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S MacLeod

Publications and source records attributed to S MacLeod.

At least 19 recordsLinked to original sources
PubMed2001

The Optimal Drug Therapy National Symposium 2001: a call for action.

There is widespread concern internationally and within Canada about the rapid escalation in pharmaceutical costs. Although there is reason to believe that the quality of prescribing has improved in recent years, with heightened emphasis on evidence-based therapeutic decision-making, there is enormous pressure to prescribe in almost every clinical situation. Busy clinicians need improved tools to aid therapeutic decision-making. Access to timely information about drug efficacy and safety is essential. Most importantly, there is a need for a new partnership model that may blend the interests of patients, professionals, payors and manufacturers to better define disease state management approaches that will lead to an optimal return on the investment in pharmaceutical care. The new model will depend on high standards of research to show what does and does not work to secure the most effective pharmacotherapy. It will also require renewed efforts in education for patients and caregivers, and progress on that front will, in turn, rely on the most effective use of expanded capacity in information technology. One early impact will be seen in the reduction of medication errors. The framework for therapeutic decision-making must evolve in keeping with the revolution in human biology. With improved understanding of human genomics and proteomics, prescribers are better able to consider highly individualized and targeted drug therapies while actively concentrating on risk minimization. The Optimal Drug Therapy National Symposium 2001 has created a consensus among stakeholders and pointed the way to improvements in drug therapy that may be achieved through enhanced research, educa- tion, public involvement and professional support. Unequivocal commitment to the laudable goal of optimal drug therapy is now required from all sides.

Canada↗
PubMed1999

In vivo human metabolism of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

To better understand the interactions of the pathways of activation and detoxification on the metabolism of the putative carcinogen, PhIP, we administered a dose of 70-84 microg [2-14C] PhIP (17.5 [microCi 14C) 48-72 h before scheduled colon surgery. Blood and urine collected for the next 48-72 h was evaluated by linear accelerator mass spectroscopy (AMS) and scintillation counting LC-MS to identify specific PhIP metabolites. The thermostable phenol sulfotransferase (SULT1A1) phenotype was correlated with the 4'-PhIP-SO4 levels in the urine at 0-4 h (R = 0.86, P = 0.059). The CYP1A2 activity had a negative correlation with PhIP serum levels at 1 h (R = 0.94, P = 0.06) and a positive correlation with urine N-OH-PhIP levels at 0-4 h (R = 0.85, P = 0.15). This low level radioisotope method of determining the influence of phenotype on metabolism will significantly improve our understanding of the interrelationships of these pathways and provide a critical foundation for the development of individual risk assessment.

Adult↗
PubMed1999

The identification of [2-(14)C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans.

[2-(14)C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), a putative human carcinogenic heterocyclic amine found in well-done cooked meat, was administered orally to three colon cancer patients undergoing a partial colonectomy. Forty-eight to seventy-two hours prior to surgery, subjects received a 70-84 microg dose of 14C. Urine and blood were analyzed by HPLC for PhIP and PhIP metabolites. Metabolites were identified based on HPLC co-elution with authentic PhIP metabolite standards, mass spectral analysis and susceptibility to enzymatic cleavage. In two subjects, approximately 90% of the administered [14C]PhIP dose was eliminated in the urine, whereas in the other, only 50% of the dose was found in the urine. One subject excreted three times more radioactivity in the first 4 h than did the others. Twelve radioactive peaks associated with PhIP were detected in the urine samples. The relative amount of each metabolite varied by subject, and the amounts of each metabolite within subjects changed over time. In all three subjects the most abundant urinary metabolite was identified as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine-N2-glucuron ide (N-hydroxy-PhIP-N2-glucuronide), accounting for 47-60% of the recovered counts in 24 h. PhIP accounted for <1% of the excreted radiolabel in all three patients. Other metabolites detected in the urine at significant amounts were 4-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate, N-hydroxy-PhIP-N3-glucuronide and PhIP-N2-glucuronide. In the plasma, N-hydroxy-PhIP-N2-glucuronide accounted for 60, 18 and 20% of the recovered plasma radioactivity at 1 h post PhIP dose in subjects 1, 2 and 3 respectively. Plasma PhIP was 56-17% of the recovered dose at 1 h post exposure. The relatively high concentration of N-hydroxy-PhIP-N2-glucuronide and the fact that it is an indicator of bioactivation make this metabolite a potential biomarker for PhIP exposure and activation. Determining the relative differences in PhIP metabolites among individuals will indicate metabolic differences that may predict individual susceptibility to carcinogenic risk from this suspected dietary carcinogen.

Administration, Oral↗
PubMed1999

Endoscopic drainage of the pancreatic pseudocyst.

