Publications by authors named "Neal M Davies"

136 Publications

Anti-Inflammatory Investigations of Extracts of .

Evid Based Complement Alternat Med 2021 6;2021:5512961. Epub 2021 Mar 6.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2P5, Canada.

has been consumed in the diet in northern Thailand and also used as a medicament in ancient scripture for arthropathies. Thus, this study aimed to evaluate the activity of various extracts from differential parts of via inhibition of inflammatory mediators (NO, TNF-, and PGE) in RAW264.7 macrophages. The chemical composition in active extracts was also analyzed by GC/MS. The parts of this plant studied were whole fruits (F), pericarp (P), and seed (O). The methods of extraction included maceration in hexane, 95% ethanol and 50% ethanol, boiling in water, and water distillation. The results demonstrated that the hexane and 95% ethanolic extract from pericarp (PH and P95) and seed essential oil (SO) were the most active extracts. PH and P95 gave the highest inhibition of NO production with IC as 11.99 ± 1.66 g/ml and 15.33 ± 1.05 g/ml, respectively, and they also showed the highest anti-inflammatory effect on TNF- with IC as 36.08 ± 0.55 g/ml and 34.90 ± 2.58 g/ml, respectively. PH and P95 also showed the highest inhibitory effect on PGE but less than SO with IC as 13.72 ± 0.81 g/ml, 12.26 ± 0.71 g/ml, and 8.61 ± 2.23 g/ml, respectively. 2,3-Pinanediol was the major anti-inflammatory compound analyzed in PH (11.28%) and P95 (19.82%) while terpinen-4-ol constituted a major anti-inflammatory compound in SO at 35.13%. These findings are the first supportive data for ethnomedical use for analgesic and anti-inflammatory activity in acute (SO) and chronic (PH and P95) inflammation.
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http://dx.doi.org/10.1155/2021/5512961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955865PMC
March 2021

Pharmacokinetics of piperine after oral administration of Sahastara remedy capsules in healthy volunteers.

Res Pharm Sci 2020 Oct 19;15(5):410-417. Epub 2020 Oct 19.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.

Background And Purpose: To investigate the pharmacokinetics of piperine after single oral doses of capsules containing Sahastara (SHT) remedy dried ethanolic extracts in healthy Thai volunteers.

Experimental Approach: Twenty-four healthy volunteers were divided into two dosage groups. They received a single oral dose of SHT remedy extract capsules of 100 or 200 mg. Blood was collected at time intervals of 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 h. Acute clinical safety was monitored by complete physical examination and laboratory tests during the study period. Piperine concentration in blood and urine was determined by liquid chromatography tandem-mass spectrometry.

Findings/results: No serious adverse events were detected, only one volunteer had abdominal pain that was self-limiting. The pharmacokinetics of piperine following SHT remedy extract capsule administration demonstrated a mean peak concentration (C) of piperine of 3.77 μg/mL and 6.59 μg/mL after dosing with 100 and 200 mg, respectively. Interestingly, a secondary maximum concentration of piperine was observed in this study, which might be related to enterohepatic recirculation. Negligible amounts of unchanged piperine were detected in urine.

Conclusion And Implication: The systemic exposure of piperine after SHT remedy ethanolic extract demonstrated dose proportionality after single oral dosing of 100-200 mg. Piperine was detectable in plasma for at least 48 h with evidence of enterohepatic recirculation. Metabolism and excretion profiles of piperine after administration of SHT remedy extract capsule need to be further explored for phytopharmaceutical product development.
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http://dx.doi.org/10.4103/1735-5362.297843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879788PMC
October 2020

Mechanistic understanding of underperforming enteric coated products: Opportunities to add clinical relevance to the dissolution test.

J Control Release 2020 09 7;325:323-334. Epub 2020 Jul 7.

Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Over the last 70 years several cases of in vivo failure of enteric coated (EC) formulations have been reported. The observed failures seem to be due to the slower than expected in vivo performance of EC products. Upon reaching the intestinal lumen, the dosage form is exposed to a bicarbonate buffered environment at much lower interfacial buffering capacity compared to those applied in compendial phosphate buffers. Hence, there is an urgent need to understand the behavior of EC products in bicarbonate buffer (BCB) and to revaluate the current dissolution methods used for such products. The current pilot study mechanistically investigated the performance of five EC products available in the Canadian market. The evaluated parameters were the buffer system (bicarbonate buffer vs. phosphate buffer), buffer capacity and medium pH. We hypothesized that the performance of EC products in BCB would be different compared with compendial phosphate buffer, giving more physiological insight, and that API properties would impact the dissolution behavior in BCB. The objective of this study was to examine the effect of the aforementioned parameters on the drug release applying physiologically relevant conditions (bicarbonate buffer at low molarities). A first step towards making the use of bicarbonate-based systems more feasible in a quality control setting is also reported. All formulations displayed a fast release in phosphate buffer and complied with the compendial performance specifications. On the other hand, they all had a much slower drug release in bicarbonate buffer and failed the USP acceptance criteria. Also, the nature of the drug (acid vs base) impacted the dissolution behavior in BCB. This pilot study indicates that compendial dissolution test for enteric coated tablets lacks physiological relevance and it needs to be reevaluated. Thus, an in vivo relevant performance method for EC products is needed.
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http://dx.doi.org/10.1016/j.jconrel.2020.06.031DOI Listing
September 2020

Phytocannabinoid drug-drug interactions and their clinical implications.

