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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.

Author(s): Cristóbal S. Berry-Cabán [sup.1] , Lindsay M. Orchowski [sup.2] , Michele Wimsatt [sup.1] , Tremaine L. Winstead [sup.1] , John Klaric [sup.1] , Kara Prisock [sup.1] , Elizabeth Metzger [...], The present study explores perceived and collective social norms pertaining to consent for sexual activity, comfort with sexism, stereotypes about rape, attitudes regarding relationships, and the use of dating apps. Data were collected via an anonymous online questionnaire administered to 338 active duty male soldiers between the ages of 18 and 24 at an Army post in the mid-South region of the United States. Analyses examined the extent soldiers accurately perceived the collective norms of their peers. Men were inaccurate in their estimation of the extent to which other male soldiers followed principles of consent in their sexual behaviors, such as stopping the first time a woman says "no" to sexual activity, stopping sexual activity even if aroused, and garnering a verbal affirmation for sex. Soldiers were inaccurate in their perception of peer norms regarding indicators of sexual interest and consent, including the belief that when a woman lets a man kiss her she wants to have sex, and if a woman wears a sexy dress she's asking for sex. Soldiers were also inaccurate in their estimations of other male soldier's comfort with sexism including feeling uncomfortable with sexist comments or sexual jokes that put down women. In addition, soldiers underestimated men's preference for a good relationship with one woman rather than many sexual partners and overestimated their peers' use of dating sites to locate sexual partners. These findings highlight the need to correct misperceived norms regarding dating and sexual activity among soldiers.

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.

Suspended human hepatocytes (SHH) have long been used in assessing hepatic drug uptake, while plated human hepatocytes in short-term monolayer culture (PHH) have gained use in recent years. This study aimed to cross-evaluate SHH and PHH in measuring the hepatic uptake mediated by organic anion transporting polypeptide 1Bs (OATP1Bs). We compared the time courses of cell-to-medium (C/M) concentration ratios and initial uptake clearance values of the OATP1B substrates (pitavastatin, rosuvastatin, cerivastatin, pravastatin, dehydropravastatin, and SC-62807) between SHH and PHH. For all compounds except cerivastatin, the C/M ratios in SHH displayed an apparent overshoot (an initial increase followed by a decrease) during the 180-min uptake experiment, but not in PHH. Based on the literature evidence suggesting the possible internalization of OATP1Bs in primary hepatocytes, separate experiments measured the drug uptake after varying lengths of pre-incubation in the drug-free medium. The initial uptake clearances of pitavastatin and rosuvastatin declined in SHH beyond an apparent threshold time of 20-min drug-free pre-incubation, but not in PHH. Kinetic modeling quantitatively captured the decline in the active uptake clearance in SHH, and more than half of the active uptake clearances of pitavastatin and rosuvastatin were prone to loss during the 180-min uptake experiment. These results suggested a partial, time-delayed loss of the functional OATP1Bs in SHH upon prolonged incubation. Our results indicate that PHH is more appropriate for experiments where a prolonged incubation is required, such as estimation of unbound hepatocyte-to-medium concentration ratio (K p,uu ) at the steady-state.

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro-in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (C b,u ), unbound plasma (C p,u ), and CSF compound concentrations (C CSF ) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (C b,u /C p,u and C CSF /C p,u ) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although C CSF does not quantitatively correspond to C b,u for efflux transporter substrates, it is mostly within 3-fold higher of C b,u in rat and NHP, suggesting that C CSF can be used as a surrogate for C b,u . Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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.)

Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems. Single-dose rifampicin, an OATP inhibitor, decreased montelukast clearance in rats and monkeys. Clinical DDIs of montelukast were evaluated using physiologically based pharmacokinetic modeling; and simulation of the interactions with gemfibrozil-CYP2C8 and OATP1B1/1B3 inhibitor, clarithromycin-CYP3A and OATP1B1/1B3 inhibitor, and itraconazole-CYP3A inhibitor, implicated OATPs-CYP2C8-CYP2C8 interplay as the primary determinant of montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions., (© 2016 American Society for Clinical Pharmacology and 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.

Introduction: It is becoming increasingly evident that transporters play an important role in the absorption, distribution and elimination of many drugs. Different approaches have been developed and validated to understand the interactions between drugs and transporters, and the in vivo role of drug transporters. These tools are helping to understand the impact of transporters on the pharmacokinetics (PK) of drugs and assess the risk of drug-drug interactions (DDIs) in drug discovery and development., Areas Covered: This article provides an overview of different approaches to evaluate the drug transporters involved in intestinal absorption, hepatic and renal clearance, and brain penetration. Specifically, it provides the best practices to evaluate the major uptake and efflux transporters in drug discovery. It also discusses the challenges and gaps in understanding the clinical relevance of drug transporters., Expert Opinion: Quantitative prediction of transporter-mediated clearance, tissue exposure, as well as DDIs is still limited. The current challenge is to develop in vitro-in vivo correlations, extrapolate and integrate data from in vitro transporter assays, and preclinical species into humans to quantitatively predict the impact of transporters on drug absorption, disposition, elimination and DDIs. With the development of a variety of novel tools, the ultimate goal is to use high quality in vitro and in vivo data to establish physiologically based PK models, which will improve the capability to predict PK, tissue exposure and DDIs in humans.

