The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.

Purpose: Both therapeutic and adverse effects of tamoxifen may be related to its tissue concentrations. We investigated concentrations of tamoxifen, 4-hydroxytamoxifen, Ndesmethyltamoxifen, and N-didesmethyltamoxifen in serum, normal breast, and breast cancer tissues during conventional dosage and two low-dose regimens. Furthermore we studied tamoxifen effects on the cancer proliferation marker Ki-67, and on sex hormone-binding globulin (SHBG).Experimental Design: From September 1999 to August 2001, 120 breast cancer patients were randomized to 20-, 5-, or 1-mg tamoxifen daily. We measured serum and tissue concentrations of tamoxifen and three metabolites after 28 days of treatment, and the changes between baseline and post-treatment levels of SHBG and Ki-67.Results: The median (range) tamoxifen concentrations (ng/ml) at doses of 1, 5, and 20 mg daily (n ‫؍‬ 38, 37, and 36) were 7.5 (2.9 -120.9), 25.2 (1.9 -180.9), and 83.6 (8.7-134.4) in serum, and 78.2 (35.9 -184), 272.3 (122-641), and 744.4 (208.6 -2556) in breast cancer tissue, respectively. Tamoxifen levels followed a dose-concentration relationship. The concentrations of tamoxifen and metabolites were related to each other. Serum and tissue concentrations of tamoxifen were associated with corresponding changes of SHBG levels, whereas changes of Ki-67 levels were not related. Conclusions:Estrogen agonistic effects of tamoxifen on SHBG decreased with lower dosage, whereas tamoxifen effects on Ki-67 expression did not change. This together with a >10-fold variation in serum tamoxifen concentrations and a serum to tissue concentration relationship suggest that tamoxifen treatment may be improved by administration of lower doses and therapeutic drug monitoring.

CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.

2One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENTThere are several major problems associated with the currently available TB treatment. First, the duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease (168). Second, adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence (19,168). Third, the increasing incidence of multidrug-resistant (MDR; resistance to at least rifampin and isoniazid) and extensively drug-resistant (XDR; MDR resistance plus resistance to a fluoroquinolone and an aminoglycoside) TB is a serious concern. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure) (175). The prevalence of MDR TB in new TB cases ranged from 0% in some Western European countries to more than 22% in Azerbaijan (2002 to 2007 survey); 14 of 72 participating countries reported an MDR TB prevalence of more than 5% (177). Second-line drugs for drug-resistant TB are not available everywhere and are less effective, more toxic, and require longer use than first-line drugs (61). Fourth, coinfection of TB and HIV is a problem by itself. Combined treatment of TB and HIV involves a high pill count with associated adherence problems, overlapping toxicity profiles of the antiretroviral and anti-TB drugs, drug interactions between rifampin and the antiretroviral protease inhibitors, and the risk of immune reconstitution syndrome (104). Fifth, prophylactic therapy of latent TB (TB infection without symptoms) with isoniazid is also associated with problems of nonadherence (180). Attempts to shorten treatment with alternative drugs resulted in severe adverse events (64,150,155).The World Health Organization (WHO) has developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources (49). In addition, TB diagnosis in the DOTS strategy is based on sputum microscopy, rather than sputum culture (173). Only advanced pulmonary TB is detected by sputum...