Prateek Lala | University of Toronto (original) (raw)

Papers by Prateek Lala

Clinical Biochemistry, Sep 1, 2014

The experience of chronic pain is one of the commonest reasons individuals seek medical attention... more The experience of chronic pain is one of the commonest reasons individuals seek medical attention, making the management of chronic pain a major issue in clinical practice. Drug metabolism and responses are affected by many factors, with genetic variations offering only a partial explanation of an individual's response. There is a paucity of evidence for the benefits of pharmacogenetic testing in the context of pain management. Design and methods: We reviewed the literature between 2000 and 2013, and references cited therein, using various keywords related to pain management, pharmacology and pharmacogenetics. Results: Opioids continue to be the mainstay of chronic pain management. Several non-opioid based therapies, such as treatment with cannabinoids, gene therapy and epigenetic-based approaches are now available for these patients. Adjuvant therapies with antidepressants, benzodiazepines or anticonvulsants can also be useful in managing pain. Currently, laboratory monitoring of pain management patients, if performed, is largely through urine drug measurements. Conclusions: Drug half-life calculations can be used as functional markers of the cumulative effect of pharmacogenetics and drug-drug interactions. Assessment of half-life and therapeutic effects may be more useful than genetic testing in preventing adverse drug reactions to pain medications, while ensuring effective analgesia. Definitive, mass spectrometry-based methods, capable of measuring parent drug and metabolite levels, are the most useful assays for this purpose. Urine drug measurements do not necessarily correlate with serum drug concentrations or therapeutic effects. Therefore, they are limited in their use in monitoring efficacy and toxicity.

Journal of Biological Chemistry, 2000

Retroviral infection of the Madin-Darby canine kidney (MDCK) renal cell line with human MDR1 cDNA... more Retroviral infection of the Madin-Darby canine kidney (MDCK) renal cell line with human MDR1 cDNA, encoding the P-glycoprotein (P-gp) multidrug resistance efflux pump, induces a major accumulation of the glycosphingolipid (GSL), globotriaosylceramide (Gal␣1-4Gal␤1-4glucosylceramide-Gb 3), the receptor for the E. coli-derived verotoxin (VT), to effect a ϳmillion-fold increase in cell sensitivity to VT. The shorter chain fatty acid isoforms of Gb 3 (primarily C16 and C18) are elevated and VT is internalized to the endoplasmic reticulum/nuclear envelope as we have reported for other hypersensitive cell lines. P-gp (but not MRP) inhibitors, e.g. ketoconazole or cyclosporin A (CsA) prevented the increased Gb 3 and VT sensitivity, concomitant with increased vinblastine sensitivity. Gb 3 synthase was not significantly elevated in MDR1-MDCK cells and was not affected by CsA. In MDR1-MDCK cells, synthesis of fluorescent N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-aminocaproyl (NBD)-lactosylceramide (LacCer) and NBD-Gb 3 via NBD-glucosylceramide (GlcCer) from exogenous NBD-C 6-ceramide, was prevented by CsA. We therefore propose that P-gp can mediate GlcCer translocation across the bilayer, from the cytosolic face of the Golgi to the lumen, to provide increased substrate for the lumenal synthesis of LacCer and subsequently Gb 3. These results provide a molecular mechanism for the observed increased sensitivity of multidrug-resistant tumors to VT and emphasize the potential of verotoxin as an antineoplastic. Two strains (I and II) of MDCK cells, which differ in their glycolipid profile, have been described. The original MDR1-MDCK parental cell was not specified, but the MDR1-MDCK GSL phenotype and glycolipid synthase activities indicate MDCK-I cells. However, the partial drug resistance of MDCK-I cells precludes their being the parental cell. We speculate that the retroviral transfection per se, or the subsequent selection for drug resistance, selected a subpopulation of MDCK-I cells in the parental MDCK-II cell culture and that drug resistance in MDR1-MDCK cells is thus a result of both MDR1 expression and a second, previously unrecognized, component, likely the high level of Glc-Cer synthesis in these cells.

