Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

Antiemetic care for patients with breast cancer: focus on drug interactions and safety concerns.

PURPOSE: The drug interactions and adverse events that should be considered when individualizing antiemetic therapy for patients undergoing treatment for breast cancer are reviewed. SUMMARY: A variety of antiemetic agents are available, including antihistamines, dopamine-receptor antagonists, serotonin-receptor antagonists, and neurokinin-receptor antagonists. To ensure optimal symptom control for each patient without unnecessarily prolonging treatment, patient- and treatment-specific risk factors must be considered. Neurokinin-receptor antagonists, the newest class of antiemetics, are effective in preventing acute and delayed chemotherapy-induced nausea and vomiting but must be used in combination with a serotonin-receptor antagonist and a corticosteroid. The serotonin-receptor antagonists have become the mainstay of antiemetic therapy, but current guidelines do not distinguish among the different agents in this class. However, there are distinct pharmacologic differences that may affect the potential for drug interactions and, ultimately, patient outcomes and the occurrence of adverse events. Therefore, the potential for drug interactions must be considered when selecting an antiemetic, particularly for patients who are taking multiple concomitant medications. Further, because a number of breast cancer therapies and some antiemetic agents carry cardiovascular warnings or precautions and since breast cancer patients may already be suffering from cardiovascular complications, the possible cardiotoxic effects of the antiemetic or chemotherapy agents or the combinations of these agents should be considered. CONCLUSION: Antiemetic treatment is essential for patients with breast cancer who are undergoing moderately to highly emetogenic cytotoxic treatment. When selecting an antiemetic, clinicians must select an agent that provides optimal protection against nausea and vomiting while avoiding drug-drug interactions and additional adverse events.     

The Role of Energy Expenditure in Energy Regulation: Findings from a Decade of Research

The role of energy expenditure in energy regulation remains a subject of continuing controversy. New data have emerged from studies conducted over the last decade demonstrating that energy expenditure is a critical factor contributing to successful energy regulation in normal individuals, as well as to the disregulation of energy balance that characterizes obesity. Reduced energy expenditure appears to facilitate weight gain in individuals susceptible to obesity and also appears to reduce the extent of body energy loss during undereating in both lean and obese individuals. The magnitude of the reduction in energy expenditure during, and perhaps after, weight loss is greater than expected on the basis of the reduction in body weight and appears to occur in response to undefined underlying determinants of energy regulation. In addition, exercise intervention studies and cross-sectional investigations of the relationship between energy expenditure for physical activity and body composition demonstrate an apparent equilibration between physical activity and body fat content. This equilibration is suggestive of a direct influence of physical activity on the underlying metabolic determinants of energy balance.     

Physiotherapy rehabilitation of the smile after long-term facial nerve palsy using video self-modeling and implementation intentions.

OBJECTIVE: To improve smiling after long-term facial nerve palsy (FNP). Physiotherapy rehabilitation of an adapted (more symmetrical) smile was investigated in FNP subjects 1 year post-onset, using video self-modeling (video replay of only best adapted smiles) and implementation intentions (preplanning adapted smiles for specific situations). STUDY DESIGN AND SETTING: Prospective, blinded clinical trial. Facial-Nerve-Palsy Clinic. RESULTS: After video self-modeling: 1) reaction time (RT) to initiation of adapted smiles became 224 ms faster whereas RT for everyday (asymmetrical) smiles became 153 ms slower; 2) adapted smiles were completed 544 ms faster; 3) adapted smiles had higher overall quality, movement control, and symmetry ratings; and 4) Facial Disability Index scores also improved. Implementation intentions after video self-modeling ensured transfer of adapted smile to everyday situations. CONCLUSION: Following intervention the smile improved, with significant changes in availability, execution speed, and quality. SIGNIFICANCE: This study supports these rehabilitation techniques to maximize quality of smiling following FNP. EBM rating: B-2b.     

Habitual physical activity and estradiol levels in women of reproductive age.

Variation in the risk of breast cancer observed among women and among populations may be explained by variation in lifetime exposure to estrogens. The suppressive effect of exercise on estradiol levels in women is well documented, but it is unknown whether habitual (i.e. typical daily) physical activity has a similar effect. Epidemiological data suggest that physical activity is one of the few modifiable factors capable of reducing the risk of breast cancer in women. We investigated whether variation in the amount of habitual activity corresponds to variation in estradiol levels in women of reproductive age. One hundred and thirty-nine regularly menstruating women 24-37 years of age collected daily saliva samples for one complete menstrual cycle and kept a daily log of physical activity. Saliva samples were analyzed for concentration of estradiol. We observed a negative relationship between habitual physical activity and salivary levels of estradiol. Mean estradiol was 21.1 pmol/l in the low, 17.9 pmol/l in the moderate and 16.6 pmol/l in the high activity group (all pairwise differences were statistically significant at P<0.009). A strong association exists between physical activity and levels of estradiol among women of reproductive age. A modern lifestyle, characterized by reduced physical activity, may therefore contribute to a rise in the levels of estradiol produced during menstrual cycles and thus to higher cumulative lifetime exposure to estradiol, resulting in a higher risk of breast cancer.     

A PACU crisis: a case study on the development and management of methemoglobinemia.

The development of methemoglobinemia requires rapid recognition, confirmation, and treatment. This case study describes the development, diagnosis, and management of a 63-year-old male scheduled for a laparoscopic cholecystectomy with an intraoperative cholangiogram who developed methemoglobinemia after benzocaine was given for intubation.     

Methodological issues associated with using different cut-off points to categorize outcome variables.

Knowledge of the factors that contribute to delay in seeking medical treatment for acute myocardial infarction (AMI) provides the basis for interventions that are intended to facilitate prompt care-seeking behaviour. However, operational definitions of delay time vary across research studies. The use of inconsistent cut-off times to distinguish between delayers and non-delayers is likely to compromise comparability and generalizability of the findings across studies. The purpose of this paper is to examine the impact of inconsistent operationalization of delay, in terms of cut-off times, on the validity of research findings pertaining to identifying its predictors. Secondary data analysis was performed using a sample of 73 patients who had recently experienced out-of-hospital AMI and concluded that their symptoms were related to the heart. Several regression models were built to examine the influence of using different cut-off times (1, 2, 3, 6, and 12 hours, median delay) on the number and nature of predictors ofAMI care-seeking delay.The impact of varying cut-off times on the explained variance, sensitivity, specificity, and predictive values associated with each regression model was examined. The use of different cut-off times produced different sets of independent predictors, which varied in number and nature.The variance explained by the different regression models as well as their classification indices varied. Use of different cut-off times for the definition of delay time led to inconsistent results. Thus, it is recommended that criteria be established among clinicians and researchers with regard to operationally defining care-seeking delay for AMI.