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Supplementary Table S1. Pharmacokinetic parameters for enzalutamide administered as a single oral dose administered on day 1 to women with breast cancer and and on day 49 to men with prostate cancer; Supplementary Table S2. Pharmacokinetic parameters for enzalutamide and its active metabolite in patients taking enzalutamide 160 mg once daily to steady state; Supplementary Table S3. Most common grade ≥3 adverse events in more than one patient in the safety population.

Relationships between aromatase inhibitor plasma exposures (AUCtau) and concentrations of (A, B) estradiol and (C, D) estrone in individual patients. Red lines indicate expected estrogen levels with anastrozole or exemestane use

Supplemental Table 1. Reasons for docetaxel discontinuation Supplemental Figure 1. Safety and PK assessment schedule

Supplementary figure legends

Purpose: Preclinical evidence suggests that both docetaxel and enzalutamide target androgen receptor translocation and signaling. This phase Ib study assessed the safety, tolerability, and pharmacokinetics of docetaxel when administered with enzalutamide as first-line systemic chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).Experimental Methods: Docetaxel-naïve patients received 21-day cycles of docetaxel (75 mg/m2). Enzalutamide (160 mg/day) was administered daily starting on day 2 of cycle 1. Patients were allowed to stop and restart docetaxel at any time following cycle 2. Treatment continued indefinitely until unacceptable toxicity or discontinuation due to investigator or patient preference.Results: A total of 22 patients received docetaxel, of whom 21 also received enzalutamide. Docetaxel was administered for a median of 5.0 cycles and enzalutamide for a median of 12.0 months. With concomitant treatment, geometric mean docetaxel exposure decreased by 11.8%, whereas peak concentrations decreased by 3.7% relative to docetaxel alone. The most common toxicities observed during the period of concomitant therapy were neutropenia (86.4%) and fatigue (77.3%). Common toxicities observed with post-docetaxel enzalutamide were constipation (23.8%), decreased appetite (19.0%), fatigue (19.0%), and musculoskeletal pain (19.0%). Treatment with enzalutamide and docetaxel resulted in prostate-specific antigen decreases in almost all patients based on exploratory analysis of available baseline and on-study prostate-specific antigen data.Conclusions: The combination of docetaxel and enzalutamide is feasible, although higher rates of neutropenia and neutropenic fever than anticipated were observed. Reductions in docetaxel exposure with enzalutamide coadministration were not considered clinically meaningful. This combination warrants further study in a larger mCRPC population. Clin Cancer Res; 22(15); 3774–81. ©2016 AACR.

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046–54. ©2017 AACR.

Individual and mean plasma exposures (AUCtau or Cmin) to endocrine therapies alone or in combination with enzalutamide. Note: Box plots provide the mean (red line), median (black line), and 25%/75% quartiles with whiskers to the last point within 1.5-times interquartile range. Sample sizes are reported in Table 2 in the article.

Plazomicin is an aminoglycoside with in vitro activity against multidrug-resistant Enterobacteriaceae. A phase 1, randomized, double-blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty-six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30-minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30-minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline-adjusted, placebo-corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1-sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was >5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was

Enzalutamide is an androgen receptor inhibitor that has been approved in several countries. Absorption, distribution, metabolism, and excretion (ADME) data in animals would facilitate understanding of the efficacy and safety profiles of enzalutamide, but little information has been reported in public. The purpose of this study was to clarify the missing ADME profile in animals.ADME ofPlasma concentrations ofRapid oral absorption was observed in rats and dogs when

