Spermidine/Spermine N1-Acetyltransferase 1 ()-A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA.

Spermidine/spermine N1-acetyltransferase 1 () responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-si) to selectively knockdown (KD) enzyme in a human glioblastoma cell line.

Use of amantadine in the evaluation of response to chemotherapy in lung cancer: a pilot study.

Aim: The assessment of tumor response to therapy is of critical importance as it permits for a prospective end point evaluation and provides a guide to clinicians for making future treatment decisions. However, current practices in early evaluation of chemotherapy are insufficient. Amantadine is a substrate for .

A High-Performing Plasma Metabolite Panel for Early-Stage Lung Cancer Detection.

The objective of this research is to use metabolomic techniques to discover and validate plasma metabolite biomarkers for the diagnosis of early-stage non-small cell lung cancer (NSCLC). The study included plasma samples from 156 patients with biopsy-confirmed NSCLC along with age and gender-matched plasma samples from 60 healthy controls. A fully quantitative targeted mass spectrometry (MS) analysis (targeting 138 metabolites) was performed on all samples.

Predictive value and clinical significance of increased SSAT-1 activity in healthy adults.

Aim: Spermidine/spermine N-acetyltransferase (SSAT-1) regulates cell growth, proliferation and death. Amantadine is converted by SSAT-1 to acetylamantadine (AA). In our earlier studies, although SSAT-1 was activated in patients with cancer, a number of ostensibly healthy adult volunteers had higher than expected AA concentration.

Use of amantadine as substrate for SSAT-1 activity as a reliable clinical diagnostic assay for breast and lung cancer.

Aim: Spermidine/spermine N-acetyltransferase (SSAT-1) plays a critical role in cell growth, proliferation and death, and is known to be activated in human cancer cells. Amantadine, a US FDA-approved antiviral drug, is a substrate for SSAT-1 and can be used to indirectly measure SSAT-1 activity because of its conversion to acetylamantadine (AA). This study was undertaken to further validate SSAT-1 activity in breast and lung cancer patients.

Theophylline-7β-d-Ribofuranoside (Theonosine), a New Theophylline Metabolite Generated in Human and Animal Lung Tissue.

While assessing the ability of mammalian lung tissue to metabolize theophylline, a new metabolite was isolated and characterized. The metabolite was produced by the microsomal fraction of lungs from several species, including rat, rabbit, dog, pig, sheep and human tissue. Metabolite production was blocked by boiling the microsomal tissue.

In vitro evaluation of the effect of linezolid and levofloxacin on Bacillus anthracis toxin production, spore formation and cell growth.

Background: Owing to its ability to form spores and toxins, Bacillus anthracis is considered a bioterror agent. Although current therapeutic strategies can be effective, treatment does not prevent sporulation and toxin production.

Objectives: To quantify the combined effect of a protein synthesis inhibitor and a bactericidal agent on B.

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.

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.

Clinical pharmacology confounders in older adults.

Major advances produced by healthcare research have resulted in an increasing number of drugs that may be used to modify disease expression and improve quality of life. These discoveries have been used by clinical pharmacologists as a basis to identify new drug candidates and to develop strategies for their optimal delivery to maximize benefit while simultaneously minimizing adverse events. Unfortunately, many of these studies do not include sufficient older persons in whom most of these drug therapy interventions are likely to apply.

The influence of sparse data sampling on population pharmacokinetics: a post hoc analysis of a pharmacokinetic study of morphine in healthy volunteers.

Background: Intensive sampling of patients for drugs with complex pharmacokinetic profiles is difficult to perform in the clinic or hospitalized patient setting. We seek to address whether sparse sampling can obtain pharmacokinetic parameter values similar to those with traditional modeling from a post hoc analysis of 2 previous clinical trials.

Objective: This study investigated whether population-guided, sparse-sampling pharmacokinetic analysis of morphine in 14 healthy volunteers allowed for optimal characterization of concentration-time profiles for a validation population of 5 young male patients receiving morphine.