Introduction: Drug transporter proteins are expressed on the cell membrane, regulating substrate exposure in systemic circulation and/or peripheral tissues. Genetic polymorphism of drug transporter genes encoding these proteins could alter the functional activity and/or protein expression, having effects on absorption, distribution, metabolism and excretion (ADME), efficacy and adverse effects., Areas Covered: The authors provide the reader with an overview of the pharmacogenetics (PGx) of 12 membrane transporters. The clinical literature is summarized as to the quantitative significance on pharmacokinetics (PK) and implications on pharmacodynamics (PD) and adverse effects, due to transporter influence on intracellular drug concentrations., Expert Opinion: Unlike polymorphisms for cytochrome P450s (CYPs) resulting in large magnitude of PK variation, genetic mutations for membrane transporters are typically less than threefold alteration in systemic PK for drugs with a few exceptions. However, substantially greater changes in intracellular drug levels may result. We are aware of 1880 exome variants in 12 of the best-studied transporters to date, and nearly 40% of these change the amino acid. However, the functional consequences of most of these variants remain to be determined, and have only been empirically evaluated for a handful. To the extent that genetic polymorphisms impact ADME, it is a variable that will contribute to ethnic differences due to substantial frequency differences for the known variants.

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.

In the present study we examined the disposition of atorvastatin, lovastatin, and simvastatin in acid and lactone forms and pravastatin in acid form in multidrug-resistant gene (mdr1a/b) knockout (KO), and wild-type (WT) mice. Each statin was administered s.c. to mdr1a/b KO and WT mice at 3.0 mg/kg (n > or = 3 mice/time point). Blood, brain, and liver samples were harvested at 0, 0.5, 1.5, and 3 h postdose. Plasma and tissue concentrations of the acid and lactone (only the acid form was determined for pravastatin) were determined using a liquid chromatography-mass spectrometry method. Both lactone and acid were observed in plasma when lactones were administered, but only acids were detected when the acid forms were administered. The plasma and liver concentrations of acid or lactone were similar between the KO and WT mice. Two- to 23-fold higher concentrations were observed in liver than in plasma, suggesting potential uptake transporters involved. A significantly higher (p < 0.05) brain penetration in the KO compared with the WT mice was observed for lovastatin acid (but the brain/plasma ratio was low for both KO and WT mice) and lactone and simvastatin lactone but not for atorvastatin or pravastatin. The present results suggest that mouse P-glycoprotein does not affect the lactone-acid interconversion or liver-plasma distribution. Furthermore, P-glycoprotein plays a limited role in restricting the brain penetration of the acid forms of atorvastatin, pravastatin, simvastatin, lovastatin, and atorvastatin lactone but may limit the brain availability of the lactone forms of simvastatin and lovastatin.

A nonblinded study was conducted to compare the pharmacokinetic properties of the selective serotonin reuptake inhibitor sertraline in 22 young (aged 18 to 45 years) and 22 elderly (> 65 years) volunteers, of whom half were male and half were female. In this study, sertraline was administered at a dosage of 200mg once daily (the maximum recommended daily dosage) for 21 days after upward dosage titration from 50 mg/day over a 9-day period. Thus, this study was designed to measure the effect of age and gender on the pharmacokinetic properties of sertraline at the maximum dosage recommended for clinical use. The terminal elimination half-life (t1/2 beta ) of sertraline was similar in young females, elderly males and elderly females (mean t1/2 beta ranged from 32.1 to 36.7 hours in these groups) but shorter (22.4 hours) in the young males. The mean maximum plasma sertraline concentration (Cmax) and the mean steady-state area under the plasma concentration-time curve from time zero to 24 hours postdose (AUC24) were also similar between the young females, elderly males and elderly females, but were approximately 25% lower in the young males. The time to Cmax was unaffected by age or gender and ranged from 6.4 to 6.9 hours. N-Demethylsertraline is the principal metabolite of sertraline and does not contribute significantly to its serotonergic actions. The mean values for N-demethylsertraline trough plasma concentrations, AUC24 and Cmax were comparable in elderly males and females and young females but lower in young males. The ratios of mean AUC24 and Cmax for N-demethylsertraline to the AUC24 and Cmax for sertraline were similar between the 4 groups.