Background: Fulvestrant (FUL), an estrogen receptor (ER) antagonist, is an effective treatment for patients (pts) with hormone receptor-positive (HR+) breast cancer (BC) whose disease has progressed or recurred during previous anti-estrogen therapy. The androgen receptor (AR), expressed in the majority of HR+ BC, may contribute to resistance to hormonal therapy. Enzalutamide (ENZA) is a potent inhibitor of AR signaling. Preclinical models with ER+/AR+ BC cell lines showed synergistic inhibitory effects for ENZA combined with FUL on tumor cell growth. ENZA is a potent CYP3A4 inducer, and in vitro studies show that CYP3A4 is the only CYP enzyme involved in the oxidative metabolism of FUL. In this phase 1 trial (NCT01597193), we evaluated the potential for ENZA to affect FUL pharmacokinetics (PK), as well as the safety and tolerability of the combination of ENZA with FUL. Methods: Postmenopausal pts with HR+/AR+ advanced BC were enrolled; any number of prior therapies were permissible. Tumor tissue was analyzed centrally for AR expression; pts who had ?10% tumor cells with nuclear AR staining were eligible. All pts received at least 3 doses of FUL (500 mg intramuscularly on days 1, 15, and 29 and once monthly thereafter) to ensure steady-state concentrations prior to initiating ENZA 160 mg/day orally. The combination of ENZA with FUL was given until disease progression. PK and hormone sampling occurred on day 1 prior to ENZA initiation and on days 29 and 57. All pts were monitored for safety and response to treatment. Results: As of 01May2015, 11 pts were enrolled; PK data are available for 8 of 11 pts, and 6 pts remain on study. Median age was 59 years; median ECOG performance status was 1. Two pts previously received FUL as a prior therapy for advanced BC; 4 pts received no prior therapy for advanced BC. The median duration of exposure to the combination was 16.6 weeks (range 4.0-42.3); the median duration of exposure to FUL (including at least 3 preloading doses) was 24.4 weeks (range 11.7-67.3). Common (>2 pts) ENZA-related adverse events (AEs) included fatigue (n=6), nausea (n=5), cognitive disorder (n=4) and diarrhea (n=3). Cognitive changes Grade 1/2 were reported in 4 pts based on the cognitive function assessment questionnaire. Two pts reported unrelated serious AEs (erosive gastritis, urinary tract infection, iron deficiency anemia, and dehydration). Four pts had AEs ≥ Grade 3: hypertension, anemia, hyperglycemia, urinary tract infection, asthenia, erosive gastritis, dehydration, and iron deficiency anemia; only asthenia and hypertension were considered treatment-related. Circulating levels of estradiol and estrone were within the expected range. Trough plasma concentrations of FUL (Cmin) were similar for FUL alone and FUL combined with ENZA (Cmin=13.7 ± 2.8 and 12.5 ± 1.8 ng/mL, respectively). Conclusions: The safety profile for the combination of daily ENZA with FUL appears to be consistent with the published data for ENZA and FUL monotherapies. ENZA with FUL achieves similar plasma exposure to FUL alone, indicating no PK drug interaction. Citation Format: Elias AD, Burris HA, Patel MR, Schwartzberg LS, Richer JK, Kavalerchik E, Stopatschinskaja S, Gibbons J, Markova D, Steinberg JL, Traina TA. MDV3100-08: A phase 1 study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women with advanced hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-05.

Plazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion., Plazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion. Total clearance declined with renal impairment, resulting in 1.98-fold and 4.42-fold higher plazomicin exposures, as measured by the area under the concentration-time curve from 0 h to infinity, in subjects with moderate and severe impairment, respectively, than in subjects with normal renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT01462136.)

CPX‐351, a dual‐drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed therapy‐related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia‐related changes. Population pharmacokinetics analyses were performed using nonlinear mixed‐effect modeling on pooled data from 3 clinical studies, and the impact of CPX‐351 exposures on efficacy and safety was assessed. The pharmacokinetics of cytarabine and daunorubicin were described using 2‐compartment models with linear elimination. None of the evaluated covariates had a clinically significant impact on plasma exposure to total cytarabine or daunorubicin, while bilirubin and formulation showed statistically significant effects on pharmacokinetic parameters of cytarabine and daunorubicin, respectively. In patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL, plasma exposures to cytarabine and daunorubicin following CPX‐351 were within the variability range for patients with normal kidney function or serum bilirubin levels. Exposure‐response analysis demonstrated that better efficacy outcomes were associated with higher CPX‐351 exposure quartiles. Early mortality rates in all CPX‐351 exposure quartiles were lower vs the 7 + 3 control group, and lower mortality rates were associated with higher exposure quartiles. A trend toward greater frequency of grade 3 treatment‐emergent adverse events (but not grade 4/5 events) was observed at higher CPX‐351 exposure quartiles. Overall, the population pharmacokinetic analyses indicate no adjustments to the recommended dose and schedule of CPX‐351 are warranted for patients with mild/moderate renal impairment or serum bilirubin ≤3 mg/dL. Results from the exposure‐response analyses suggest the current CPX‐351 regimen provides a favorable risk‐benefit profile.