BACKGROUND: Pancreatic pseudocyst is a common complication of chronic pancreatitis occurring in 20% to 40% of cases. Pseudocysts can be treated by endoscopic cystenterostomy or transpapillary drainage, percutaneously with computed tomography guidance or operatively. METHODS: A total of 36 endoscopic pancreatic pseudocyst drainage procedures were performed in 29 patients with 34 pseudocysts. Eighty percent presented with chronic pain, 25% had recurrent pancreatitis, and approximately one half of the patients had either gastric outlet obstruction or a palpable abdominal mass. RESULTS: Thirty-six endoscopic drainage procedures were performed, 27 cystenterostomies and 9 transpapillary drainages. Endoscopic treatment achieved complete resolution of the pseudocyst in 24 of 29 patients (83%), and the other 5 (17%) eventually required surgery. Two patients required distal pancreatectomy because of their pancreatic pathology, 2 cystgastrostomies for persistence of the pseudocyst, and 1 external drainage of an infected pancreatic cyst. The mean follow-up after the initial drainage was 16 months. There were no deaths attributed to the procedures and no complication that required surgery. Only 1 nonadherent pseudocyst (cystadenoma) required immediate operation after attempted endoscopic drainage. CONCLUSIONS: The conclude that endoscopic drainage of pancreatic pseudocysts can be both safe and effective, and definitive treatment. It should be considered as an alternative option before standard surgical drainage in selected patients.

Cystadenoma↗
PubMed1997

Polymorphisms of CYP1A1 and GSTM1 influence the in vivo function of CYP1A2.

Differences in human cancer susceptibility have been attributed to polymorphisms of carcinogen metabolizing enzymes. Our efforts have focused on the systems responsible for metabolism of aromatic and heterocyclic amines found in cigarette smoke and in cooked foods. Cytochrome P4501A2 (CYP1A2), which catalyzes aromatic and heterocyclic amine N-oxidation, has been implicated as a risk factor in both urinary bladder and colorectal cancer. In the present study we used the results of caffeine phenotyping experiments to measure the effects of cigarette smoke and compounds present in meat cooked at high temperature on CYP1A2 activity. Subjects in the smoking cessation study had mean CYP1A2 activity of 17.8 (expressed as the urinary molar ratio of [17X + 17U]/137X) while smoking: however, this activity decreased to 10.9 three weeks after cessation of smoking. Subjects in the cooked meat feeding study had mean CYP1A2 activity of 9.01 after 1 week of consuming meat cooked at low temperature, but this value increased to 12.7 after 1 week of consuming meat cooked at high temperature. Because no association has been identified between differences in CYP1A2 activity and variations in the CYP1A2 structural gene, we sought to determine whether the activities of other carcinogen metabolizing enzymes are involved in the regulation of CYP1A2 activity. CYP1A2 activity was higher in individuals who express the GSTM1 null allele compared to those expressing the GSTM1*A,B allele, 10.2 vs. 8.5 for unexposed conditions and 15.0 vs. 12.3 for exposed conditions. CYP1A1 genotyping demonstrated that individuals possessing the Ile/Ile CYP1A1 genotype had greater mean CYP1A2 activity than those who had the heterozygous Ile/Val allelic variant of the CYP1A1 gene. However, upon exposure to cigarette smoke or high-temperature cooked meat, individuals possessing the heterozygous form of the CYP1A1 gene had significantly increased CYP1A2 activity (18.1) compared to those with the more common Ile/Ile CYP1A1 genotype (13.3). These results indicate that CYP1A2, CYP1A1, and GSTM1 gene-gene interactions could be important confounders in the interpretation of molecular epidemiology studies.

Arylamine N-Acetyltransferase↗
PubMed1994

Interleukin-6 prevents dexamethasone-induced myeloma cell death.

The effects of dexamethasone on the growth of four human multiple myeloma cell lines were studied. In addition, the effects on the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes were investigated by the use of reverse-transcriptase polymerase chain reaction. Dexamethasone (Dex) concentrations of 10(-7) to 10(-6) mol/L inhibited IL-6 gene expression in three of four cell lines studied, whereas the higher concentration of the hormone inhibited also IL-6R gene expression. Dex effects were modulated through the glucocorticoid receptor (GR). Dex treatment resulted in killing of sensitive cells associated with DNA fragmentation, which could be reversed by concomitant treatment with IL-6. The reversal of Dex-mediated effects by IL-6 did not result from an inhibition of GR function as measured by receptor nuclear translocation or Dex-regulated reporter gene function. These results indicate that blockage of the IL-6 signaling pathway is essential for effective myeloma cell kill by Dex.

Base Sequence↗
PubMed1992

Effects of glucocorticoids on expression of the fos protooncogene in AtT-20 cells.