Pharmacol Ther 2020 11 30;215:107621. Epub 2020 Jun 30.

Faculty of Pharmacy & Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Edmonton, Alberta T6G 2E1, Canada. Electronic address:

Cannabis is a plant with a long history of human pharmacological use, both for recreational purposes and as a medicinal remedy. Many potential modern medical applications for cannabis have been proposed and are currently under investigation. However, its rich chemical content implies many possible physiological actions. As the use of medicinal cannabis has gained significant attention over the past few years, it is very important to understand phytocannabinoid dispositions within the human body, and especially their metabolic pathways. Even though the complex metabolism of phytocannabinoids poses many challenges, a more thorough understanding generates many opportunities, especially regarding possible drug-drug interactions (DDIs). Within this context, computer simulations are most commonly used for predicting substrates and inhibitors of metabolic enzymes. These predictions can assist to identify metabolic pathways by understanding individual CYP isoform specificities to a given molecule, which can help to predict potential enzyme inhibitions and DDIs. The reported in vivo Phase I and Phase II metabolisms of various phytocannabinoids are herein reviewed, accompanied by a parallel in silico analysis of their predicted metabolism, highlighting the clinical importance of such understanding in terms of DDIs and clinical outcomes.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107621DOI Listing
November 2020

Biphasic Dissolution as an Exploratory Method During Early Drug Product Development.

Pharmaceutics 2020 May 2;12(5). Epub 2020 May 2.

Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.

Dissolution testing is a major tool used to assess a drug product's performance and as a quality control test for solid oral dosage forms. However, compendial equipment and methods may lack discriminatory power and the ability to simulate aspects of in vivo dissolution. Using low buffer capacity media combined with an absorptive phase (biphasic dissolution) increases the physiologic relevance of in vitro testing. The purpose of this study was to use non-compendial and compendial dissolution test conditions to evaluate the in vitro performance of different formulations. The United States Pharmacopeia (USP)-recommended dissolution method greatly lacked discriminatory power, whereas low buffer capacity media discriminated between manufacturing methods. The use of an absorptive phase in the biphasic dissolution test assisted in controlling the medium pH due to the drug removal from the aqueous medium. Hence, the applied non-compendial methods were more discriminative to drug formulation differences and manufacturing methods than conventional dissolution conditions. In this study, it was demonstrated how biphasic dissolution and a low buffer capacity can be used to assess in vitro drug product performance differences. This can be a valuable approach during the early stages of drug product development for investigating in vitro drug release with improved physiological relevance.
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http://dx.doi.org/10.3390/pharmaceutics12050420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284338PMC
May 2020

Development and validation of a compact on-person storage device (SMHeartCard) for emergency access to acetylsalicylic acid and nitroglycerin.

CMAJ Open 2020 Jan-Mar;8(1):E75-E82. Epub 2020 Feb 11.

Faculties of Pharmacy and Pharmaceutical Sciences (Le, Davies) and of Medicine and Dentistry (Paterson), University of Alberta; Alberta Health Services (Mackey), Cross Cancer Institute, Edmonton, Alta.

Background: Guidelines recommend that patients with coronary artery disease (CAD) carry and immediately use acetylsalicylic acid (ASA) and sublingually administered nitroglycerin at the onset of chest pain; however, compliance with these recommendations is poor. We designed and tested a compact on-person storage device for these medications.

Methods: We designed an airtight, light-proof and chemically inert holder to carry four 81-mg ASA tablets and three 0.3-mg Nitrostat (nitroglycerin, Pfizer) tablets. After establishing the temperatures ranges in wallets and pockets, we tested nitroglycerin dissolution and release of the stored Nitrostat tablets across a range of relevant temperatures and a variety of tablet enclosure systems.

Results: Microcalorimeter thermal conduction studies as well as dissolution and release testing showed that nitroglycerin tablets were stable at temperatures ranging from -20°C to 60°C for 1 week. In testing up to 24 weeks, 0.3-mg Nitrostat tablets enclosed completely in polytetrafluoroethylene (PTFE) performed similarly to those stored in the manufacturer's borosilicate glass packaging across a wide range of temperatures relevant to on-person carriage. Real-world on-person testing for 24 weeks confirmed these results. Non-PTFE enclosures performed poorly.

Interpretation: The PTFE enclosure with a PTFE-coated cap liner maintained long-term performance of 0.3-mg Nitrostat tablets under laboratory and real-world conditions. This storage device is now commercially available as the SMHeartCard to improve compliance and provide immediate access to emergency cardiac medications.
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http://dx.doi.org/10.9778/cmajo.20190147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012633PMC
February 2021

Pharmacy's Trojan horse.

Authors:
Neal M Davies

Can Pharm J (Ott) 2019 Sep-Oct;152(5):284. Epub 2019 Aug 5.

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http://dx.doi.org/10.1177/1715163519865738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739660PMC
August 2019

Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors.

Pharmaceutics 2019 Sep 17;11(9). Epub 2019 Sep 17.

Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada.

