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Toronto, Canada

Bolger G.T.,Nucro Technics
Biochemical Pharmacology

From the fall of 1978 until the summer of 1982, I was a graduate student in the Laboratory of Dr. David Triggle in the Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo. This contribution permits me the opportunity to take you back in time into David's laboratory and tell you the story of how my early research career was borne and to provide a glimpse into some of the accomplishments that David, I and my fellow graduates students made. The central theme of my research was to bring together the many events that controlled the contraction of Guinea-pig ileal longitudinal muscle, from the binding of muscarinic agonists, the movement of mono- and divalent cations that control depolarization to contraction itself and the differences between muscarinic and non-muscarinic mediated contraction and tachyphylaxis. From these studies, we were able to provide concrete data supporting a fluid muscarinic receptor-effector coupling model that challenged the concept of spare receptors. We also were able to develop methods to quantitate the binding sites for dihydropyrine calcium channel antagonists thereby opening the door to a flood of studies that furthered our understanding of these clinically employed drugs, providing a new target to elucidate the mechanism(s) of action of drugs that act outside of and within the central nervous system. © 2015 Elsevier Inc. Source

Storka A.,Medical University of Vienna | Vcelar B.,Polymun Scientific Immunbiologische Forschung GmbH | Klickovic U.,Medical University of Vienna | Gouya G.,Medical University of Vienna | And 5 more authors.
International Journal of Clinical Pharmacology and Therapeutics

Introduction: Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects. Material and methods: 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 - 400 mg/m2; n = 2 - 6 per group) or placebo over 2 hours intravenously. Results: Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 - 60 minutes below the limit of quantification. Mean urinary excretion was 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages = 120 mg/m2. Conclusion: Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity. © 2015 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965. Source

Alipour M.,Lakehead University | Smith M.G.,Amaox Ltd | Pucaj K.,Nucro Technics | Suntres Z.E.,Lakehead University
Journal of Liposome Research

Liposomes have been used for the delivery of antioxidants to different tissues and organs for the treatment of oxidative stress-induced injuries. In this study, the acute toxicity of a single dose of intravenously (i.v.) administered liposomal antioxidant formulation, containing N-acetylcysteine (NAC) with or without α-tocopherol (α-T) or γ-tocopherol (γ-T), in rats was examined. Each group consisted of 5 male and 5 female Sprague-Dawley rats, with a control group receiving empty dipalmitoylphosphatidylcholine (DPPC) liposomes (660 mg/kg) and test groups receiving DPPC liposomes (660 mg/kg) entrapped with 1) NAC (200 mg/kg), 2) NAC (200 mg/kg) and α-T (83.3 mg/kg), and 3) NAC (200 mg/kg) and γ-T (71.4 mg/kg). These dose levels were determined from the dose-rangefinding study and were considered to be the maximum feasible dose (MFD) levels, based on the volume of 10 mL/kg and physical properties and viscosity of the test articles that could be safely administered to rats by an i.v. injection. Two weeks after treatment (day 15), rats in the control group and three test groups exhibited no clinical signs of toxicity during the dosing period or during the 14-day post-treatment period. Weight gain and food consumption in all animals was appropriate for the age and sex of animals. Clinical pathology findings (e.g., hematology, coagulation, clinical chemistry, and urinalysis) were unremarkable in all rats and in all groups. In conclusion, the results of this study showed no treatment-related toxicity in rats at the MFD level by a single bolus i.v. administration. © 2012 Informa Healthcare USA, Inc. Source

Alipour M.,Lakehead University | Pucaj K.,Nucro Technics | Smith M.G.,Amaox Ltd | Suntres Z.E.,Lakehead University
Drug and Chemical Toxicology

Ricin toxin A chain (RTA) is the cytotoxic component of the dimeric protein, ricin, one of the most potent and deadly plant toxins extracted from the seeds of Ricinus communis. RTA has been investigated as a potential candidate for cancer chemotherapy, in the form of immunotoxins, and as a method for depleting macrophages in vivo. The toxicity of RTA immunotoxins is mostly characterized by inflammation and necrosis and has been attributed to the RTA moiety of the conjugate. The present study was carried out to investigate the toxicity of intravenously (i.v.) administered RTA alone and to assess whether the observed tissue injuries are associated with increases in oxidative stress (OS) and inflammation. RTA (10 or 90 g/kg body weight) was administered to animals i.v., and 5 or 24 hours later, liver, lungs, kidneys, and hearts were examined. RTA, at a dose of 90 g/kg (i.v.), resulted in significant increases (P < 0.05) in an inflammatory response (i.e., increases in hepatic and lung myeloperoxidase activity) and increases in oxidant response (increases in lipid peroxidation and decreases in glutathione levels in hepatic and lung homogenates). These data suggest that i.v. administration of RTA resulted in organ injuries that were associated with inflammation and OS. © 2013 Informa Healthcare USA, Inc. Source

Grenfell-Lee D.,Microbia | Zeller S.,Microbia | Zeller S.,Unilever | Cardoso R.,Nucro Technics | Pucaj K.,Nucro Technics
Food and Chemical Toxicology

Crystalline β-carotene from genetically modified Yarrowia lipolytica is an alternative source of β-carotene for use as a nutritional supplement. To support the use of β-carotene from Y. lipolytica as a food ingredient, the genotoxic and subchronic toxicity potential of this compound was determined. Genotoxicity was examined using Salmonella typhimurium and Escherichia coli (Ames test), a chromosomal aberration assay in Chinese Hamster Ovary WBL cells, and the micronucleus test in CD-1 mice. All three assays showed no significant results due to β-carotene from Y. lipolytica. In a subchronic toxicity study in SD rats, β-carotene from Y. lipolytica was administered by oral gavage for 13. weeks at 0, 125, 250 or 500. mg/kg per day. Adverse effects were not observed following clinical, clinical pathology and gross- and histopathological evaluations of dosed rats; thus, the no-observed-adverse effect level (NOAEL) for β-carotene from Y. lipolytica was 500. mg/kg, the highest dose used in the study. In conclusion, β-carotene derived from Y. lipolytica was shown in genotoxicity models and a standard rat subchronic rat study to have a safety profile similar to that of the current commercial products (synthetic and natural) with no unexpected finding attributable to the alternative source. © 2013 Elsevier Ltd. Source

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