Evaluation of the ToxRTool's ability to rate the reliability of toxicological data for human health hazard assessments.

Regulatory agencies often utilize results from peer reviewed publications for hazard assessments. A problem in doing so is the lack of well-accepted tools to objectively, efficiently and systematically assess the quality of published toxicological studies. Herein, we evaluated the publicly available software-based ToxRTool (Toxicological data Reliability assessment Tool) for use in human health hazard assessments. The ToxRTool was developed by the European Commission's Joint Research Center in 2009. It builds on Klimisch categories, a rating system established in 1997, by providing additional criteria and guidance for assessing the reliability of toxicological studies. It also transparently documents the study-selection process. Eight scientists used the ToxRTool to rate the same 20 journal articles on thyroid toxicants. Results were then compared using the Finn coefficient and "AC1" to determine inter-rater consistency. Ratings were most consistent for high-quality journal articles, but less consistent as study quality decreased. Primary reasons for inconsistencies were that some criteria were subjective and some were not clearly described. It was concluded, however, that the ToxRTool has potential and, with refinement, could provide a more objective approach for screening published toxicology studies for use in health risk evaluations, although the ToxRTool ratings are primarily based on study reporting quality.

Aflatoxicosis in chickens (Gallus gallus): an example of hormesis?

Poultry has commonly been considered highly susceptible to aflatoxins. However, among domestic fowl there is wide variability in specific species sensitivity to these mycotoxins. Comparative toxicological studies in avian species have shown that ducklings and turkey poults are the most sensitive species to aflatoxins, quails show intermediate sensitivity, whereas chickens are the most resistant. Hormesis is a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition. The low-dose stimulation is typically maximal at only about 30 to 60% greater than controls. Hormesis has been noted in regards to changes in body weight in numerous studies, including those performed for the US National Toxicology Program, with over 50 chemicals. The present paper assesses how relatively low levels of aflatoxin consumption in feed may affect the growth rate of chickens. In general, multiple independent investigations have shown that such aflatoxin consumption affects growth in a hormetic-like biphasic manner with a low dose stimulation and a high dose inhibition. Such observations were then generalized to other toxic agents and animal models, suggesting that low doses of stressor agents induce adaptive responses as reflected in accelerated growth rates. The implications of such hormetic dose responses are briefly discussed.

Individualization of bypassing agent treatment for haemophilic patients with inhibitors utilizing thromboelastography.

The treatment of bleeding for haemophilic patients with inhibitors relies on the use of the bypassing agents, recombinant factor VIIa and factor eight inhibitor bypass activity (FEIBA). While both therapies are effective in the majority of bleeding episodes, there is a significant amount of interindividual variability when it comes to the response to therapy. As of yet, there is no reliable laboratory parameter that can predict the response to therapy in the same manner that factor VIII and factor IX levels predict response in non-inhibitor patients. Developing such a laboratory parameter is vital in order to maximize the clinical efficacy of these agents. Thromboelastography (TEG) is a device, which assesses clot formation over time in whole blood and has several characteristics which suggest it may be an effective way to monitor bypass agent therapy. We studied the ability of TEG to individualize the treatment regimens of three patients with high titre inhibitors assessing the response to recombinant factor VIIa, FEIBA, and when both were used sequentially. The TEG allowed for individualization of treatment for each of the three patients and resulted in more effective, convenient and less expensive treatment regimens. We thus believe that TEG is a promising device for monitoring of bypass agent therapy and should be studied further.

The Single Exposure Carcinogen Database: assessing the circumstances under which a single exposure to a carcinogen can cause cancer.

