Search

The reduction of infant mortality (IM) continues to be a primary goal throughout much of the developing world, and a suite of methods have been proposed with which to achieve it. However, most attempts at IM reduction have taken place within the context of an almost bewilderingly complex regimen of simultaneous changes occurring in the physical environment, sociopolitical structure, and health care. Which of these various elements is truly causal in reducing IM and which may be merely a correlated but nonprimary agent? During the past two decades Mexico has constituted an extraordinary field laboratory with which to decipher the roles of these various potential agents of IM reduction. Health resources include community access to proper drainage, safe drinking water, electrical power, as well as a suite of individual, if highly intercorrelated, family and household characteristics. Despite considerable demographic and socioeconomic heterogeneity, dramatic reductions in IM have been achieved, and additional ones are certainly possible. We weigh the factors that have reduced infant mortality in this country. Particular infrastructure improvements in the Pacific South, the Gulf, and the Yucatan peninsula must be continued. This would impact both inequality and, in turn, infant health and survival in this country.

Several studies utilizing Rhodiola rosea , which contains a complex mixture of phytochemicals, reported some positive drug-drug interaction (DDI) findings based on in vitro CYP450's enzyme inhibition, MAO-A and MAO-B inhibition, and preclinical pharmacokinetic studies in either rats or rabbits. However, variation in and multiplicity of constituents present in Rhodiola products is a cause for concern for accurately evaluating drug-drug interaction (DDI) risk. In this report, we examined the effects of bioengineered, nature-identical salidroside on the inhibition potential of salidroside on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 utilizing human liver microsomes, the induction potential of salidroside on CYP1A2, CYP2B6 and CYP3A4 in cryopreserved human hepatocytes, the inhibitory potential of salidroside against recombinant human MAO-A and MAO-B, and the OATP human uptake transport inhibitory potential of salidroside using transfected HEK293-OATP1B1 and OATP1B3 cells. The results demonstrate that the bioengineered salidroside at a concentration exceeding the predicted plasma concentrations of <2 µM (based on 60 mg PO) shows no risk for drug-drug interaction due to CYP450, MAO enzymes, or OATP drug transport proteins. Our current studies further support the safe use of salidroside in combination with other drugs cleared by CYP or MAO metabolism or OATP-mediated disposition.

In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-free C max values (0.06, 0.66, 2.57, and 7.79 µ M, respectively) spanning the reported in vitro IC 50 values for OATP1B1 and OATP1B3 (≤1.7 μ M). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v. 2 H 4 -pitavastatin, 0.2 mg/kg) was increased 1.2-, 2.4-, 3.8-, and 4.5-fold, respectively. Plasma of RIF-dosed cynomolgus monkeys was subjected to a liquid chromatography-tandem mass spectrometry method that supported the analysis of 30 different BAs. Monkey urine was profiled, and we also determined that the impact of RIF on BA renal clearance was minimal. Although sulfated BAs comprised only 1% of the plasma BA pool, a robust RIF dose response (maximal ≥50-fold increase in plasma AUC) was observed for the sulfates of five BAs [glycodeoxycholate (GDCA-S), glycochenodeoxycholate (GCDCA-S), taurochenodeoxycholate, deoxycholate (DCA-S), and taurodeoxycholate (TDCA-S)]. In vitro, RIF (≤100 μ M) did not inhibit cynomolgus monkey liver cytosol-catalyzed BA sulfation and cynomolgus monkey hepatocyte-mediated uptake of representative sulfated BAs (GDCA-S, GCDCA-S, DCA-S, and TDCA-S) was sodium-independent and inhibited (≥70%) by RIF (5 μ M); uptake of taurocholic acid was sensitive to sodium removal (74% decrease) and relatively refractory to RIF (≤21% inhibition). We concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs and that exploration of their utility as circulating human OATP biomarkers is warranted., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices.

This column describes the first year of efforts in New Mexico to reform the behavioral health system. The process, guided by principles of cultural exchange theory, seeks to establish a "collaborative culture" among all stakeholders involved, including state agencies, consumers, families, advocates, and providers. Challenges have included inadequate system funding; insufficient development of skill sets among state personnel; underestimation of time and labor needed to address complex tasks; varying federal statutory and funder requirements for individual agencies; lack of a solid infrastructure for data collection, management, and dissemination; and clear definitions of the roles and relationships of local stakeholders to the state leadership group.

Hemoglobin synthesis was studied in vitro in reticulocytes from a patient with the anti-Lepore variant Hb Lincoln Park. Incorporation of L-leucine-3H into the alpha and beta delta chains of Hb Lincoln Park was substantially less than the incorporation into the corresponding globin chains of Hb A, with the rate of synthesis of the beta delta chain being similar to that of the delta chain of Hb A2. Synthesis of the alpha and total non-alpha globin components was unbalanced, with a substantial excess of alpha chain synthesis. These findings help to explain the mild hemolytic disease present in individuals with this hemoglobin variant.

Hematologic evaluation of a Nigerian obstetrical patient disclosed the presence of sickle-cell trait as well as evidence of a hemoglobin alpha-chain abnormality. Hemoglobins containing the variant alpha-chain were isolated by DEAE-cellulose column chromatography, and analysis of the purified alpha-chain demonstrated a ser replaced by cys substitution at alpha-81. The abnormal alpha-chain represented approximately 45% of the total, and hemoglobins containing this alpha-chain appeared to have normal stability and functional properties. In addition to the abnormal hemoglobins that were identified in this patient, she also was found to have persistent microcytosis in the absence of iron deficiency, and the percentage of HbS in her erythrocytes was less than that usually present in individuals with sickle cell trait. These findings, together with a reduced alpha/beta globin synthesis ratio from her peripheral blood reticulocytes, indicated that the presence of alpha-thalassemia trait. Hematologic findings from members of the patients's family suggest that an alpha-thalassemia gene may be linked to that of the structurally abnormal alpha-chain.

Silent carrier alpha-thalassemia was identified in two individuals, one with sickle-cell trait and the other hemoglobin (Hb) C trait. Both are parents of a child with characteristic hematologic features of the Hb SC-alpha thalassemia syndrome, including microcytosis and an unbalanced pattern of globin synthesis. In contrast to the typical findings that accompany heterozygous Hb S or Hb C with concomitant alpha-thalassemia trait, neither of the parents had microcytosis nor a percent of the abnormal hemoglobin in their erythrocytes that was below the normal range. In both, however, globin synthesis of peripheral blood reticulocytes was unbalanced, consistent with mild alpha-thalassemia. These findings suggest that the alpha-thalassemia silent carrier may be hematologically indistinguishable from the nonthalassemic individual, even when hemoglobin S or C are present.