Background: Enzalutamide (ENZA) is a potent novel oral inhibitor of androgen receptor (AR) signaling. AR expression is observed in ∼70% of breast cancers (BC) and across the 3 major histologic subtypes (ER+, HER2+ and triple negative) [Collins LC et al. Mod Pathol 2011; 24:924-31]. Based on findings in preclinical models of AR+ BC, the potential therapeutic effect of ENZA in AR+ BC is being evaluated. This is the first trial of ENZA in women with advanced BC (aBC). Methods: This Phase 1 study in patients (pts) with aBC comprised a dose-escalation stage evaluating ENZA 80 mg/d or 160 mg/d (3+3 design) to determine the Phase 2 dose, and a dose-expansion stage evaluating the Phase 2 dose alone (C1) or in combination with the aromatase inhibitors (AI), anastrozole (C2) or exemestane (EXE; C3). Pts on single-agent ENZA must have received ≥2 treatment regimens for aBC. Tumor tissue was collected at screening for central analysis of AR expression. In the dose-escalation stage, single-dose ENZA was given on Day 1 with pharmacokinetic (PK) sampling through Day 8, followed by ENZA daily until discontinuation criteria were met, dose-limiting toxicities (DLTs) were recorded through Day 35. In C2 and C3, pts received ≥14 days of AI before starting ENZA, and AI PK sampling occurred on Days -1 and 29 of ENZA dosing to assess PK interactions. Blood for central assessment of estrogens was collected at Days 1, 29 and with tumor assessments performed at 2 months then ∼every 3 months thereafter. Results: The dose-escalation stage (n = 15) defined the Phase 2 dose as 160 mg/d. A single DLT (adrenal insufficiency) occurred in a pt at the 80 mg/d dose. This pt had pre-existing history of adrenal insufficiency and a PK interaction with her daily steroids could not be excluded. As of 1 May 2013, the dose-expansion stage has enrolled 3 pts in C1, 10 in C2, and 16 in C3. For pts receiving single-agent ENZA (n = 18) median age/ECOG was 58/1 and median prior therapies for aBC was 5; these values were 55/0 and 3 for combination cohorts (n = 26). Common (>15%) treatment-related adverse events (AEs) in the single-agent ENZA cohorts included nausea and nasal congestion and in C2 and C3 included nausea, fatigue, back pain, decreased appetite, and hot flush. To date, no serious treatment-related AEs have been reported for single-agent ENZA (other than the DLT) or in C2; in C3 back pain, hypercalcemia and nausea were observed. For single-agent ENZA, a preliminary PK analysis indicates that the apparent clearance and volume of distribution are approximately 0.4 L/h and 120 L, respectively, and steady-state trough concentration is approximately 13 μg/mL. ENZA + EXE resulted in ∼50% reduction in exposure to EXE (AUC pre vs post ENZA: 134±65 vs 70±39 ng.h/mL). PK, tolerability, estrogen levels and anti tumor activity in all cohorts will be presented. Conclusions: The PK and tolerability of single-agent ENZA appear similar in women with aBC vs. data reported in men. As ENZA reduced exposure to EXE, effects on estrogens (i.e., EXE pharmacodynamics) are being assessed and will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-6.

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046–54. ©2017 AACR.