The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model. Transient opening of the BBB in response to HAV6 peptide administration was quantitatively characterized using both a gadolinium magnetic resonance imaging (MRI) contrast agent and adenanthin (Ade), the intended therapeutic agent. The effects of HAV6 peptide on BBB integrity and the efficacy of concurrent administration of HAV6 peptide and the small molecule inhibitor, Ade, in the growth and progression of an orthotopic medulloblastoma mouse model using human D425 tumor cells was examined. Systemic administration of HAV6 peptide caused transient, reversible disruption of BBB in mice. Increases in BBB permeability produced by HAV6 were rapid in onset and observed in all regions of the brain examined. Concurrent administration of HAV6 peptide with Ade, a BBB impermeable inhibitor of Peroxiredoxin-1, caused reduced tumor growth and increased survival in mice bearing medulloblastoma. The rapid onset and transient nature of the BBB modulation produced with the HAV6 peptide along with its uniform disruption and biocompatibility is well-suited for CNS drug delivery applications, especially in the treatment of brain tumors.
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http://dx.doi.org/10.3390/pharmaceutics11090481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781504PMC
September 2019

Simulated, biorelevant, clinically relevant or physiologically relevant dissolution media: The hidden role of bicarbonate buffer.

Eur J Pharm Biopharm 2019 Sep 10;142:8-19. Epub 2019 Jun 10.

Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

In-vitro dissolution testing of pharmaceutical formulations has been used as a quality control test for many years. At early drug product development, in vivo predictive dissolution testing can be used for guidance in the rational selection of candidate formulations that best fit the desired in vivo dissolution characteristics. At present, the most widely applied dissolution media are phosphate-based buffers and, in some cases, the result of dissolution tests performed in such media have demonstrated reasonable/acceptable IVIVCs. However, the presence of phosphates in human GI luminal fluids is insignificant, which makes the use of such media poorly representative of the in vivo environment. The gastrointestinal lumen has long been shown to be buffered by bicarbonate. Hence, much interest in the development of suitable biorelevant in vitro dissolution media based on bicarbonate buffer systems has evolved. However, there are inherent difficulties associated with these buffers, such as maintaining the pH throughout the dissolution test, as CO tends to leave the system. Various mathematical models have been proposed to analyze bicarbonate buffers and they are discussed in this review. Approaches such as using simpler buffer systems instead of bicarbonate have been proposed as surrogate buffers to produce an equivalent buffer effect on drug dissolution on a case-by-case basis. There are many drawbacks related to simpler buffers systems including their poor in vivo predictability. Considerable discrepancies between phosphate and bicarbonate buffer dissolution results have been reported for certain dosage forms, e.g. enteric coated formulations. The role and need of bicarbonate-based buffers in quality control testing requires scientific analysis. This review also encompasses on the use of bicarbonate-based buffers as a potentially in vivo predictive dissolution medium for enteric coated dosage forms.
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http://dx.doi.org/10.1016/j.ejpb.2019.06.006DOI Listing
September 2019

The Antioxidant Activity of Recombinant Rat Hepatic Fatty Acid Binding Protein T94A Variant.

J Pharm Pharm Sci 2018 ;21(1s):309s-324s

College of Pharmacy, Pharmaceutical Analysis Laboratory, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Purpose: Liver fatty acid binding protein (FABP1) is a cytoplasmic polypeptide that transports substrates throughout the cytosol and functions as an antioxidant. A common polymorphic variant, FABP1 T94A has a minor allele frequency of 26-38%, 8.3±1.9% homozygous in the human population. The purpose of this study was to mutate and isolate recombinant rat FABP1 to the T94A variant to evaluate the mutant's antioxidant activity using in vitro studies.

Methods: Site-directed mutagenesis was used to generate a mutation in rat cDNA within a pGEX-6p-2 vector. This plasmid was transformed into competent cells and cultured for expression of FABP1 T94A mutant. The mutated protein was purified using GSTrap Fastflow columns within an ÄKTA FPLC system. A 2,7-dichlorofluorescein (DCF) assay was used to screen the T94A variant antioxidant activity. Additionally, Thiobarbituric Acid Reactive Substances (TBARS) assay was used in determining T94A mutant antioxidant activity in hydrophilic and lipophilic environments through the use of the azo compounds AAPH and MeO-AMVN, respectively and in the presence and absence of the long-chain fatty acid palmitate and α-bromo palmitate.

Results: Although the FABP1 T94A (20 μM) mutant significantly reduced DCF fluorescence compared to control (no protein; P< 0.001), there were no significant difference when compared to the wild-type (WT) FABP1. T94A was able to diminish the formation of malondialdehyde (MDA) in both lipophilic and hydrophilic systems. There were significant differences between T94A mutant and WT FABP1 at concentrations 1 and 10 μM (P< 0.05) in the hydrophilic milieu, however, this was not seen at 20 μM and also not seen in the lipophilic milieu at all concentrations. When T94A was pre-incubated with the long-chain fatty acids palmitate or α -bromo palmitate, MDA formation was decreased in both lipid peroxidation systems. There were no statistical differences between the WT FABP1 and T94A bound with fatty acids in both lipid peroxidation systems, however, there was a slight statistical difference when the T94A and WT FABP1 bound α-Br-PA in the AAPH lipid peroxidation system only.

Conclusions: The T94A has antioxidant activity in both hydrophilic and lipophilic environments. The T94A variant of FABP1 does not have a loss of function in regard to acting as an antioxidant but the extent of function may be influenced by ligand binding. We conclude that populations having the minor T94A allele frequency would have similar ROS scavenging potential as those with nascent FABP1.
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http://dx.doi.org/10.18433/jpps30246DOI Listing
October 2019

Application of in Silico Tools in Clinical Practice using Ketoconazole as a Model Drug.