The effect of the selective serotonin reuptake inhibitor (SSRI) sertraline 200 mg/day on the metabolism of intravenously administered tolbutamide was examined in a randomised nonblinded parallel-group study in 25 healthy male volunteers. There was a small but statistically significant decrease (16%) in the clearance of tolbutamide in patients receiving the maximum recommended dosage of sertraline. The terminal elimination rate constant was also significantly reduced, corresponding to the increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not associated with any significant changes in plasma protein binding or in the apparent volume of distribution of tolbutamide. This suggests that the change in tolbutamide clearance may be due to a slight inhibition of the cytochrome P450 (CYP) isoenzyme CYP2C9/10 when sertraline was administered in its maximum recommended dosage. However, the small changes in the volume of distribution and plasma binding of tolbutamide after sertraline treatment indicate that there is a minimal interaction between sertraline and tolbutamide.

The effect of sertraline on the plasma protein binding of warfarin was investigated in a nonblinded randomised placebo-controlled parallel trial in 12 healthy male volunteers. The study participants received single doses of warfarin before administration of sertraline or placebo and again after sertraline or placebo had been administered for 22 days. Treatment with sertraline for 26 days increased the area under the mean prothrombin time vs time curve by 145 sec *h (7.9%), compared with a decrease of 17 sec *h (-1.0%) in the placebo group. Although statistically significant (p = 0.02), this difference was not felt to be clinically meaningful. There appeared to be a slight delay in the normalisation of the prothrombin time in the sertraline-treated group after the second dose of warfarin, which also would not be expected to be clinically significant. After 22 days, a statistically significant (p = 0.02) increase in unbound warfarin was observed in the sertraline group compared with the placebo-treated individuals. Neither the change in prothrombin time nor the change in plasma protein binding were considered to have any clinical relevance; however, good clinical practice dictates that prothrombin time should be monitored in patients treated concurrently with warfarin and sertraline to ensure that the integrity of coagulation response is maintained. The metabolism of warfarin is principally mediated by the cytochrome P450 (CYP) isoenzyme CYP2C9/10. Thus, sertraline appears to have a minimal effect on the CYP2C9/10 isoenzyme.

An open-label, placebo-controlled study was conducted to determine the effects of sertraline on the steady-state levels and renal clearance of lithium in 20 healthy volunteers. Subjects received 600 mg of lithium twice daily for 9 days. On the evening of day 8, subjects received orally either placebo or 100 mg of sertraline; these were administered twice, 8 hours apart, beginning 2 hours after the evening dose of lithium. In a comparison of day 8 with day 9 (before administration of the morning doses of lithium), sertraline was associated with only a 0.01 mEq/L (1.4%) decrease in steady-state levels and a 0.11 L/hour (6.9%) increase in the renal clearance of lithium. Neither change was statistically significant relative to placebo. Four subjects were excluded from analysis because of protocol violations or laboratory abnormalities unrelated to sertraline. Seven subjects who received lithium plus sertraline experienced side effects, mainly tremors, possibly related to treatment, whereas none of those administered lithium plus placebo experienced side effects. No sertraline-related laboratory abnormalities were observed.

State service delivery systems have had limited success in meeting the needs of persons with major mental illness and substance abuse problems. Systems issues that create barriers to effective services include rigid program boundaries, inadequate assessment and diagnosis, lack of trained staff, the limited array of special services, and inflexible funding patterns. The state of Virginia, which administers mental health and substance abuse services through a single agency, has addressed these issues by clearly communicating that services for mentally ill substance abusers should be given high priority, by instituting a collaborative working relationship between mental health and substance abuse services, and by providing funding incentives. Additional efforts to develop advocacy organizations for mentally ill substance abusers, to train mental health professionals to serve this population, and to improve program evaluation and assessment are needed.

Salicylate administration increased glucuronyltransferase activity, with o-aminophenol as the substrate, in chicken kidney homogenates, but did not affect glucuronyltransferase activity in chicken liver homogenates. In addition, salicylate administration increased in vivo renal glucuronidation of catechol and p-nitrophenol without affecting renal sulfate conjugation of these compounds. These results suggest that salicylate administration selectively enhances renal glucuronide conjugation, thereby promoting a more rapid metabolism and elimination of circulating phenols, especially at high plasma phenol concentrations. Isolated human kidney perfusion experiments reveal that glucuronide and sulfate conjugates of phenol, p-nitrophenol, and 1-naphthol are formed in the human kidney, suggesting that the effect of salicylate treatment on renal glucuronidation may apply to humans.

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.