SummaryWhat is known and objective Enzalutamide is an androgen receptor inhibitor approved for treatment of metastatic castration-resistant prostate cancer. Enzalutamide is highly protein bound and eliminated primarily by hepatic metabolism; therefore, it is important to understand whether enzalutamide pharmacokinetics is altered by hepatic impairment. Methods Pharmacokinetic data were obtained from two non-randomized, open-label, single-dose, phase 1 studies conducted in patients with mild (Child-Pugh class A, n = 6) or moderate (Child-Pugh class B, n = 8) hepatic impairment (NCT01901133) or severe (Child-Pugh class C, n = 8) hepatic impairment (NCT02138162) and their corresponding matched healthy controls; data from both studies are presented here. Subjects with hepatic impairment had liver cirrhosis (n = 19) or chronic hepatitis (n = 3). All subjects received a single oral dose of 160 mg enzalutamide under fasting conditions, with blood samples collected predose and up to 49 days post-dose. Results and discussion Exposure to enzalutamide active moieties, based on the area under the curve of the sum of enzalutamide and N-desmethyl enzalutamide (an active metabolite with similar potency to enzalutamide), increased by 13%, 18% and 4% in subjects with mild, moderate and severe hepatic impairment, respectively, relative to matched controls. Compared with healthy controls, the mean maximum plasma concentration for enzalutamide active moieties was 24% higher in subjects with mild hepatic impairment and 11% and 41% lower in subjects with moderate and severe hepatic impairment, respectively. Enzalutamide was generally well tolerated, with no clinically significant trends in abnormal laboratory findings, vital signs or electrocardiograms. What is new and conclusions No major differences in single-dose pharmacokinetics were observed in subjects with hepatic impairment vs. matched healthy controls. Therefore, these studies indicate that no initial dose adjustment is necessary when administering enzalutamide to patients with hepatic impairment.

Background and Objectives Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide. Methods Results are reported from five clinical studies. Results In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30–360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration–time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child–Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (Ctrough) versus overall survival (n = 1103) showed that active treatment Ctrough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of Ctrough was associated with a statistically significant better response. Conclusions Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day. Electronic supplementary material The online version of this article (doi:10.1007/s40262-015-0271-5) contains supplementary material, which is available to authorized users.

This is an ethnographic study of girls’ orphanages in Egypt. It examines cultural notions of unwanted children and explores the attitudes, perceptions and managerial practices of six orphanages in and around Cairo. The institutions are characterized by various styles of surrogate mothering, educational and administrative practices, occupational training, and the marital aspirations and attitudes of their occupants.

This research addresses delineations of gender roles, agency, and change in a modern urban women’s residence in north India. It explores the social relations of residents in a women’s hostel where the shaping of special community creates empowermenf through self-reflection, interaction, and negotiation, yet where also reside tensions, paradoxes, and constraints, in the merging and interplay of traditional values and those of modernity.

Dear Editors, We thank Dr. Paul Hutson for his thorough commentary [1] on our recent article entitled ‘Enzalutamide: a step towards pharmacokinetic-based dosing in men with metastatic castration-resistant prostate cancer’ [2]. We would like to provide an important correction to Dr. Hutson’s commentary, regarding the following statements: Gibbons et al. do not report the renal clearance or the effect of renal failure on the clearance of enzalutamide or its active N-desmethyl metabolite, and to date no other reports of enzalutamide renal clearance are available to guide dosing. The mass-balance studies in the present study demonstrate that approximately 60 % of the dose was recovered in the urine, suggesting that dosing of the drug may need to be reduced in patients with kidney dysfunction. While not emphasized, the article does describe renal clearance on page 1050 (paragraph 2): The major route of excretion of 14C-radioactivity was urine (71.0 % of dose), primarily as metabolites. The remainder of the radioactivity was excreted in feces (13.6 % of dose). Based on LC–MS/MS analysis, the main component in urine was the carboxylic acid metabolite, which accounted for 62.7 % of the dose. A trace amount of unchanged parent enzalutamide was excreted in urine. N-Desmethyl enzalutamide was too low to quantitate in urine by LC–MS/MS. Based on this information, renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. As indicated in this excerpt, 62.7 % of the dose was recovered in urine as the inactive carboxylic acid metabolite, and the remainder was additional minor metabolites; enzalutamide and N-desmethyl enzalutamide (active metabolite) were present in urine at only trace amounts. These data indicate that renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. Further details are captured in the US prescribing information for XTANDI® (enzalutamide) capsules (product label), which states the following: A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment [30 mL/min ≤ creatinine clearance (CrCL) ≤ 89 mL/min] compared to patients and volunteers with baseline normal renal function (CrCL ≥90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL

The manifestation of gender in the Japanese puppet theatre is also a study of men who depict male and female roles. The visual sociologist must take into consideration the intermeshing and communication of voice (tayu), with music (shamisen player) and puppeteers on stage in the dramaturgy of roles and their enactment. The researcher explores aspects of front and backstage as we learn about male and female role making and taking. It could be argued that women are fictionalized, idealized and subject to stylization, while men are allowed to be more free in their depiction of emotional variation. At the same time there is a long tradition of gender interpretation which contains sexual ambiguities and varied meaning levels. This research addresses the masked and unmasked aspects of the Bunraku theatre and the ways that maleness and femaleness can be visually and verbally conceived.