J Pharm Pharm Sci 2018 ;21(1s):242s-253s

Department of Pharmacy, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Av. Prof. Lineu Prestes, 580, Cidade Universitária, 05508-000, Butantã, SP, Brazil. Faculty of Pharmacy & Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Canada.

Hypochlorhydria is a condition where the production of hydrochloric acid in the stomach is decreased. As a result, the intragastric pH is elevated. This condition can be due to a series of causes, such as disease (gastric mucosal infection caused by Helicobacter pylori and is prominent in AIDS patients), ethnicity, age and also the use of antisecretory agents. This may significantly impact the absorption of other drugs that have pH-dependent solubility, such as ketoconazole, a weak base. Within this context, the purpose of this study was to demonstrate how GastroPlusTM - a physiological based software program- can be used to predict clinical pharmacokinetics of ketoconazole in a normal physiological state vs. elevated gastric pH. A simple physiologically based pharmacokinetic model was built and validated to explore the impact that different physiologic conditions in the stomach (hypochlorhydria, drug administered with water and Coca Cola®) had on ketoconazole's bioavailability. The developed model was able to accurately predict the impact of increased pH and beverage co-administration on dissolution and absorption of the drug, and confirmed that complete gastric dissolution is essential. Particle size only mattered in hypochlorhydric conditions due to the incomplete gastric dissolution, as its absorption would depend on intestinal dissolution, which corroborates with previous studies. Therefore, in silico approaches are a potential tool to assess a pharmaceutical product's performance and efficacy under different physiological and pathophysiological states supporting the assessment of different dosing strategies in clinical practice.
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http://dx.doi.org/10.18433/jpps30227DOI Listing
October 2019

Lymphatic Drug Absorption via the Enterocytes: Pharmacokinetic Simulation, Modeling, and Considerations for Optimal Drug Development.

J Pharm Pharm Sci 2018 ;21(1s):254s-270s

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Faculty of Pharmacy & Pharmaceutical Sciences, 2142J Katz. Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada.

Most orally administered drugs gain access to the systemic circulation by direct passage from the enterocyte layer of the intestinal tract to the mesenteric blood capillaries. Intestinal lymphatic absorption is another pathway that certain drugs may follow to gain access to the systemic circulation after oral administration. Once absorbed, drug diffuses into the intestinal enterocyte and while in transit may associate with fats as they are processed into chylomicrons within the cells. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, thus avoiding the hepatic first-pass liver metabolism, and ultimately entering to the systemic circulation for disposition and action. Due to the possibility of parallel and potentially alternative absorptive pathways, mesenteric blood capillary and lymphatic drug exposure are both potential pathways of systemic availability for any individual drug. In this report, an in silico modeling approach was adopted to delineate the salient pharmacokinetic features of lymphatic absorption, and provide further guidance for the rationale design of drugs and drug delivery systems for lymphatic drug transport. The importance of hepatic extraction ratio, absorption lag time, lipoprotein binding, and the influence of competing portal and lymphatic pathways for systemic drug availability were explored using simulations. The degree of hepatic extraction was found to be an essential consideration when examining the influence of lymphatic uptake to overall oral drug bioavailability. Lymphatic absorption could potentially contribute to multiple peaking phenomena and flip flop pharmacokinetics of orally administered drugs.
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http://dx.doi.org/10.18433/jpps30217DOI Listing
October 2019

DOX-Vit D, a Novel Doxorubicin Delivery Approach, Inhibits Human Osteosarcoma Cell Proliferation by Inducing Apoptosis While Inhibiting Akt and mTOR Signaling Pathways.

Pharmaceutics 2018 Sep 4;10(3). Epub 2018 Sep 4.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.

Doxorubicin (DOX) is a very potent and effective anticancer agent. However, the effectiveness of DOX in osteosarcoma is usually limited by the acquired drug resistance. Recently, Vitamin D (Vit-D) was shown to suppress the growth of many human cancer cells. Taken together, we synthesized DOX-Vit D by conjugating Vit-D to DOX in order to increase the delivery of DOX into cancer cells and mitigate the chemoresistance associated with DOX. For this purpose, MG63 cells were treated with 10 µM DOX or DOX-Vit D for 24 h. Thereafter, MTT, real-time PCR and western blot analysis were used to determine cell proliferation, genes and proteins expression, respectively. Our results showed that DOX-Vit D, but not DOX, significantly elicited an apoptotic signal in MG63 cells as evidenced by induction of death receptor, Caspase-3 and BCLxs genes. Mechanistically, the DOX-Vit D-induced apoptogens were credited to the activation of p-JNK and p-p38 signaling pathway and the inhibition of proliferative proteins, p-Akt and p-mTOR. Our findings propose that DOX-Vit D suppressed the growth of MG63 cells by inducing apoptosis while inhibiting cell survival and proliferative signaling pathways. DOX-Vit D may serve as a novel drug delivery approach to potentiate the delivery of DOX into cancer cells.
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http://dx.doi.org/10.3390/pharmaceutics10030144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161239PMC
September 2018

Correction to: Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative.

Drug Deliv Transl Res 2018 10;8(5):1592

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2R3, Canada.

