Nucro Technics

Toronto, Canada

Nucro Technics

Toronto, Canada
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Alipour M.,Lakehead University | Alipour M.,Laurentian University | Buonocore C.,Lakehead University | Omri A.,Laurentian University | And 4 more authors.
Journal of Drug Targeting | Year: 2013

Background: Acetaminophen (APAP) is an antipyretic analgesic drug that when taken in overdose causes depletion of glutathione (GSH) and hepatotoxicity. N-acetylcysteine (NAC) is the antidote of choice for the treatment of APAP toxicity; however, due to its short-half-life repeated dosing of NAC is required. Purpose: To determine whether a NAC-loaded liposomal formulation (Lipo-NAC) is more effective than the conventional NAC in protecting against acute APAP-induced hepatotoxicity. Methods: Male Sprague-Dawley rats were challenged with an intragastric dose of APAP (850mg/kg b.wt.); 4h later, animals were administered saline, NAC, Lipo-NAC or empty liposomes and sacrificed 24h post-APAP treatment. Results: APAP administration resulted in hepatic injury as evidenced by increases in plasma bilirubin, alanine (AST) and aspartate (ALT) aminotransferase levels and tissue levels of lipid peroxidation and myeloperoxidase as well as decreases in hepatic levels of reduced GSH, GSH peroxidase and GSH reductase. Treatment of animals with Lipo-NAC was significantly more effective than free NAC in reducing APAP-induced hepatotoxicity. Histological evaluation showed that APAP caused periacinar hepatocellular apoptosis and/or necrosis of hepatocytes around the terminal hepatic venules which was reduced by NAC treatment, the degree of reduction being greater for Lipo-NAC. Conclusion: These data suggest that administration of Lipo-NAC ameliorated the APAP-induced hepatotoxicity. © 2013 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.

Buonocore C.,Lakehead University | Alipour M.,Laurentian University | Omri A.,Laurentian University | Pucaj K.,Nucro Technics | And 3 more authors.
Journal of Drug Targeting | Year: 2011

Background: The toxicity of ricin resides in the ricin A-chain (RTA) and is attributed to the inhibition of protein synthesis but inflammation and oxidative stress have also been implicated. RTA can independently enter cells producing comparable tissue injury and inflammation, although at much higher concentrations than intact ricin. Treatment for exposure to ricin or RTA is supportive. Purpose: To examine the effectiveness of conventional or liposome-encapsulated N-acetylcysteine (Lipo-NAC) in ameliorating RTA-induced hepatotoxicity. Methods: Four hours after RTA administration (90 g/kg b.wt, iv), rats were treated with conventional NAC or Lipo-NAC (25mg/kg NAC). The hepatoprotective effects of the antioxidant formulations were assessed by measuring indexes for liver injury (alanine [ALT] and aspartate [AST] aminotransferase activities), inflammation (myeloperoxidase, tumor necrosis factor-α, chloramine levels), and oxidant response (lipid peroxidation, nitrotyrosine, glutathione levels) 24-h post-RTA exposure. Results: Administration of RTA to animals resulted in hepatotoxicity as demonstrated by elevated plasma ALT and AST levels, increases in an inflammatory response, and increases in oxidant response. Treatment of animals with the antioxidant formulations reversed the RTA-induced hepatotoxicity, being most evident following the administration of Lipo-NAC. Conclusion: NAC, administered in a liposomal form, may serve as a potentially effective pharmacological agent in the treatment of RTA-induced liver injuries. © 2011 Informa UK, Ltd.

Matabudul D.,Nucro Technics | Pucaj K.,Nucro Technics | Bolger G.,Nucro Technics | Vcelar B.,Immunbiologische Forschung GmbH | And 2 more authors.
Anticancer Research | Year: 2012

This study interrogated whether different durations of intravenous infusions of lipocurc™ would alter curcumin metabolism, tissue distribution and whether treating necropsied tissues of Beagle dogs with phosphoric acid prior to measuring curcumin and its metabolite, tetrahydrocurcumin (THC), would stabilize the compounds allowing for accurate analytic measurements. Two cohorts comprising two male and two female dogs were infused each intravenously with 10 mg/kg lipocurc™, either over two hours or over eight hours. Tissue data from each cohort was averaged from four dogs. Curcumin and THC distributed among all 13 tissues were examined at necropsy. The highest curcumin level was observed in the lungs followed by the liver. Tissue levels of curcumin in the lung, spleen and liver increased substantially following the eight-hour infusion compared to the two-hour infusion. The pancreas, kidney and urinary bladder also contained relatively high curcumin levels. Tissue partition coefficients for curcumin and THC were also higher for the eight-hour infusion than the twohour infusion. The tissue THC/curcumin ratio varied in a tissuespecific manner and was lower for the eight-hour compared to the two-hour infusion. In conclusion, this raised the possibility that prolonged infusion of curcumin may facilitate distribution into tissues via a transporter-dependent mechanism and elevated tissue concentrations of curcumin may inhibit or saturate a putative reductase enzyme converting curcumin to THC. The addition of phosphoric acid stabilized the levels of curcumin and THC in some but not all the examined tissues, raising issues of tissue-specific curcumin and THC stability.

