The plant growth-promoting rhizobacterium Enterobacter cloacae UW5 synthesizes the plant growth hormone indole-3-acetic acid (IAA) via the indole-3-pyruvate pathway utilizing the enzyme indole-3-pyruvate decarboxylase that is encoded by ipdC. In this bacterium, ipdC expression and IAA production occur in stationary phase and are induced by an exogenous source of tryptophan, conditions that are present in the rhizosphere. The aim of this study was to identify the regulatory protein that controls the expression of ipdC. We identified a sequence in the promoter region of ipdC that is highly similar to the recognition sequence for the Escherichia coli regulatory protein TyrR that regulates genes involved in aromatic amino acid transport and metabolism. Using a tyrR insertional mutant, we demonstrate that TyrR is required for IAA production and for induction of ipdC transcription. TyrR directly induces ipdC expression, as was determined by real-time quantitative reverse transcription-PCR, by ipdC promoter-driven reporter gene activity, and by electrophoretic mobility shift assays. Expression increases in response to tryptophan, phenylalanine, and tyrosine. This suggests that, in addition to its function in plant growth promotion, indolepyruvate decarboxylase may be important for aromatic amino acid uptake and/or metabolism.Auxins are an important class of phytohormones that are essential for many aspects of plant growth and development, including organogenesis; tropic responses; cellular processes such as cell expansion, division, and differentiation; and gene regulation (1,9,21,25,60). The predominant natural auxin is indole-3-acetic acid (IAA) (8,21,60). In addition to synthesis in plant tissues, many plant-associated bacteria also produce and secrete IAA that can influence the health of host plants. Production of IAA by some phytopathogenic bacteria causes plant diseases such as gall tumor formation by Agrobacterium tumefaciens, Erwinia herbicola pv. gypsophilae, and Pseudomonas syringae pv. savastanoi and necrotic lesions caused by Pseudomonas syringae pv. syringae (15,16,35,38,42,63). Loss of the ability to synthesize IAA, through mutagenesis, reduces the virulence of these pathogens (2, 16).Paradoxically, IAA produced by plant growth-promoting rhizobacteria (PGPR) has been found to enhance host root system development. Plant roots colonized with the PGPR species Azospirillum brasilense Sp6, Enterobacter cloacae UW5, and Pseudomonas putida GR12-2 displayed increases in root hair formation, the number and length of lateral roots, and/or primary root length that were dependent on bacterial IAA production. Mutants that were unable to synthesize IAA did not increase root proliferation (7,23,45,58,65). Well-developed root systems are important for natural nutrient uptake and for anchoring plants in soil. The differences in the effect of IAA produced by these two groups of bacteria may be due to differences in the levels of IAA production in planta or other contributing factors (46,57,65).A number of IAA biosynthetic ...

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The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25–750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.

Purpose Our objective was to evaluate the pharmacokinetics (PK) of doxorubicin during pregnancy compared to previously published data from non-pregnant subjects. Methods During mid- to late-pregnancy, serial blood and urine samples were collected over 72 hours from 7 women treated with doxorubicin for malignancies. PK parameters were estimated using noncompartmental techniques. Pregnancy parameters were compared to those previously reported non-pregnant subjects. Results During pregnancy, mean (± SD) doxorubicin PK parameters utilizing 72 hour sampling were: clearance (CL), 412 ± 80 mL/min/m2; steady-state volume of distribution (Vss), 1132 ± 476 L/m2; and terminal half-life (T1/2), 40.3 ± 8.9 hr. The BSA-adjusted CL was significantly decreased (p < 0.01) and T1/2 was not different compared to non-pregnant women. Truncating our data to 48 hours, PK parameters were: CL, 499 ± 116 ml/min/m2; Vss, 843 ± 391 L/m2; and T1/2, 24.8 ± 5.9 hr. The BSA-adjusted CL in pregnancy compared to non-pregnant data was significantly decreased in 2 of 3 non-pregnant studies (p < 0.05, < 0.05, NS). Vss and T1/2 were not significantly different. Conclusions In pregnant subjects, we observed significantly lower doxorubicin CL in our 72 hour and most of our 48 hour sampling comparisons with previously reported non-pregnant subjects. However, the parameters were within the range previously reported in smaller studies. At this time, we cannot recommend alternate dosage strategies for pregnant women. Further research is needed to understand the mechanism of doxorubicin pharmacokinetic changes during pregnancy and optimize care for pregnant women.

Oral hypoglycemic agents such as glyburide (second generation sulfonylurea) and metformin (biguanide) are attractive alternatives to insulin due to lower cost, ease of administration, and better patient adherence. The majority of evidence from retrospective and prospective studies suggests comparable efficacy and safety of oral hypoglycemic agents such as glyburide and metformin as compared to insulin when used in the treatment of women with gestational diabetes mellitus (GDM). Glyburide and metformin have altered pharmacokinetics during pregnancy and both agents cross the placenta. In this article, we review the efficacy, safety and dosage of oral hypoglycemic agents for the treatment of gestational diabetes mellitus. Additional research is needed to evaluate optimal dosage for glyburide and metformin during pregnancy. Comparative studies evaluating the effects of glyburide and metformin on long-term maternal and fetal outcomes are also needed.