Glucocorticoid regulation of expression of the protooncogene fos has been examined in AtT-20 cells at both the RNA and protein levels. When cells were incubated continuously in the presence of dexamethasone, an early (30 min) rise in the expression of fos mRNA was observed, which declined by 1 h, but rose again after 2 h of hormone treatment. Six hours after hormone treatment, fos mRNA levels had returned to control levels in spite of the continued presence of dexamethasone. Serum treatment resulted in a sustained increase in fos mRNA levels; however, the glucocorticoid and serum effects were additive. Dexamethasone and/or serum both increased the steady state levels of fos protein. Glucocorticoid treatment of AtT-20 cells results in complex changes in fos expression, but does not affect their viability or growth rate; these results suggest that fos may play a role in mediation or modulation of glucocorticoid effects other than growth.

Animals↗
PubMed1989

Interpretation of elevated postmortem serum concentrations of digoxin in infants and children.

The relationship between excessive postmortem digoxin concentrations (greater than 6.4 nmol/L) and administered dose, and antemortem levels and time of sampling after death were determined in 27 digitalized children who died in our hospital between March 24, 1981 and September 1, 1983. In all 27 cases, postmortem concentrations were higher than antemortem levels (9.5 +/- 2.5 nmol/L and 3.12 +/- 1.72 nmol/L, respectively). In none of these patients was there clinical or electrocardiographic evidence of digitalis toxicity. There was a significant correlation between antemortem and postmortem determinations, and between time of sampling after death and postmortem concentration. Positive correlation existed between antemortem or postmortem concentrations and dose per kilogram. The degree of elevation in digoxin levels was uniform in most cases, and the likelihood of elevation falling in the range 3.5 to 7.0 nmol/L was 66%. If the estimated concentration of digoxin at the time of death was taken as baseline, in 75% of cases the subsequent elevation was between 5.3 and 8.3 nmol/L (mean, 6.5 +/- 1.1 nmol/L). Digoxin concentrations measured in newborn infants not receiving digoxin were significantly higher after death (1.5 +/- 0.3 nmol/L) than in age-matched living infants not receiving digoxin (0.5 +/- 0.3 nmol/L). These data indicate that the size of antemortem dose, the time of sampling after death, and existence of endogenous digoxinlike factors affect postmortem readings of digoxin levels. Consequently, excessive postmortem determinations cannot be directly interpreted as proof of toxic antemortem levels.

Child, Preschool↗
PubMed1988

Is pinworm a vanishing infection? Laboratory surveillance in a New York City medical center from 1971 to 1986.

Records of our parasitology laboratory were reviewed to determine trends in the frequency of specimens submitted for diagnosis of pinworm infection, the proportion of such specimens that were positive, and the proportion of such positive results for the pediatric age group from 1971 to 1986 in a major New York City medical center. These data demonstrate a markedly declining trend in the absolute number of sticky tape tests sent for pinworm diagnosis, from 248 in 1971 to 38 in 1986, an average of 8% decline per year. The number of specimens identifying Enterobius vermicularis among those submitted has similarly declined, from 57 in 1971 to none being positive in 1986, an average of 16% decline per year. The dramatic decline in pinworm identification and the fall in the number of specimens sent by practitioners at this medical center, and reported elsewhere in the United States by other investigators, may reflect a genuine decline in oxyuriasis occurring in the patient populations served.

Adolescent↗
PubMed1988

The effects of maternal age and parity on birthweight: a population-based study in New York City.

New York City birth certificates for singletons born from September 1-December 31, 1981 (N = 36,056) were analyzed using multivariate regression techniques. The effects of maternal age and parity on birthweight were assessed. There was a significant progression of birthweight with advancing age. Birthweight similarly increased from parity 1 to parity 3, but dropped markedly in the higher parity groups. On stratification by gestational age, we found that age and parity influence birthweight by affecting fetal growth rather than the length of pregnancy.

Adolescent↗
PubMed1988

Effects of quinidine on the renal tubular and biliary transport of digoxin: in vivo and in vitro studies in the dog.

Quinidine is known to inhibit the renal clearance of digoxin without affecting glomerular filtration rate. The renal interaction between these drugs was investigated by a combination of in vivo and in vitro methods. The uptake of digoxin by brush border membrane vesicles was not affected by quinidine. Similarly, digoxin did not inhibit the uptake of the cation N-methylnicotinamide by these vesicles and did not alter the binding kinetics of digoxin to the Na+, K+-adenosine triphosphatase by the antiluminal membrane vesicles. By using the in vivo multiple indicator dilution technique transtubular transport of digoxin was documented; renal-artery infusion of quinidine did not affect the recovery of digoxin in the renal vein or urine. Clearance studies documented that the decrease in the renal clearance of digoxin is paralleled by a significant fall in renal blood flow evidenced by a decrease in p-aminohippuric acid clearance. It is concluded that quinidine inhibits the renal excretion of digoxin not by competition at the tubular cell membrane level, but rather by decreasing renal blood flow. A parallel decrease in biliary clearance of digoxin is documented and may suggest a similar mechanism.

Animals↗