A relational retrieval database has been developed compiling toxicological studies that assess whether a single dose of a chemical or physical agent, without exogenous promotional stimuli, could cause tumor development in animal models. This database allows for an evaluation of these studies over numerous parameters important to tumor outcome, which include type and quality of the studies as well as physical/chemical properties of the agents. An assessment of the database, which currently contains approximately 5500 studies involving about 800 chemicals from 2000 articles, reveals that a single dose of an agent can cause tumors to develop in males and females of numerous animal models in all principal age groups. In addition, the range of the 426 agents causing a positive response is chemically diverse, with representatives from over several dozen chemical classes. The dose caused a tumor endpoint was generally not acutely life threatening and was frequently a low proportion of the LD50 (i.e., less than 1/50 LD50). Positive responses also were reported via multiple routes of exposure, mainly oral, by injection, or dermal. These findings indicate that the phenomenon of single-exposure carcinogenesis is widespread and highly generalizable across chemical class, route, dose range, species, age, and gender. Single-exposure carcinogenesis, a concept long de-emphasized by regulatory agencies, requires a careful and formal consideration, especially as it may pertain to accidental spills, leaks, fires, explosions, and exposure excursions, but not necessarily limited to these.

Susceptibility to chlordecone-carbon tetrachloride induced hepatotoxicity and lethality is both age and sex dependent.

The present paper examines the susceptibility to chlordecone (Kepone, CD) and carbon tetrachloride across different ages (35, 45, and 63-days-old) in male and female Sprague-Dawley rats using different lengths of time on a CD diet (10 ppm). The principal findings are that the hepatotoxicity and mortality associated with CD-CCl4 interaction is highly age-dependent for both sexes. There was marked hepatotoxicity occurring in both sexes as they reached 45 days-of-age and females were considerably more susceptible than males to both CD-CCl4-induced hepatotoxicity and lethality. While 63-day-old females are more susceptible to the CD-CCl4 interaction than their male counterparts, the magnitude of the sex difference is diminished from that observed in 45-day-old rats. These findings challenge the hypothesis of Mehendale (1990, Med. Hypotheses 33, 289-299) that chlordecone (CD) pretreatment eliminates the well-established sex difference in CCl4-treated rats. In contrast to the CD-CCl4 findings, the sex difference in CCl4-induced hepatotoxicity was not age-dependent and was consistent over the three ages studied. The findings that CD-CCl4 interaction is highly age-dependent (within the 3 ages tested) but that CCl4-induced hepatotoxicity is not, suggest that the CD-CCl4 interaction acts via a mechanism that does not primarily involve CCl4 potentiation.

Off-pump revascularization of the circumflex artery: technical aspect and short-term results.

BACKGROUND: Beating heart surgery is a technique currently used for revascularization of the anterior and inferior territory. However, revascularization of the circumflex artery is more problematic. With a specific apparatus and surgical technique, we have extended the use of beating heart surgery to more than 90% of patients with multivessel disease, including those necessitating circumflex artery revascularization. METHODS: Between October 1996 and November 1997, 140 patients underwent beating heart surgery by the same surgeon (R.C.). Among these patients, 111 required reconstruction of the circumflex artery territory and were followed up prospectively. They represent the cohort of patients presented in this study. There were 90 men and 21 women averaging 64+/-9.9 years of age. Mean left ventricular ejection fraction was 55%+/-13.7%, and a significant left main coronary artery disease was present in 27% of the patients. Five patients had prior coronary revascularization. RESULTS: An average of 3.1+/-0.1 grafts/patient were performed. Complete revascularization was achieved in 95%. Only 1 patient needed conversion to cardiopulmonary bypass because of spontaneous ascending aortic dissection. Perioperative and postoperative bleeding were 446+/-245 mL and 644+/-442 mL, respectively. Homologous transfusions were required in 40% of the patients. Myocardial infarction occurred in 2.7% and operative mortality in 0.7% (1 patient). Average hospital stay was 6.6+/-3.1 days, and no patient exhibited early recurrence of angina. Early coronary angiograms (first 8 patients) demonstrated a 100% patency with 95% freedom from significant stenosis. CONCLUSIONS: Complete coronary artery revascularization is feasible on the beating heart without the assistance of cardiopulmonary bypass with a low morbidity and mortality and excellent early angiographic results. Long-term follow-ups are needed to substantiate the potential long-term benefits of this technique.

Triple coronary artery revascularization on the stabilized beating heart: initial experience.