Oseltamivir, an influenza neuraminidase inhibitor drug, does not affect the steady-state pharmacokinetic characteristics of cyclosporine, mycophenolate, or tacrolimus in adult renal transplant patients.

Background: An influenza neuraminidase inhibitor drug, oseltamivir (Os) may be prescribed to renal transplant patients to prevent and treat influenza A and B illness. A pharmacokinetic (PK) interaction between Os and immunosuppressive drugs might adversely affect the efficacy and/or toxicity of the latter agents. This study was conducted to determine whether adverse symptoms and acute drug interactions occur during their coadministration.

Potential teratogenic effects of allopurinol: a case report.

We report on a case of a multiple congenital anomalies in a newborn infant whose mother was on allopurinol treatment through the pregnancy. The pattern of congenital anomalies that was noted in our patient was similar to the pattern described in a number of published reports following mycophenolate mofetil [CellCept®] treatment during pregnancy. The anomalies present in our patient include: diaphragmatic hernia, unilateral microtia and absence of external auditory canal, micrognathia, microphthalmia, optic nerve hypoplasia, hypoplasia of the corpus callosum, unilateral renal agenesis, pulmonary agenesis, and cleft lip and palate.

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza.

Background: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza.

Methods: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain.

Protein kinase inhibition differentially regulates organic cation transport.

Previous studies showed that amantadine transport increased while tetraethylammonium (TEA) transport decreased in kidney tissue from diabetic rats. Changes in transport activity were reversed by exogenous insulin. We hypothesized that this difference in transport regulation is due to differential regulation of different transport systems.

Impact of acute exposure to increased hydrostatic pressure and reduced shear rate on conduit artery endothelial function: a limb-specific response.

Unlike quadrupeds, humans exhibit a larger hydrostatic pressure in the lower limbs compared with the upper limbs during a major part of the day. It is plausible that repeated episodes of elevated pressure in the legs may negatively impact the endothelium, hence contributing to the greater predisposition of atherosclerosis in the legs. We tested the hypothesis that an acute exposure to increased hydrostatic pressure would induce conduit artery endothelial dysfunction.

Aging issues in drug disposition and efficacy.

The elderly represent a very rapidly increasing segment of human society worldwide. As people age, they accumulate multiple and chronic diseases that are very often managed with drug therapy. This approach to health maintenance is reflected by the fact that the elderly use a disproportionate amount of prescribed and over-the-counter medications compared to their numbers in the population.

Use of antiviral prophylaxis in influenza outbreaks in long term care facilities.

Influenza is a major cause of illness and death in residents of long term care facilities for the elderly, in part because residents' age and underlying illness increase the risk of serious complications, and in part because institutional living increases the risk of influenza outbreaks. The administration of antiviral medications active against influenza to persons exposed to influenza has been shown to protect them effectively from illness, and mass antiviral prophylaxis of residents is an effective means of terminating influenza A outbreaks in long term care facilities. The only antiviral currently licensed in Canada for influenza prophylaxis is amantadine, a medication active against influenza A but not influenza B.

Pharmacokinetics/pharmacodynamics of levofloxacin 750 mg once daily in young women with acute uncomplicated pyelonephritis.

This pilot study was undertaken to characterise the pharmacokinetics, pharmacodynamics and potential clinical efficacy of levofloxacin 750 mg once daily for 5 days for treatment of women with acute uncomplicated pyelonephritis. Four women diagnosed with acute pyelonephritis were enrolled. Following pre-therapy specimen collection, an initial oral dose of 750 mg levofloxacin was administered.

Adventures in drug disposition: pas seulement pâté de foie.

Interindividual variability in drug disposition and effect has served to confound the optimization of drug therapy. Over my career, I have focused on delineating mechanisms that contribute to this variability, with the goal of improving the benefit : risk ratio when drug therapy is chosen as an intervention strategy. In this manuscript, I present some of our experimental findings that I believe have contributed to an increased understanding of variability in drug disposition and efficacy.