnitine (ALC), are able to prolong the chronological aging of yeast cells during the stationary phase. Lifespan extension is significantly reduced in yca1 mutants as well in rho 0 strains, suggesting that the protective effects pass through the Yca1 caspase and mitochondrial functions. ALC can also prevent apoptosis in pro-apoptotic mutants, pointing to the importance of mitochondrial functions in regulating yeast apoptosis and aging. We also demonstrate that ALC attenuates mitochondrial fission in aged yeast cells, indicating a correlation between its protective effect and this process. Our findings suggest that ALC, used as therapeutic for stroke, myocardial infarction and neurodegenerative diseases, besides the well-known anti-oxidant effects, might exert protective effects also acting on mitochondrial morphology.

August K.J.,Childrens Mercy Hospital | Miller W.P.,University of Minnesota | Dalton A.,Childrens Mercy Hospital | Shinnick S.,Sigma-Tau Pharmaceuticals
Journal of Pediatric Hematology/Oncology | Year: 2013

INTRODUCTION:: Polyethylene-glycolated (PEG)-asparaginase (PEG-ASP) is a crucial component of pediatric acute lymphoblastic leukemia therapy. Although hypersensitivity reactions to PEG-ASP occur less frequently than with other formulations, they are not uncommon and have an adverse impact on patient outcomes. Intravenous (IV) administration of PEG-ASP reduces patient pain and anxiety and is being used with increasing frequency in children. MATERIALS AND METHODS:: A retrospective review was performed to compare the incidence of hypersensitivity reactions to PEG-ASP in children when administered either by intramuscular (IM) or IV routes between January 2006 and May 2008. RESULTS:: Of 68 patients studied, 7 experienced a hypersensitivity reaction (10.3%). Two of 16 patients (12.5%) who received only IV PEG-ASP and 3 of 27 patients (11.1%) exposed to only IM PEG-ASP experienced a hypersensitivity reaction. Severe reactions (grade 3 or 4) occurred only once after 119 total doses (0.8%) of IV PEG-ASP and once after 215 total doses (0.5%) of IM PEG-ASP (P=1.0). Thrombosis or pancreatitis were rare and were not increased after IV PEG-ASP administration. DISCUSSION:: IV PEG-ASP is well tolerated and does not result in a significant increase in the incidence of hypersensitivity reactions in children. Copyright © 2013 by Lippincott Williams & Wilkins.

Sigma-Tau Pharmaceuticals | Date: 2014-02-27

Pharmaceutical preparations for the prevention and treatment of disorders of the nervous system, the immune system, the cardio-vascular system including diabetes and metabolic diseases, the respiratory system, the musculoskeletal system, the genitourinary system, for the treatment of inflammatory disorders, for use in dermatology, in haematology, in oncology in transplantation, in ophthalmology, for use in the gastroenterological areas and the prevention and treatment of ocular disorders or diseases, anti-infectives, pharmaceutical preparations treating bacterial-bases disease, antivirals, anti-biotics, antifungals, vaccines, diagnostic preparations for medical use.

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