This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of 'monoamine oxidase inhibitors', 'major depression', 'depressive disorder' and 'depression (emotion)'. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The "bad reputation" and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients.

The reader's ability to judge the validity of pharmacokinetic research can be greatly compromised by the incomplete reporting of study information. Using consensus methods, we have developed a tool to guide transparent and accurate reporting of clinical pharmacokinetic studies. Endorsement and implementation of these guidelines by researchers, clinicians and journals would promote more consistent reporting of these studies and allow for better assessment of utility for clinical applications.

The CYP3A4 enzyme contributes to the disposition of more than 60 therapeutically important drugs and displays marked person-to-person variability of the catalytic function. However, the extent of genetic contribution to variability in CYP3A4 activity remains elusive. Recently, we showed that a comparison of between- (SDb2) and within-person (SDW2) variances provides an estimate of the genetic component of variability in drug disposition. The aim of the present analysis was to assess the genetic control of CYP3A4 activity in vivo. A computerized literature search was conducted covering 1966 to September 1999 to identify studies reporting repeated administration of CYP3A4 substrates. The genetic contribution (rGC) to disposition of each CYP3A4 substrate was obtained by the formula (SDb2-SDW2)/SDb2. The rGC values approaching 1.0, point to overwhelming genetic control, whereas those close to zero suggest that environmental factors dominate. A total of 16 studies with 10 different CYP3A4 substrates were identified (n = 161 subjects). The rGC for hepatic CYP3A4 activity as measured by midazolam plasma clearance or the erythromycin breath test was 0.96 (0.92-0.98) (95% Cl) and 0.89 (0.65-0.98), respectively (P < 0.05). The point estimates of rGC for composite (hepatic + intestinal) CYP3A4 activity measured after oral administration of cyclosporine, ethinylestradiol, ethylmorphine, nifedipine and nitrendipine, ranged from 0.66-0.98 (median: 0.83) (P < 0.05). Cyclosporine data suggested a higher genetic control of CYP3A4 at night than during the day. These data indicate that further molecular genetic investigations are warranted to identify genetic variants at CYP3A4 or elsewhere in the genome which contribute to regulation of CYP3A4 activity.

BACKGROUND: Treatment of febrile neutropenia (FN) is costly, because it typically involves hospitalization. As cancer rates continue to increase, the number of patients suffering from FN will also increase, making it important to quantify the costs of treating this condition accurately and comprehensively. METHODS: A consecutive sample of patients admitted to an inpatient hematology/oncology ward at a tertiary care hospital for the treatment of chemotherapy-induced FN was enrolled in this study. Patients were followed prospectively during hospitalization, and information on medical resource utilization including length of stay, medications, and laboratory and diagnostic tests was collected. Costs, extracted from hospital and provincial databases, were used to calculate the overall cost per FN episode, from the hospital perspective. RESULTS: Fifty-one episodes of FN that occurred in 46 patients were included in the study. Approximately 52% of these episodes occurred in women, and 65% of these episodes occurred in patients with hematologic malignancies. The mean AE standard deviation age of patients was 60.3 AE 13.4 years. The mean length of stay per episode was 6.8 AE 4.9 days. The mean overall cost per episode was 6324 AE 4783 in 2007 Canadian dollars. CONCLUSIONS: Hospitalization for the treatment of FN is expensive. The results of this study could be used in future economic evaluations of preventive measures and treatments for FN, including primary prophylactic administration of hematopoietic growth factors and outpatient treatment of this condition. Cancer 2010;116:742-8.

Improved quantifi cation of diverse CH 4 sources at the urban scale is needed to guide local GHG mitigation strategies in the Anthropocene. Herein, we focus on landfi ll CH 4 emissions in California, challenging the current IPCC methodology which focuses on a climate dependency for landfi ll CH 4 generation (methanogen-esis), but does not explicitly consider climate or soil dependencies for emissions. Relying on a comprehensive California landfi ll database, a fi eld-validated process-based model for landfi ll CH 4 emissions (CALMIM), and select fi eld measurements at 10 California sites with a variety of methods, we support the contrary position: Limited climate dependency for methanogenesis, but strong climate dependency for landfi ll CH 4 emissions. Contrary to the historic IPCC empirical model for methanogenesis with kinetic constants related to climate, we demonstrate a simpler and more robust linear empirical relationship (r 2 = 0.85; n=128) between waste mass and landfi ll biogas recovery [126 × 10-6 Nm 3 CH 4 hr-1 Mg waste-1 ]. More interestingly, there are no statistically signifi cant relationships with climate, site age, or status (open/closed) for landfi ll biogas recovery. Th e current IPCC methodology does not consider soil or climate drivers for gaseous transport or seasonal methanotrophy in diff erent cover soils. On the other hand, we illustrate strong climate and soil dependencies for landfi ll emissions-e.g., average intermediate cover emissions below 20 g CH 4 m-2 d-1 when the site's mean annual precipitation is >500 mm y-1. Th ereby, for the California landfi ll CH 4 inventory, the highest-emitting sites shift from landfi lls containing the largest mass of waste to sites dominated by intermediate cover types having a reduced rate of soil CH 4 oxidation during the annual cycle. Th ese diff erences have profound implications for developing more realistic, science-based urban and regional scale GHG inventories for landfi ll CH 4 while reducing uncertainties for this important anthropogenic source.

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

In mid-2000, a broiler chicken company in Alabama experienced high early mortality rates in chicks from two different hatcheries. Five isolates of Pseudomonas aeruginosa, obtained from these contaminated hatcheries and resulting broiler chicks with omphalitis, were selected to determine virulence of the bacteria. One-day-old specific-pathogen-free white leghorn chicks were placed into positive pressure isolation units (10 chicks per unit); feed and water were provided ad libitum. The five isolates of P. aeruginosa (1 x 10(1) or 1 x 10(1) colony-forming units/bird) were used to challenge two replicates of 10 chicks via yolk sac inoculation. Two control groups were injected with 0.1 ml of phosphate-buffered saline, and two groups received no treatment. Mortality was recorded daily, and the chicks that died were necropsied and liver and yolk sacs were cultured. After 14 days, the remaining chickens were euthanatized and necropsied. Bacterial isolates retrieved from liver and yolk sacs were identified by the API 20 NE typing system to confirm that they were the same as the challenge isolate. Virulence varied greatly among the isolates, resulting in mortality rates from 0 to 90%. The challenge isolates produced different and often distinctive postmortem lesion patterns. Antibiotic sensitivity tests showed that all five isolates were resistant to sulfisoxazole, ceftiofur, penicillin, lincomycin, bacitracin, oxytetracycline, erythromycin, naladixic acid, and tetracycline. The isolates varied in sensitivity to other antibiotics, but all isolates were sensitive to gentamicin.

Primary prophylaxis against febrile neutropenia with either filgrastim or pegfilgrastim is not cost-effective in DLBCL patients.