OBJECTIVE: To decrease health costs and morbidity related to extracorporeal circulation, surgeons have modified the coronary artery bypass (CAB) technique so that it can be completed without the use of extracorporeal circulation. This study summarizes initial experience with direct coronary artery revascularization on the beating heart using a coronary stabilizer. DESIGN: A case series. SETTING: The Montreal Heart Institute, a university-affiliated centre, specializing in the treatment of cardiac illnesses. PATIENTS: Ten patients underwent CAB by this technique. They presented with double or triple coronary artery disease with no intramyocardial, heavily calcified, diffused atheromatous coronary vessels, or left main coronary disease. INTERVENTION: CAB grafting in the beating heart. The anterior wall was grafted in all patients, the inferior wall in 7 and the posterior wall in 7. MAIN OUTCOME MEASURES: Patient survival and graft patency. RESULTS: One patient died of multiple organ failure not related to the grafting technique itself, and 1 patient suffered a non-Q myocardial infarction. Early coronary angiography performed on 8 patients showed 100% graft patency, most with excellent distal runoff (21/22 grafts). CONCLUSION: In patients with adequate anatomy, performance of CAB without extracorporeal circulation can achieve excellent early results provided there is appropriate mechanical stabilization of the beating heart.

Hemodynamic and pharmacodynamic comparison of doxacurium and high-dose vecuronium during coronary artery bypass surgery: a cost-benefit study.

Doxacurium (DOX), a new nondepolarizing neuromuscular blocking drug (NMBD), was compared in a randomized, double-blind fashion to high-dose vecuronium (VEC) in 60 coronary artery bypass grafting (CABG) patients. A third group of 15 patients older than 70 years of age (DOX-70) was added to compare the effects of DOX to VEC in the older population. Endpoints of the study were hemodynamic stability, ease of ventilation and intubation, anesthesiologist's satisfaction, drug interventions to correct hemodynamic instability, and total cost of the drug. Anesthesia was induced with fentanyl (30 micrograms/kg) along with the NMBD (DOX 80 micrograms/kg, VEC 400 micrograms/kg) over a 2-minute period. Following induction, heart rate (HR) and mean arterial pressure (MAP) were decreased (P < 0.01) in all groups. Tracheal intubation caused the HR to return to baseline in the DOX-70 group. There was no difference in central venous pressure, pulmonary artery occlusive pressure, cardiac index, systemic vascular resistance, and drug intervention for DOX and VEC. None of the patients had evidence of myocardial ischemia. There was a statistically significant but clinically irrelevant decrease in central venous pressure and systemic vascular resistance in the DOX-70 group. The durations of the induction and maintenance doses of DOX were similar in the younger and older patients. Although the intubating dose of VEC had a faster onset of action, this had no effect on the ease of ventilation, conditions for tracheal intubation, and overall anesthesiologist satisfaction. The total cost for each NMBD was not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Multidimensional narrow bore liquid chromatography analysis of Ro 24-0238 in human plasma.

A highly sensitive LC method has been developed and validated for quantitation of Ro 24-0238 in human plasma using Ro 24-2446 as an internal standard. With 1 ml of plasma, the limit of quantitation of the method was 50 pg ml-1 of Ro 24-0238. After solid-phase extraction with C18 reversed-phase cartridges, the samples were reconstituted in an acidic buffer solution; under these conditions, Ro 24-0238 and Ro 24-2446 (IS) were converted to their cationic forms. The LC system employed a strong cation exchange column and a narrow bore reversed-phase column, connected via a column switching valve. The cationic analyte and internal standard were separated from most of the endogenous components of plasma on the cation exchange column. A small fraction containing the analyte and the internal standard was transferred by automated valve switching to the narrow bore reversed-phase column, which further resolved the individual components. The chromatography was monitored by UV absorption at 322 nm. The overall intra-assay precision was 3.6% (RSD) and the per cent error was less than +/- 11%. The overall inter-assay precision was 3.9% (RSD). Linearity was demonstrated in a concentration range of 50-5000 pg ml-1. This method has been applied to pharmacokinetic studies of Ro 24-0238 in man.

Determination of a new antibacterial agent (Ro 23-9424) by multidimensional high-performance liquid chromatography with ultraviolet detection and direct plasma injection.