Helson L.,Signpath Pharma | Bolger G.,Nucro Technics | Majeed M.,Sabinsa Corporation | Vcelar B.,Polymun Scientific | And 2 more authors.
Anticancer Research | Year: 2012

Curcumin's instability and its metabolite, tetrahydrocurcumin (THC) pose a major issue for the establishment of dependable pharmacokinetics and excretion profiles. Additional pharmacokinetic variances are associated with durations of intravenous infusions. We found that stabilizing curcumin with phosphoric acid allows accurate quantitative determinations of curcuminoids in the plasma and bile, by preventing degradation during the analytical processes. Two male and two females dogs were infused with Lipocurc™ 10 mg/kg over two hours, and another four dogs (two males and two females) were infused with Lipocurc™ 10 mg/kg over eight hours. Plasma levels of curcumin and THC were determined during the infusions and at necropsy. THC levels were 6.3-9.6-fold higher than curcumin during both infusion rates, suggesting a combination of a high-rate of enzymatic curcumin metabolism and a comparatively slower rate of blood THC clearance. When levels of curcumin and THC were compared during infusion durations, the two-hour infusion levels were significantly higher than the eight-hour infusion. The plasma half-lives of both compounds following the two-hour infusion ranged from 0.4-0.7 hours, and was a consequence of both hepatic and renal clearance However, at higher plasma concentrations renal excretion predominated, particularly with THC. Enhanced clearance rates were noted during eight-hour infusions, which prevented achieving a steady state. These observations suggest that for leukemias and lymphomas, the two-hour infusion may be advantageous based upon higher concentration profiles, and unstimulated clearance rates, however data on curcumin penetration into circulating hematopoietic cancer cells and efficacy data are required in order to confirm these suggestions.

PubMed | Nucro Technics, Shopp Nonclinical Consulting LLC and Signpath Pharma
Type: | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2016

Tetrahydrocurcumin (THC), a major metabolite of curcumin, is often quantified by LC-MS or LC-MS/MS using acidic mobile phases due to the concern of its instability in a basic medium. However, acidic mobile phases often lead to poor chromatography (e.g. split or double peaks) and reduced detection sensitivity in the commonly used negative ionization mode. To overcome these shortcomings, a basic mobile phase was used for the first time in the LC-MS/MS quantification of THC. In comparison with the acidic mobile phases, a single symmetrical chromatographic peak was obtained and the sensitivity increased by 7-fold or more under the equivalent conditions. The new LC-MS/MS method using the basic mobile phase has been successfully validated for the quantification of THC in human EDTA plasma over the concentration range of 5-2500ng/ml. The within-batch accuracy (% nominal concentration) was between 88.7 and 104.9 and the between-batch accuracy ranged from 96.7 to 108.6. The CVs for within- and between-batch precisions were equal to or less than 5.5% and 9.1%, respectively. No significant matrix interference or matrix effect was observed from normal or lipemic and hemolytic plasma matrices. In addition, the common stabilities with adequate durations were established, including up to 5days of post-preparative stability. Furthermore, when the validated method was applied to a clinical study, the passing rate of ISR samples was 83%, indicating the good reproducibility of the method. The success of the unconventional approach presented in this article demonstrates that a mobile phase could be selected based mainly on its merits to facilitate LC separation and/or MS detection. There is no need for excessive concern about the stability of the compound(s) of interest in the selected mobile phase because the run time of modern LC-MS or LC-MS/MS methods is typically only a few minutes.

PubMed | SD Scientific Inc., Nucro technics, Mississauga and Cynapsus Therapeutics
Type: Journal Article | Journal: Therapeutic delivery | Year: 2016

Determine the potential for cheek pouch buccal mucosa irritation in hamsters following administration of apomorphine hydrochloride film (APL-130277).Three studies were conducted with Syrian golden hamsters. (First study, four hamsters received APL-130277 three times a day [TID] for 7 days. Second study, four hamsters received APL-130277 once a day [QD] for days 1-3, twice a day [BID] for days 4-7 and TID for days 8-21. Third study, 32 hamsters received either a placebo strip or APL-130277-dosed TID for 28 days). For all the studies, the macroscopic appearance of the buccal cavities was evaluated throughout the study. In the third study, all animals were necropsied on day 29, and macroscopic and histopathological examinations were performed.In the first and second studies, the buccal mucosa of the cheek pouch did not show any signs of irritation. In the third study, administration of APL-130277-dosed TID for 28 consecutive days did not result in observable local irritation of the buccal mucosa.In all the studies, APL-130277 produced no irritation of the cheek pouch buccal mucosa.

Alipour M.,Lakehead University | Smith M.G.,Amaox Ltd | Pucaj K.,Nucro Technics | Suntres Z.E.,Lakehead University
Journal of Liposome Research | Year: 2012

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.

Grenfell-Lee D.,Microbia | Zeller S.,Microbia | Zeller S.,Unilever | Cardoso R.,Nucro Technics | Pucaj K.,Nucro Technics
Food and Chemical Toxicology | Year: 2014

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.

Bolger G.T.,Nucro Technics
Biochemical Pharmacology | Year: 2015

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.

PubMed | Nucro Technics
Type: | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2016

This paper presents the trouble-shooting for a very unusual stability case. Tetracaine was found unstable in neat solutions only at high concentrations, but not at low concentrations. Moreover, its stable-isotope labeled internal standard did not show similar behavior. A series of trouble-shooting experiments were conducted to uncover the root cause. Some generally applicable precautions/insights can be drawn from this investigation to avoid potential stability issues during bioanalytical method development and validation.

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