In the XML of the original article, M. Laird Forrest's name was tagged incorrectly. M. Laird is his first name.
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http://dx.doi.org/10.1007/s13346-018-0569-6DOI Listing
October 2018

Effects of low-level laser therapy on bone healing and signs of pain in dogs following tibial plateau leveling osteotomy.

Am J Vet Res 2018 Aug;79(8):893-904

OBJECTIVE To assess the effect of low-level laser therapy (LLLT) on markers of synovial inflammation and signs of pain, function, bone healing, and osteoarthritis following tibial plateau leveling osteotomy (TPLO) in dogs with spontaneous cranial cruciate ligament rupture (CCLR). ANIMALS 12 client-owned dogs with unilateral CCLR. PROCEDURES All dogs were instrumented with an accelerometer for 2 weeks before and 8 weeks after TPLO. Dogs were randomly assigned to receive LLLT (radiant exposure, 1.5 to 2.25 J/cm; n = 6) or a control (red light; 6) treatment immediately before and at predetermined times for 8 weeks after TPLO. Owners completed a Canine Brief Pain Inventory weekly for 8 weeks after surgery. Each dog underwent a recheck appointment, which included physical and orthopedic examinations, force plate analysis, radiography and synoviocentesis of the affected joint, and evaluation of lameness and signs of pain, at 2, 4, and 8 weeks after surgery. Select markers of inflammation were quantified in synovial fluid samples. Variables were compared between the 2 groups. RESULTS For the control group, mean ground reaction forces were greater at 2 and 4 weeks after TPLO and owner-assigned pain scores were lower during weeks 1 through 5 after TPLO, compared with corresponding values for the LLLT group. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the LLLT protocol used had no beneficial effects on signs of pain or pelvic limb function following TPLO. Further research is necessary to evaluate the effects of LLLT and to determine the optimum LLLT protocol for dogs with CCLR.
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http://dx.doi.org/10.2460/ajvr.79.8.893DOI Listing
August 2018

Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies.

J Pharm Pharm Sci 2018 ;21(1s):29683

College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Purpose: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery.

Methods: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. In vitro cardiotoxicity was assessed using human cardiomyocytes (RL-14) while effects on CYP3A4 metabolic enzyme and antioxidant activity were examined using commercial kits. A novel HPLC assay was developed to measure MyoNovin concentration in serum, and delineate initial pharmacokinetic and acute toxicity after intravenous administration (20 mg/kg) to male Sprague-Dawley rats.

Results: MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*107) compared to guaifenesin (0.66 cm/s*107), and ~10-fold higher effective jejunal permeability (2.24 cm/s*104) compared to guaifenesin (0.26 cm/s*104). In vitro, MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 μM and did not inhibit CYP3A4 or show antioxidant activity. In vivo, MyoNovin had a short half-life (t1/2) of 0.16 h, and a volume of distribution Vss of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels.

Conclusions: The predicted high lipophilicity and skin permeability of MyoNovin render it a potential candidate for transdermal administration while its favourable intestinal permeation suggests it may be suitable for oral administration. Pharmacokinetics following IV administration of MyoNovin were delineated for the first time in a rat model. Preliminary single 20 mg/kg dose assessment of MyoNovin suggest no influenceon cardiac troponin or β-N-Acetylglucosaminidase. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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http://dx.doi.org/10.18433/J3MS8HDOI Listing
October 2019

Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape-A Summary of This Indispensable Special Issue.

Pharmaceutics 2018 Jan 16;10(1). Epub 2018 Jan 16.

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 2Z4, Canada.

Canadian Pharmaceutical Scientists have a rich history of groundbreaking research in pharmacokinetics and drug metabolism undertaken primarily throughout its Pharmacy Faculties and within the Pharmaceutical and Biotechnology industry.[...].
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http://dx.doi.org/10.3390/pharmaceutics10010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874826PMC
January 2018

Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids.

Pharmaceutics 2017 Oct 12;9(4). Epub 2017 Oct 12.

The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC-MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate. In-vitro antioxidant activity, histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity and anti-inflammatory inhibitory activity were examined using commercial assay kits. Anticancer activity was determined in Sup-T1 lymphoma cells. Our results indicate THC was poorly absorbed after oral administration and primarily excreted via non-renal routes. All curcuminoids exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α. Unlike curcumin and calebin-A, THC did not inhibit HDAC1 and PCAF and displayed a weaker growth inhibition activity against Sup-T1 cells. We show evidence for the first time that curcumin and calebin-A inhibit HAT and PCAF, possibly through a Michael-addition mechanism.
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http://dx.doi.org/10.3390/pharmaceutics9040045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750651PMC
October 2017

Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative.

Pharmaceutics 2017 Sep 13;9(3). Epub 2017 Sep 13.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada.