Analysis of a new antibacterial agent, Ro 23-9424 (I), in plasma has been complicated by the fact that its metabolite, fleroxacin (II), is formed not only in vivo, but also nonenzymatically by the hydrolysis of the ester bond of I. In order to minimize sample preparation time and possible hydrolysis during sample preparation, a high-performance liquid chromatographic procedure was developed which features direct injection of plasma and multidimensional chromatography. The first dimension size-exclusion separation allows plasma proteins to elute with the column void volume. The second dimension reversed-phase column provides a high-resolution separation dependent upon the hydrophobicity of the sample species. With a 5-microliters injection, the limit of quantitation of the method is 0.35 microgram/ml for I and 0.27 microgram/ml for II. The method was used to determine steady state plasma vs. time profiles for I and II from 750 mg i.v. doses of I administered twice daily.

Determination of Ro 23-7637 in dog plasma by multidimensional ion-exchange-reversed-phase high-performance liquid chromatography with ultraviolet detection.

Ro 23-7637 (I) is a new drug under development for the treatment of metabolic diseases. A high-performance liquid chromatographic-ultraviolet detection (HPLC-UV) analytical procedure for its analysis in dog plasma was developed and is reported here. Following C18 solid-phase extraction, the sample is applied to a strong cation-exchange column in the first dimension. The analyte and internal standard, Ro 24-4558 (II), are transferred to a base-deactivated C18 reversed-phase column in the second dimension (orthogonal separation mechanism), with UV detection at 254 nm. The reversed-phase solid-phase extraction provides a gross isolation of the drug, based on hydrophobicity. The first-dimension ion-exchange separation allows neutral species and anions to elute with the column void volume, while separating basic species according to pKa. The second dimension provides a high-resolution separation dependent upon the hydrophobicity of the sample species. The rationale for using orthogonal multidimensional chromatography was that an exhaustive examination of reversed-phase and normal-phase columns invariably resulted in co-elution of I with endogenous plasma components, which limited the sensitivity of the method. We have utilized C18 solid-phase extraction, followed by multidimensional HPLC-UV, to develop an accurate and precise analytical method whose limit of quantitation, 5 ng/ml using 0.5 ml of plasma, is determined by inherent detector sensitivity. Increased sensitivity can be readily achieved by using more sample or by using microbore HPLC on the second dimension.

The stratification of cardiac surgical procedures according to use of blood products: a retrospective analysis of 1480 cases.

The use of blood products in 1480 consecutive cases of adult cardiac surgical procedures over a period of 15 mth was studied retrospectively using the database of the Department of Anaesthesia of the Institut de Cardiologie de Montréal. Use of blood products was compared in patients having (1) coronary artery bypass grafting, (2) valvular surgery, (3) or a combination of 1 and 2. First operations were compared with reoperations. Overall, the use of homologous blood products was greatest in patients of Group 3, intermediate in patients of Group 2, and smallest in patients of Group 1. Reoperations were associated with an increase in intraoperative transfusion of packed red blood cells, but postoperative chest drainage was similar to first operations. When all blood products (packed red blood cells, fresh frozen plasma and platelets) were taken into consideration, patients undergoing primary CABG or valve surgery were the least exposed to homologous blood donors (five and six units transfused respectively). Repeat CABG was associated with an intermediate exposure to homologous blood products (eight units). Finally, primary and repeat combined procedures, and repeat valve surgery were associated with the greatest exposure to foreign blood products (10, 13 and 10 units respectively). The data presented in this study provide a rational basis for stratification of procedures according to the expected use of blood products, particularly in view of future studies which may be planned to examine the efficiency of blood conservation strategies.

Double-blind comparison of pefloxacin and cefazolin as prophylaxis in elective cardiovascular surgery.