Handbook of Developmental Neurotoxicology, 1998

Breastfeeding is associated with tangible benefits for the mother and infant, including lower inf... more Breastfeeding is associated with tangible benefits for the mother and infant, including lower infection rates and higher cognitive function in the infant. Beneficial effects of breast milk on infant neurocognitive development are particularly intriguing. Although the effects of confounding factors cannot be ruled out, or will never be ruled out, there is no reason to believe that infant formula is superior to breast milk under most circumstances. Besides nutritional factors, milk apparently contains molecular information of the surrounding habitat (including food the mother ingests), which is communicated to the infant through the ingested milk, modifying the offspring’s immune function for later life. Indeed, the current pediatric practice guidelines invariably advocate exclusive breastfeeding for at least the first 6 months of life. However, the presumed role of the mammary gland as an information-processing organ of the surrounding environment also indicates that non-nutrient substances such as drugs the mother takes are excreted into milk. Importantly, more than half of breastfeeding women take medications, highlighting the magnitude of the problem. In this chapter, our focus is on environmental toxins and maternal medications, describing their impacts on infant neurodevelopment.

This book has been designed to remain as one book or to be taken apart into smaller booklets. Ide... more This book has been designed to remain as one book or to be taken apart into smaller booklets. Identify the beginning and end of a particular section; then carefully bend the pages in such a way that a small crease can be identified on the spine of the book. Finally, use a sharp knife/exacto knife to cut out the section of the spine; remember, always cut away from yourself.

Clinical Biochemistry, 2012

ABSTRACT

Clinical Biochemistry, 2014

Objective: The experience of chronic pain is one of the commonest reasons individuals seek medica... more Objective: The experience of chronic pain is one of the commonest reasons individuals seek medical attention, making the management of chronic pain a major issue in clinical practice. Drug metabolism and responses are affected by many factors, with genetic variations offering only a partial explanation of an individual's response. There is a paucity of evidence for the benefits of pharmacogenetic testing in the context of pain management.

Neurosurgery, 1999

OBJECTIVE: Amplification of the epidermal growth factor receptor (EGFR) is a common event in the ... more OBJECTIVE: Amplification of the epidermal growth factor receptor (EGFR) is a common event in the molecular pathogenesis of high-grade astrocytic tumors, occurring in 50% of glioblastoma multiforme (GBM) cases. A subset of GBMs also express a constitutively phosphorylated truncated receptor (EGFRvIII). Expression of transfected EGFRvIII in cells has been reported to activate the Ras-mitogen-activated protein kinase pathway and to provide a growth advantage. Novel therapeutic agents targeting signal transduction pathways are entering early clinical trials; determination of which GBMs express EGFRvIII might help identify patients who might benefit from these biological agents.

Leukemia Research, 2000

Post-transplant lymphoproliferative disease (PTLD) is an invasive, EBV expressing B lymphoma and ... more Post-transplant lymphoproliferative disease (PTLD) is an invasive, EBV expressing B lymphoma and a major cause of morbidity and mortality following organ transplantation. Presently there is limited therapy available; rather the patient often loses the allograft or succumbs to the malignancy. CD77 (or globotriaosyl ceramide -Gb 3 ) is a germinal center B cell marker [Gregory et al. expressed on most EBV infected B cells and is the receptor for the E. coli derived verotoxin (VT) [Lingwood CA. Advances in Lipid Research 1993;25:189-212]. We present the basis of a possible novel approach to PTLD therapy utilizing the specific targeting of VT to the infiltrating lymphoma cells. Biopsies of adenoid, kidney or liver tissue of four PTLD patients were stained with verotoxin to determine expression of CD77. VT is a potent inducer of necrosis/apoptosis of receptor positive cells. In each PTLD case, the infiltrating EBV positive B lymphoma cells were strongly and selectively stained with VT, identifying CD77 as a new marker for these cells. For such individuals, VT might provide the basis of an approach to control their malignancy.

cDNA, encoding the P-glycoprotein (P-gp) multidrug resistance efflux pump, induces a major accumu... more cDNA, encoding the P-glycoprotein (P-gp) multidrug resistance efflux pump, induces a major accumulation of the glycosphingolipid (GSL), globotriaosylceramide (Gal␣1-4Gal␤1-4glucosylceramide-Gb 3 ), the receptor for the E. coli-derived verotoxin (VT), to effect a ϳmillion-fold increase in cell sensitivity to VT. The shorter chain fatty acid isoforms of Gb 3 (primarily C16 and C18) are elevated and VT is internalized to the endoplasmic reticulum/nuclear envelope as we have reported for other hypersensitive cell lines. P-gp (but not MRP) inhibitors,