Doxorubicin (Dox) is an effective anti-cancer medication with poor oral bioavailability and systemic toxicities. DoxQ was developed by conjugating Dox to the lymphatically absorbed antioxidant quercetin to improve Dox's bioavailability and tolerability. The purpose of this study was to characterize the pharmacokinetics and safety of Dox after intravenous (IV) and oral (PO) administration of DoxQ or Dox (10 mg/kg) and investigate the intestinal lymphatic delivery of Dox after PO DoxQ administration in male Sprague-Dawley rats. Drug concentrations in serum, urine, and lymph were quantified by HPLC with fluorescence detection. DoxQ intact IV showed a 5-fold increase in the area under the curve (AUC)-18.6 ± 1.98 compared to 3.97 ± 0.71 μg * h/mL after Dox-and a significant reduction in the volume of distribution (V): 0.138 ± 0.015 versus 6.35 ± 1.06 L/kg. The fraction excreted unchanged in urine (f) of IV DoxQ and Dox was ~5% and ~11%, respectively. Cumulative amounts of Dox in the mesenteric lymph fluid after oral DoxQ were twice as high as Dox in a mesenteric lymph duct cannulation rat model. Oral DoxQ increased AUC of Dox by ~1.5-fold compared to after oral Dox. Concentrations of β-N-Acetylglucosaminidase (NAG) but not cardiac troponin (cTnI) were lower after IV DoxQ than Dox. DoxQ altered the pharmacokinetic disposition of Dox, improved its renal safety and oral bioavailability, and is in part transported through intestinal lymphatics.
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http://dx.doi.org/10.3390/pharmaceutics9030035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620576PMC
September 2017

Pharmacokinetic Analysis of an Oral Multicomponent Joint Dietary Supplement (Phycox) in Dogs.

Pharmaceutics 2017 Aug 18;9(3). Epub 2017 Aug 18.

College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.

Despite the lack of safety, efficacy and pharmacokinetic (PK) studies, multicomponent dietary supplements (nutraceuticals) have become increasingly popular as primary or adjunct therapies for clinical osteoarthritis in veterinary medicine. Phycox is a line of multicomponent joint support supplements marketed for joint health in dogs and horses. Many of the active constituents are recognized anti-inflammatory and antioxidant agents. Due to a lack of PK studies in the literature for the product, a pilot PK study of select constituents in Phycox was performed in healthy dogs. Two novel methods of analysis were developed and validated for quantification of glucosamine and select polyphenols using liquid chromatography-tandem mass spectrometry. After a single oral (PO) administrated dose of Phycox, a series of blood samples from dogs were collected for 24 h post-dose and analyzed for concentrations of glucosamine HCl, hesperetin, resveratrol and naringenin. Non-compartmental PK analyses were carried out. Glucosamine was detected up to 8 h post-dose with a of 2 h and of 9.69 μg/mL. The polyphenols were not found at detectable concentrations in serum samples. Co-administration of glucosamine in the Phycox formulation may enhance the absorption of glucosamine as determined by comparison of glucosamine PK data in the literature.
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http://dx.doi.org/10.3390/pharmaceutics9030030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620571PMC
August 2017

Stereospecific pharmacokinetic characterization of liquiritigenin in the rat.

Res Pharm Sci 2017 Jun;12(3):176-186

College of Pharmacy, Roseman University of Health Sciences, South Jordan, Utah, United States.

Liquiritigenin is a chiral flavonoid present in licorice and other medicinal plants. The nature of its biological fate with respect to the individual enantiomers has not been examined. In this study, we characterize, for the first time, the stereoselective pharmacokinetics of liquiritigenin. Liquiritigenin was intravenously (20 mg/kg) and orally (50 mg/kg) administered to male Sprague-Dawley rats (n = 4 per route of administration). Concentrations in serum and urine were characterized via stereospecific reversed-phase, isocratic HPLC method with UV detection. Serum concentrations were quantified but rapidly fell to undetectable levels. S-liquiritigenin showed a short half-life (0.25-0.54 h), while a better estimation of half-life (26-77 h) and other pharmacokinetic parameters was observed using urinary data. The flavonoid is predominantly excreted via non-renal routes (f values of 0.16-3.46 %), and undergoes rapid and extensive phase II metabolism. Chiral differences in the chemical structure of the compound result in some pharmacokinetic differences. Serum concentrations rapidly declined, making modeling difficult. S-liquiritigenin showed an increased urinary half-life.
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http://dx.doi.org/10.4103/1735-5362.207197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465826PMC
June 2017

Comments on "Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model" by Dalesio et al, Anesth Analg. 2016;123: 1611-1617.

Anesth Analg 2017 07;125(1):361

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada,

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http://dx.doi.org/10.1213/ANE.0000000000002178DOI Listing
July 2017

Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative.

Drug Deliv Transl Res 2017 08;7(4):582-597

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2R3, Canada.

Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC. Antioxidant activity, CYP3A4 inhibition, and P-gp inhibitory effects were examined using commercial assay kits. Drug potency was assessed utilizing triple-negative murine breast cancer cells, and cardiotoxicity was assessed utilizing adult rat and human cardiomyocytes (RL-14). Levels of reactive oxygen species and gene expression of cardiotoxicity markers, oxidative stress markers, and CYP1B1 were determined in RL-14. DoxQ was less cytotoxic to both rat and human cardiomyocytes and retained anticancer activity. Levels of ROS and markers of oxidative stress demonstrate lower oxidative damage induced by DoxQ compared to doxorubicin. DoxQ also inhibited the expression and catalytic activity of CYP1B1. Additionally, DoxQ inhibited CYP3A4 and demonstrated higher cellular uptake by MDCK-MDR cells than doxorubicin. DoxQ provides a novel therapeutic approach to mitigate the cardiotoxicity and poor oral bioavailability of doxorubicin. The cardioprotective mechanism of DoxQ likely involves scavenging ROS and CYP1B1 inhibition, while the mechanism of improving the poor oral bioavailability of doxorubicin is likely related to inhibiting CYP3A4 and P-gp.
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http://dx.doi.org/10.1007/s13346-017-0379-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522622PMC
August 2017

Simultaneous quantification of reparixin and paclitaxel in plasma and urine using ultra performance liquid chromatography-tandem mass spectroscopy (UHPLC-MS/MS): Application to a preclinical pharmacokinetic study in rats.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Mar 3;1046:165-171. Epub 2017 Feb 3.