A total of 162 patients (134 males and 28 females) scheduled for coronary artery bypass grafting (144) or valve surgery (18) were randomly assigned to receive, under double-blind conditions, either pefloxacin 400 mg iv or cefazolin 1.0 g 30 min before the surgical incision and then post-operatively 12-hourly x 4 or 6-hourly x 8, respectively. Positive per- and post-operative cultures were seen in 27 patients (11 pefloxacin, 16 cefazolin) and 47 micro-organisms were isolated: 34 per-operatively (21 pefloxacin, 13 cefazolin) and 13 post-operatively (4 pefloxacin, 9 cefazolin). There were five failures of prophylaxis (2 pefloxacin, 3 cefazolin): two early (less than 5 days: 1 pefloxacin, 1 cefazolin) and three late (greater than or equal to 5 days, 1 pefloxacin, 2 cefazolin) divided into (i) one major primary failure in the cefazolin group (1 cefazolin resistant Staphylococcus epidermidis mediastinitis); (ii) two minor primary failures, one in each group (Gram-positive sternal incision abscesses) and (iii) two secondary failures (1 cefazolin resistant Enterobacter cloacae and Pseudomonas aeruginosa UTI in the cefazolin group and one culture negative pneumonia in the pefloxacin group). Tolerance to both antibiotics was excellent. In our sample of patients, the efficacy and safety of pefloxacin was not different from those of cefazolin in prophylaxis in cardiovascular surgery.

Safety of protamine sulfate administration in vasectomized men.

The majority of vasectomized men develop antibodies against different sperm antigens, including protamine. Due to the fact that salmon protamine is used clinically for heparin reversal and that a cross-reactivity has been observed between human and salmon protamine, vasectomized men may be at risk for adverse reactions to protamine sulfate. In order to explore this possibility, serum samples were analyzed for the presence of anti-sperm and anti-protamine antibodies in 20 vasectomized and 20 non-vasectomized men (controls) about to undergo major heart surgery requiring heparin reversal. The patients were closely monitored for any possible reaction following the injection of protamine. Anti-sperm antibodies were detected in the serum of 15 of the vasectomized men whereas only two of the non-vasectomized subjects had this type of antibody. Twenty-five percent of the vasectomized men presented with anti-protamine antibodies; in the control group, none of the patients had developed this type of antibody. Following the administration of protamine sulfate, none of the patients in either group showed any adverse reaction to the drug. It is concluded that vasectomized men are not at increased risk towards adverse reactions following the injection of protamine sulfate.

End-tidal carbon dioxide tension and temperature changes after coronary artery bypass surgery.

Variations in end-tidal carbon dioxide partial pressure (PETCO2) and temperature were measured for six hours following coronary artery bypass surgery in twenty patients. In the recovery room, the patients were mechanically ventilated with a tidal volume of 12 ml X kg-1. Arterial blood gases were drawn every two hours, and the respiratory frequency was adjusted to maintain arterial carbon dioxide pressure (PaCO2) in the range of 30-45 mmHg. Naso-pharyngeal temperature was recorded every 30 minutes, and PETCO2 was measured continuously. The mean difference between temperature-corrected arterial and end-tidal CO2 pressure measurements was 3.2 mmHg (SD = 2.8; r = 0.963). This difference did not vary with time, temperature or PCO2. The largest temperature increases (mean 1.7 degree C/hour) occurred at a mean of 253 minutes after the end of surgery. End-tidal PCO2 increased markedly as temperature rose, in spite of a coincident increase in ventilation and then decreased as temperature stabilized. Large increases in CO2 production, caused by the metabolic demands during rewarming, most likely account for these changes. It is concluded that end-tidal CO2 recordings are reliable, and can help in maintaining normocarbia during the short but unstable period associated with rewarming following cardiac surgery.

Middle ear pressure variations during nitrous oxide and oxygen anaesthesia.

Many authors have reported middle ear pressure variations during inhalation of high concentrations of nitrous oxide. An on-going study on subjects anaesthetized with nitrous oxide and oxygen supplemented with halogens or narcotics and excluding operations on the ear enables us to register three typical curves of middle ear pressure according to the patency of the Eustachian tube. We recorded significant negative middle ear pressures during the recovery period when there was important obstruction of the Eustachian tube. The presence of a tympanic "neomembrane" due to an old perforation associated with important obstruction of the Eustachian tube could lead to a tympanic perforation that may be unnoticed by the anaesthetist if it is not specifically investigated. In our series, we report one case of tympanic perforation and one case of haemotympanum as examples of such consequences.