A method for the quantitative determination of organ contribution to in vivo excretory metabolism is described. By excretory metabolism, we mean metabolism of a compound by an organ with direct excretion. The technique separately and simultaneously quantifies clearance of circulating metabolite and clearance of circulating precursor by excretory metabolism. For xenobiotics, the method involves the simultaneous infusion of radiolabeled precursor and unlabeled metabolite. The method is dependent upon the achievement of steady-state plasma concentrations of precursor and metabolite and on the ability to accurately analyze, both chemically and radioactively, the precursor in plasma, and the metabolite in both plasma and excretory fluid. The technique is not compromised by in vivo conversion of metabolite to precursor. This method is suitable for the simultaneous quantitative determination of the contribution of several organs to the formation of any number of metabolites present in excretory fluids. The simultaneous contribution of excretory metabolism to the urinary and biliary elimination of 1-naphthol in the rat is presented.

The simultaneous in vivo renal sulfate and glucuronide conjugations of 1-naphthol (1-N) and p-nitrophenol (PNP) were determined in the rat. In mammals, 1-N and PNP are excreted almost entirely in the urine, mainly as the glucuronide and sulfate conjugates. In male Sprague-Dawley rats, greater than 98% of the infused [14C]1-N (1.0 mumole X min-1 X kg-1) or [14C]PNP (2.0 mumoles X min-1 X kg-1) recovered in urine was identified as the sulfate and glucuronide conjugates. Renal metabolism accounted for a minimum of 20% of the endogenously formed conjugates of either substrate excreted in the urine. The rat kidney formed the glucuronide and sulfate conjugates of PNP at equal rates, whereas the glucuronide: sulfate conjugate ratio for renally formed 1-N conjugates was 3:1. When the conjugates of either 1-N or PNP were infused systemically, in vivo hydrolysis contributed significantly to the amount of circulating parent phenol.

By use of the Sperber in vivo chicken preparation method (1948, Ann. R. Agric. Coll. Swed. 15, 317-349), infusion of radiolabeled terephthalic acid ([14C]TPA) into the renal portal circulation revealed a first-pass excretion of the unchanged compound into the urine. This model was utilized further to characterize the excretory transport of [14C]TPA and provide information on the structural specificity in the secretion of dicarboxylic acids. At an infusion rate of 0.4 nmol/min. 60% of the [14C]TPA which reached the kidney was directly excreted. An infusion rate of 3 or 6 mumol/min resulted in complete removal of [14C]TPA by the kidney. These results indicate that TPA is both actively secreted and actively reabsorbed when infused at 0.4 nmol/min and that active reabsorption is saturated with the infusion of TPA at higher concentrations. The secretory process was saturated with the infusion of TPA at 40 mumol/mn. The excretory transport of TPA was inhibited by the infusion of probenecid, salicylate, and m-hydroxybenzoic acid, indicating that these organic acids share the same organic anion excretory transport process. m-Hydroxybenzoic acid did not alter the simultaneously measured excretory transport of p-aminohippuric acid (PAH), suggesting that there are different systems involved in the secretion of TPA and PAH. The structural specificity for renal secretion of dicarboxylic acids was revealed by the use of o-phthalic acid and m-phthalic acid as possible inhibitors of TPA secretion. m-Phthalate, but not o-phthalate, inhibited TPA excretory transport, indicating that there is some specificity in the renal secretion of carboxy-substituted benzoic acids. TPA was actively accumulated by rat and human cadaver renal cortical slices.

Sertaline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- naphthalenamine] is a potent and selective inhibitor of neuronal serotonin uptake and is currently under development for the treatment of depression and of obesity. The drug is greater than 97% bound to plasma proteins, yet extensively distributes into tissues. The whole brain concentration of sertraline in the rat is more than 40-fold higher than that in plasma, and the volume of distribution is about 25 liters/kg in the rat and dog. Sertraline is extensively metabolized by the rat and dog prior to excretion. The metabolic clearance of sertraline is greater than 35 ml of blood/min/kg in each species, and first-pass metabolism occurs with oral administration. Initial metabolic steps include N-demethylation, N-hydroxylation, oxidative deamination, and glucuronidation of sertraline carbamic acid, which in solution is in equilibrium with sertraline and carbon dioxide. The N-desmethyl metabolite, which is 10-fold less potent as an inhibitor of serotonin uptake, is formed in both species. Plasma AUC for desmethyl-sertraline is 66 to 270% of that for sertraline, and is dependent on the species examined and route of drug administration. Sertraline and desmethyl-sertraline undergo oxidative deamination to the corresponding ketone, which is subsequently hydroxylated at the alpha-carbon, forming a diastereomeric metabolite pair. The glucuronides of sertraline carbamic acid, N-hydroxy sertraline, and the alpha-hydroxy ketone diastereomers comprise 45% and 82% of the total radiolabel excreted in urine and bile of bile duct-cannulated rats and dogs, respectively. Bile is the major route of elimination in both species.

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.