College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R3E 0T5, Canada. Electronic address:

A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay was developed and validated to simultaneously quantify anticancer drugs reparixin and paclitaxel in this study. The compounds were extracted from plasma and urine samples by protein precipitation with acetone (supplemented with 0.1% formic acid). Chromatographic separation was achieved using a C18 column, and drug molecules were ionized using dual ion source electrospray and atmospheric pressure chemical ionization (DUIS: ESI-APCI). Reparixin and paclitaxel were quantified using negative and positive multiple reaction monitoring (MRM) mode, respectively. Stable isotope palcitaxel-D5 was used as the internal standard (IS). The assay was validated for specificity, recovery, carryover and sample stability under various storage conditions; it was also successfully applied to measure drug concentrations collected from a pharmacokinetic study in rats. The results confirmed that the assay was accurate and simple in quantifying both reparixin and paclitaxel in plasma and urine with minimal sample pretreatment.
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http://dx.doi.org/10.1016/j.jchromb.2016.12.015DOI Listing
March 2017

Disparate Effects of Stilbenoid Polyphenols on Hypertrophic Cardiomyocytes In Vitro vs. in the Spontaneously Hypertensive Heart Failure Rat.

Molecules 2017 Feb 1;22(2). Epub 2017 Feb 1.

College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.

Stilbenoids are bioactive polyphenols, and resveratrol (trans-3,5,40-trihydroxystilbene) is a representative stilbenoid that reportedly exerts cardioprotective actions. As resveratrol exhibits low oral bioavailability, we turned our attention to other stilbenoid compounds with a history of medicinal use and/or improved bioavailability. We determined the effects of gnetol (trans-3,5,20,60-tetrahydroxystilbene) and pterostilbene (trans-3,5-dimethoxy-40-hydroxystilbene) on cardiac hypertrophy. In vitro, gnetol and pterostilbene prevented endothelin-1-induced indicators of cardiomyocyte hypertrophy including cell enlargement and protein synthesis. Gnetol and pterostilbene stimulated AMP-activated protein kinase (AMPK), and inhibition of AMPK, using compound C or shRNA knockdown,abolished these anti-hypertrophiceffects. In contrast,resveratrol, gnetol, nor pterostilbene reduced blood pressure or hypertrophy in the spontaneously hypertensive heart failure (SHHF) rat. In fact, AMPK levels were similar between Sprague-Dawley and SHHF rats whether treated by stilbenoids or not. These data suggest that the anti-hypertrophic actions of resveratrol (and other stilbenoids?) do not extend to the SHHF rat, which models heart failure superimposed on hypertension. Notably, SHHF rat hearts exhibited prolonged isovolumic relaxationtime(an indicator of diastolicdys function),and this was improved by stilbenoid treatment.In conclusion, stilbenoid-based treatment as a viable strategy to prevent pathological cardiac hypertrophy,a major risk factor for heart failure,may be context-dependent and requires furtherstudy.
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http://dx.doi.org/10.3390/molecules22020204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155878PMC
February 2017

Pharmacological characterization of liquiritigenin, a chiral flavonoid in licorice.

Res Pharm Sci 2016 Oct;11(5):355-365

College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; College of Pharmacy, Roseman University of Health Sciences, South Jordan, Utah, United States.

Liquiritigenin is a chiral flavonoid present in plant based food, nutraceuticals, and traditional medicines. It is also an important ingredient present in licorice. The purpose of this study is to explore the pharmacological activity of racemic liquiritigenin utilizing several in vitro assays with relevant roles in colon cancer and diabetes. Where possible, the pure enantiomers were tested to identify the stereospecific contribution to the activity. In vitro antioxidant, anticancer, anti-inflammatory activities (cyclooxygenase inhibition), antidiabetic activities (alpha-amylase and alpha-glucosidase inhibition) as well as cytochrome P450 (CYP450) inhibitory activities were assessed. Racemic liquiritigenin demonstrated a dose-dependent inhibition of alpha-amylase enzyme whereas its pure enantiomers did not. Racemic liquiritigenin showed moderate antiproliferative activity on a HT-29 (human colorectal adenocarcinoma) cancer cell line that was dose-dependent and potent inhibitory effects on the cyclooxygenase-2 enzyme. The flavonoid did not inhibit the activity of cytochrome CYP2D6 over the concentration range studied but was a potent antioxidant. The current study demonstrated the importance of understanding the stereospecific pharmacological effects of liquiritigenin enantiomers in alpha-amylase inhibition.
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http://dx.doi.org/10.4103/1735-5362.192484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122824PMC
October 2016

Hepatic Stellate Cells in Liver Fibrosis and siRNA-Based Therapy.

Rev Physiol Biochem Pharmacol 2016 ;172:1-37

College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T5.

