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Title: Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research

Abstract

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting thatmore » CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [4];  [5]
  1. Department of Pediatrics, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1 (Canada)
  2. Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba (Canada)
  3. Departments of Internal Medicine and, Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba (Canada)
  4. (Canada)
  5. Department of Pediatrics, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1 (Canada). E-mail: hasans@ucalgary.ca
Publication Date:
OSTI Identifier:
20976832
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 218; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.10.019; PII: S0041-008X(06)00398-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL STRESS; CHEMOTHERAPY; CLEARANCE; CORTICOSTERONE; HUMAN POPULATIONS; INFANTS; NICOTINE; PREGNANCY; RADIATION DOSES; RATS; TOBACCO SMOKES; TOXICITY

Citation Formats

Hussein, Jabeen, Farkas, Svetlana, MacKinnon, Yolanda, Ariano, Robert E., Sitar, Daniel S., Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, and Hasan, Shabih U. Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.10.019.
Hussein, Jabeen, Farkas, Svetlana, MacKinnon, Yolanda, Ariano, Robert E., Sitar, Daniel S., Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, & Hasan, Shabih U. Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research. United States. doi:10.1016/j.taap.2006.10.019.
Hussein, Jabeen, Farkas, Svetlana, MacKinnon, Yolanda, Ariano, Robert E., Sitar, Daniel S., Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, and Hasan, Shabih U. Mon . "Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research". United States. doi:10.1016/j.taap.2006.10.019.
@article{osti_20976832,
title = {Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research},
author = {Hussein, Jabeen and Farkas, Svetlana and MacKinnon, Yolanda and Ariano, Robert E. and Sitar, Daniel S. and Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba and Hasan, Shabih U.},
abstractNote = {Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.},
doi = {10.1016/j.taap.2006.10.019},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 218,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
  • Epidemiological studies support an association between perinatal cigarette smoke (CS) exposure and a number of severe pre- and postnatal complications. However, the mechanisms through which CS enhances such risks largely remain unknown. One of the reasons for our inability to discover such mechanisms has been the unavailability of a clinically relevant and physiologically concordant animal model. A number of studies have previously used nicotine (Nic) as surrogate for CS. We sought to (1) establish the amount of CS exposure to achieve plasma Nic concentrations observed among moderate to heavy smokers (20-60 ng/ml) (2) investigate the temporal changes in plasma Nicmore » concentrations, carboxyhemoglobin, and hematocrit with advancing pregnancy, and (3) elucidate the effects of CS exposure on pregnancy outcome. Pregnant Sprague-Dawley rats were exposed to various doses of CS or room air (Sham) from days 6 to 21 of gestation. Exposure to 6000 ml/day of CS led to very high plasma Nic concentrations and increased maternal and fetal mortality (P < 0.001). The plasma Nic concentrations remained higher than those observed in moderate smokers until the CS dose was reduced to 1000 ml/day and showed dose-dependent temporal changes with advancing gestational age. Significant increases in carboxyhemoglobin and hematocrit were observed in the CS group as compared with the Sham group (P < 0.001). In addition, prenatally CS exposed fetuses had lower birth weight as compared with the Sham group (P = 0.04). Our current study establishes a newly standardized and physiologically relevant model to investigate the mechanisms of CS-mediated adverse effects during the critical period of fetal development.« less
  • Purpose: To investigate the biochemical control rates and survival for Gleason score 7-10 prostate cancer patients undergoing permanent prostate brachytherapy as a function of the biologic effective dose (BED). Methods and Materials: Six centers provided data on 5,889 permanent prostate brachytherapy patients, of whom 1,078 had Gleason score 7 (n = 845) or Gleason score 8-10 (n = 233) prostate cancer and postimplant dosimetry results available. The median prostate-specific antigen level was 7.5 ng/mL (range, 0.4-300). The median follow-up for censored patients was 46 months (range, 5-130). Short-term hormonal therapy (median duration, 3.9 months) was used in 666 patients (61.8%)more » and supplemental external beam radiotherapy (EBRT) in 620 (57.5%). The patients were stratified into three BED groups: <200 Gy (n = 645), 200-220 Gy (n = 199), and >220 Gy (n = 234). Biochemical freedom from failure (bFFF) was determined using the Phoenix definition. Results: The 5-year bFFF rate was 80%. The bFFF rate stratified by the three BED groups was 76.4%, 83.5%, and 88.3% (p < 0.001), respectively. Cox regression analysis revealed Gleason score, prostate-specific antigen level, use of hormonal therapy, EBRT, and BED were associated with bFFF (p < 0.001). Freedom from metastasis improved from 92% to 99% with the greatest doses. The overall survival rate at 5 years for the three BED groups for Gleason score 8-10 cancer was 86.6%, 89.4%, and 94.6%, respectively (p = 0.048). Conclusion: These data suggest that permanent prostate brachytherapy combined with EBRT and hormonal therapy yields excellent bFFF and survival results in Gleason score 7-10 patients when the delivered BEDs are >220 Gy. These doses can be achieved by a combination of 45-Gy EBRT with a minimal dose received by 90% of the target volume of 120 Gy of {sup 103}Pd or 130 Gy of {sup 125}I.« less
