Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval.

BACKGROUND: The QT interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. OBJECTIVES: The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. METHODS: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 microg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. RESULTS: At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P <.001). However, the Framingham and Hodges formulas did not alter the accuracy of the assessment of QT interval change. CONCLUSION: Rate correction of QT intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.     

GLUT1 and GLUT8 in endometrium and endometrial adenocarcinoma.

Glucose is provided to cells by a family of glucose transport facilitators known as GLUTs. These transporters are expressed in a tissue specific manner and are overexpressed in many primary tumors of these tissues. Regulation of glucose transport facilitator expression has been demonstrated in endometrial tissue and endometrial adenocarcinoma. The following experiments were conducted to quantify and localize the expression of GLUT1 and GLUT8 in benign endometrium and compare this expression to endometrial cancer. Endometrial tissue samples were obtained from random hysterectomy specimens of patients with benign indications for surgery and endometrial cancer. Immunoblot and immunolocatization studies were performed using GLUT1 and GLUT8 specific antisera. Endometrial samples from 65 women who had undergone hysterectomy were examined (n=38 benign, n=27 malignant). A 44 and a 35.4 kDa immunoreacive species was demonstrated in endometrium and endometrial cancer for GLUT1 and GLUT8, respectively. Upregulation of GLUT1 expression was demonstrated with increasing grade of tumors (P<0.002). GLUT8 expression was increased in all tumor subtypes compared to atrophic endometrium (P<0.001). Apical localization by GLUT1 and GLUT8 was demonstrated in endometrial glands. GLUT1 and GLUT8 demonstrated diffuse intracellular localization in the cancer subtypes. GLUT1 and GLUT8 are expressed in both human endometrium and endometrial cancer. There appears to be a step-wise progression in GLUT1 and GLUT8 expression as tumor histopathology worsens. GLUT1 and GLUT8 may be important markers in tumor differentiation, as well as providing energy to rapidly dividing tumor cells.     

Mortality studies of machining fluid exposure in the automobile industry III: A case-control study of larynx cancer

A case-control study of larynx cancer was conducted within a cohort of automobile workers exposed to metal working fluids, commonly referred to as machining fluids (MF). Results are based on 108 cases of larynx cancer and 5:1 matched controls. Risks associated with specific types of MF, as well as specific components of the fluids were evaluated. Based on a retrospective exposure assessment, lifetime exposures to straight and soluble fluids, grinding particulate, biocides, selected metals, sulfur, and chlorine were examined. Exposure to asbestos and acid mists at two of the three study sites was also characterized. Results suggest that straight mineral oils are associated with almost a two-fold excess in larynx cancer risk. There was also evidence of an association with elemental sulfur, commonly added to straight MF to improve the integrity of the materials under extreme pressure and heat. It is not clear whether sulfur is causally related to an excess relative risk of larynx cancer or whether the observed association is the result of unmeasured confounding by another contaminant or process feature. For example, the high stress operations that require MF enriched with sulfur are also more likely to produce polycyclic aromatic hydrocarbons (PAHs) during the process. Thus, the observed association with sulfur may be due to an association with PAH. The finding of excess risk of laryngeal cancer associated with MF is consistent with several previous reports in the literature. This is the first study, however, to distinguish straight mineral oils from other types of MF. Based on these findings, a general reduction in concentrations of straight mineral oil particulate in occupational environments would be prudent.     

Concurrent quantification of tissue metabolism and blood flow via 2H/31P NMR in vivo. III. Alterations of muscle blood flow and metabolism during sepsis.

In the conclusion of this series of reports, the application of 31P/2H NMR to investigate the pathophysiology of sepsis in rat hindlimb muscle is demonstrated. Sepsis decreased muscle [PCr] by 18%, 18 +/- 4 SD vs 22 +/- 4 SD mmol/kg tissue wet wt (P = 0.01) in control rats but [ATP] was unchanged, 6 mmol/kg tissue wet wt (P = 0.2). The derived free cytosolic [ADP] in the two groups was similar, [ADP]septic = 0.023 +/- 0.004 SD and [ADP]control = 0.021 +/- 0.003 SD mmol/kg tissue wet wt, and not statistically different (P = 0.14). Likewise [Pi] in the septic and control groups was not statistically different, [Pi]septic = 1.1 +/- 0.5 SD and [Pi]control = 1.2 +/- 0.4 SD mmol/kg tissue wet wt (P = 0.2). Septic rats presented the symptom of respiratory alkalosis evidenced by elevated blood pH. Sepsis decreased muscle blood flow by 33%, P = 0.003, but examination of individual subjects did not demonstrate a correlation with the reduction in [PCr]. Thus, a metabolic energy deficit caused by cellular ischemia/hypoxia is not a likely cause of cellular abnormality in rat hindlimb muscle during sepsis.     

Decreased activity of rat A10 dopamine neurons following withdrawal from repeated cocaine.

Electrophysiological techniques were used to determine the basal activity of A10 dopamine (DA) neurons in the rat ventral tegmental area after a 10-14 day withdrawal from repeated cocaine treatment (10.0 mg/kg i.p. twice daily for 14 days). The number of spontaneously active A10 DA cells was significantly decreased (42%) in the cocaine-treated rats. This decreased activity may underlie the diminished basal levels of synaptic DA within the nucleus accumbens previously reported in cocaine-withdrawn rats and may account for anhedonia, anergia and cocaine craving reported by withdrawn cocaine addicts.