Hepatic fibrosis is a reversible wound-healing response to either acute or chronic liver injury caused by hepatitis B or C, alcohol, and toxic agents. Hepatic fibrosis is characterized by excessive accumulation and reduced degradation of extracellular matrix (ECM). Excessive accumulation of ECM alters the hepatic architecture leading to liver fibrosis and cirrhosis. Cirrhosis results in failure of common functions of the liver. Hepatic stellate cells (HSC) play a major role in the development of liver fibrosis as HSC are the main source of the excessive production of ECM in an injured liver. RNA interference (RNAi) is a recently discovered therapeutic tool that may provide a solution to manage multiple diseases including liver fibrosis through silencing of specific gene expression in diseased cells. However, gene silencing using small interfering RNA (siRNA) is encountering many challenges in the body after systemic administration. Efficient and stable siRNA delivery to the target cells is a key issue for the development of siRNA therapeutic. For that reason, various viral and non-viral carriers for liver-targeted siRNA delivery have been developed. This review will cover the current strategies for the treatment of liver fibrosis as well as discussing non-viral approaches such as cationic polymers and lipid-based nanoparticles for targeted delivery of siRNA to the liver.
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http://dx.doi.org/10.1007/112_2016_6DOI Listing
June 2017

Quantification of cefazolin in serum and adipose tissue by ultra high performance liquid chromatography-Tandem mass spectrometry (UHPLC-MS/MS): application to a pilot study of obese women undergoing cesarean delivery.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Sep 18;1031:94-98. Epub 2016 Jul 18.

The Rady Faculty of Health Sciences, College of Pharmacy, Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address:

Higher doses of cefazolin are required in obese patients for preoperative antibiotic prophylaxis, owing to its low lipophilicity. An ultra high performance liquid chromatography-tandem mass spectrometry method was developed to quantify cefazolin in serum and adipose tissue from 6 obese patients undergoing cesarean delivery, and using stable-isotope labeled cefazolin as an internal standard. The method has a 2μg/g lower limit of quantitation. The concentration in adipose tissue was 3.4±1.6μg/mL, which is less than half of the reported minimum inhibitory concentration of 8μg/mL for cefazolin. Serum cefazolin concentrations were more than 30-fold higher than in adipose tissue.
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http://dx.doi.org/10.1016/j.jchromb.2016.07.032DOI Listing
September 2016

Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation.

Mol Pharm 2016 06 24;13(6):1904-14. Epub 2016 May 24.

College of Pharmacy, University of Manitoba , Winnipeg, Manitoba, Canada , R3E 0T5.

Hyaluronic acid (HA) has emerged as a versatile polymer for drug delivery. Multiple commercial products utilize HA, it can be obtained in a variety of molecular weights, and it offers chemical handles for cross-linkers, drugs, or imaging agents. Previous studies have investigated multiple administration routes, but the absorption, biodistribution, and pharmacokinetics of HA after delivery to the lung is relatively unknown. Here, pharmacokinetic parameters were investigated by delivering different molecular weights of HA (between 7 and 741 kDa) to the lungs of mice. HA was labeled with either a near-infrared dye or with iodine-125 conjugated to HA using a tyrosine linker. In initial studies, dye-labeled HA was instilled into the lungs and fluorescent images of organs were collected at 1, 8, and 24 h post administration. Data suggested longer lung persistence of higher molecular weight HA, but signal diminished for all molecular weights at 8 h. To better quantitate pharmacokinetic parameters, different molecular weights of iodine-125 labeled HA were instilled and organ radioactivity was determined after 1, 2, 4, 6, and 8 h. The data showed that, after instillation, the lungs contained the highest levels of HA, as expected, followed by the gastrointestinal tract. Smaller molecular weights of HA showed more rapid systemic distribution, while 67 and 215 kDa HA showed longer persistence in the lungs. Lung exposure appeared to be optimum in this size range due to the rapid absorption of <67 kDa HA and the poor lung penetration and mucociliary clearance of viscous solutions of HA > 215 kDa. The versatility of HA molecular weight and conjugation chemistries may, therefore, provide new opportunities to extend pulmonary drug exposure and potentially facilitate access to lymph nodes draining the pulmonary bed.
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http://dx.doi.org/10.1021/acs.molpharmaceut.6b00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200957PMC
June 2016

Pharmacologic Activities of 3'-Hydroxypterostilbene: Cytotoxic, Anti-Oxidant, Anti-Adipogenic, Anti-Inflammatory, Histone Deacetylase and Sirtuin 1 Inhibitory Activity.

J Pharm Pharm Sci 2015 ;18(4):713-27

Department of Pharmaceutical Sciences, Ben and Maytee Fisch College of Pharmacy, The University of Texas at Tyler, Tyler, Texas. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington.

Purpose: Delineate the selected pharmacodynamics of a naturally occurring stilbene 3'-Hydroxypterostilbene.

Objective: Characterize for the first time the pharmacodynamics bioactivity in several in-vitro assays with relevant roles in heart disease, inflammation, cancer, and diabetes etiology and pathophysiology.

Methods: 3'-Hydroxypterostilbene was studied in in-vitro assays to identify possible bioactivity.

Results: 3'-Hydroxypterostilbene demonstrated anti-oxidant, anti-inflammatory, cytotoxic, anti-adipogenic, histone deacetylase, and sirtuin-1 inhibitory activity.

Conclusions: The importance of understanding individual stilbene pharmacologic activities were delineated. Small changes in chemical structure of stilbene compounds result in significant pharmacodynamic differences. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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http://dx.doi.org/10.18433/j33w4cDOI Listing
September 2016