  • Purpose: To determine in a prospective study, the correlation between radiation dose/volume, clinical toxicities and patient-reported, quality of life (QOL) resulting from lung SBRT. Methods: For 106 non-small cell lung cancer (NSCLC) patients receiving SBRT (12 Gy × 4), symptoms including cough, dyspnea, fatigue and pneumonitis were measured at baseline (before treatment), after treatment and 3, 6, and 12 months post-treatment. Toxicity was graded from zero to five. Dosimetric parameters such as the MLD, D10%, D20%, and lung subvolumes (V10 and V20) were obtained from the treatment plan. Dosimetric parameters and number of patients demonstrating toxicity ≥ grade 2 weremore » tabulated. Linear regression analysis was used to calculate correlations between MLD and D10, D20, V10 and V20. Results: The percentages of patients with > grade 2 pneumonitis, fatigue, cough, and dyspnea over 3 to 12 months increased from 0.0% to 3.5%, 3.2% to 10.5%, 4.3% to 8.3%, and 10.8% to 18.8%, respectively. Computed dose indices D10%, D20% were 7.9±4.8 Gy and 3.0±2.3 Gy, respectively. MLD ranged from 0.34 Gy up to 9.9 Gy with overall average 3.0±1.7 Gy. The averages of the subvolumes V10 and V20 were respectively 8.9±5.3% and 3.0±2.4%. The linear regression analysis showed that V10 and D10 demonstrated the strongest correlation to MLD; R2= 0.92 and 0.87, respectively. V20, and D20 were also strongly correlated with MLD; R2 = 0.81 and 0.84 respectively. A correlation was also found to exist between MLD > 2 Gy and ≥ grade 2 cough and dyspnea. Subvolume values for 2Gy MLD were 5.3% for V10 and 2% for V20. Conclusion: Dosimetric indices: MLD ≥ 2Gy, D10 ≥ 5Gy and V10 ≥ 5% of the total lung volume were predictive of > grade 2 cough and dyspnea QOL data. The QOL results are a novel component of this work. acknowledgement of the Varian grant support.« less
  • Purpose: To evaluate whether the risk of local recurrence depends on the biologic effective dose (BED) or fractionation dose in patients with resectable rectal cancer undergoing preoperative radiotherapy (RT) compared with surgery alone. Methods and Materials: A meta-analysis of randomized controlled trials (RCTs) was performed. The MEDLINE, Embase, CancerLit, and Cochrane Library databases were systematically searched for evidence. To evaluate the dose-response relationship, we conducted a meta-regression analysis. Four subgroups were created: Group 1, RCTs with a BED >30 Gy{sub 10} and a short RT schedule; Group 2, RCTs with BED >30 Gy{sub 10} and a long RT schedule; Groupmore » 3, RCTs with BED {<=}30 Gy{sub 10} and a short RT schedule; and Group 4, RCTs with BED {<=}30 Gy{sub 10} and a long RT schedule. Results: Our review identified 21 RCTs, yielding 9,097 patients. The pooled results from these 21 randomized trials of preoperative RT showed a significant reduction in mortality for groups 1 (p = .004) and 2 (p = .03). For local recurrence, the results were also significant in groups 1 (p = .00001) and 2 (p = .00001).The only subgroup that showed a greater sphincter preservation (SP) rate than surgery was group 2 (p = .03). The dose-response curve was linear (p = .006), and RT decreased the risk of local recurrence by about 1.7% for each Gy{sub 10} of BED. Conclusion: Our data have shown that RT with a BED of >30 Gy{sub 10} is more efficient in reducing local recurrence and mortality rates than a BED of {<=}30 Gy{sub 10}, independent of the schedule of fractionation used. A long RT schedule with a BED of >30 Gy{sub 10} should be recommended for sphincter preservation.« less
  • Purpose: The expressions of six cell-cycle-associated proteins were analyzed in cervical squamous cell carcinomas in correlation in a search for prognostic correlations in tumors treated with concurrent chemoradiation therapy (cCRT). Methods and Materials: The expressions of p53, p21/waf1/cip1, molecular immunology borstel-1 (MIB-1), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor type 2 (HER2), and Bcl-2 were studied using an immunohistochemical method in 57 cases of cervical squamous cell carcinoma treated with cCRT. Patients received cCRT between 1998 and 2005. The mean patient age was 61 years (range, 27-82 years). The number of patients with Stage II, III, andmore » IVA disease was 18, 29, and 10, respectively. Results: The number of patients with tumors positive for p53, p21/waf1/cip1, MIB-1, EGFR, HER2, and Bcl-2 was 26, 24, 49, 26, 13, and 11, respectively; no significant correlation was noted. The 5-year overall survival rates of HER2-positive and -negative patients was 76% vs. 44%, which was of borderline significance (p = 0.0675). No significant correlation was noted between overall survival and expressions of p53, p21/waf1/cip1, MIB-1, EGFR, and Bcl-2. No correlation was observed between local control and expression of any of the proteins. Conclusion: Expression of HER2 protein had a weak impact of borderline significance on overall survival in squamous cell carcinoma of the uterine cervix treated with cCRT. However, no clinical associations could be established for p53, p21/waf1/cip1, MIB-1, EGFR, and Bcl-2 protein expressions.« less