Background: Enzalutamide is an androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. Oral enzalutamide was recently approved by the US FDA and health authorities in other regions for the treatment of patients with metastatic castration-resistant prostate cancer who previously received docetaxel. The objective of this study was to validate a method for quantification of enzalutamide and its two major metabolites in human plasma. Results: The analytes were extracted from plasma by an LLE procedure, separated by reversed phase HPLC and detected by MS/MS in positive mode ESI. The quantitation range was 0.0200–50.0 µg/ml. Conclusion: The method proved to be rapid and simple, and met FDA validation criteria.

This article discusses the lives of women in prison in the new South Africa. It describes observations during site visits by the author to prisons in the Durban and Cape Town areas in the summer of 1995 and the spring of 1997. The article covers topics ranging from educational and employment opportunities to child care and maintenance of family ties, concluding that the ambitions of the country's new Constitution remain a far cry from the social and economic realities for the vast majority of its imprisoned women.

This research is part of a larger project that examines the working lives of South African women prisoners. The data gathered represent one of the occupational sectors inside a women's prison in the Western Capearea where lace‐making and embroidery represent key working activity for the day. Lace‐making is a symbolic link between European and colonial heritage and is associated with hegemonic relations. Women who are involved in lace‐making must bring eye, hand and mind into creative dialogue. The sociologist as photographer attempts to draw the observer in, through the eyes of the worker and to indicate the intricacy of physical involvement and sense of necessary patience that must take place with work of this detail. (The wrong placing or direction of fine thread can raise moral, psychological and pedagogical questions to the working whole.) Lace making may be interpreted as an ‘engaging’ pedagogical vehicle and/or as a futile, oppressive vestige of colonialism.

Purpose. Understanding how chemical structures influence transport across the intestinal mucosa will greatly enhance the discovery of orally available drugs. In an attempt to accelerate defining such relationships between structure and transport, six arbitrary mixtures of N-substituted glycine (NSG) peptoids containing 24 physicochemically diverse compounds were evaluated in the Caco-2 model of intestinal absorption.

Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.

The objective of this study was to examine the potential for a specific ligand of carcinogen binding protein (CBP) to induce changes in the overall character of hepatic microsomal cytochromes P-450 (P450) and to compare potential changes with those induced by an Ah receptor ligand. Benzo[e]pyrene (BeP) was previously shown to bind CBP with high affinity and Ah receptor with low affinity. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) binds Ah receptor avidly and CBP weakly. Hepatic microsomes were prepared from C57BL/6J (B6) and DBA/2J (D2) mice treated with corn oil, BeP or TCDD. Relative to corn oil controls, pretreatment of B6 mice with BeP or TCDD increased the nmol P450/mg microsomal protein content 26 and 28%, respectively. In D2 mice, nmol P450/mg microsomal protein was increased 23% in the BeP pretreatment, while TCDD pretreatment had no effect relative to the corn oil controls. For the O-alkyl ethers of resorufin, rates of metabolism (per nmol P450) were affected differently in B6 and D2 by BeP pretreatment. Pentoxyresorufin O-dealkylase activity was reduced to 44% of control activity in B6 mice and increased 39% relative to controls in D2 mice. BeP pretreatment had no effect on ethoxyresorufin O-dealkylase activity in B6 mice, while this activity was decreased to 58% of controls in D2 mice. Additionally, benzyloxyresorufin O-dealkylase activity was reduced to 65% of control levels in B6 mice and not affected in D2 mice. Methoxyresorufin O-dealkylase activity was reduced in both strains to an average of 55% of control values. As expected, TCDD pretreatment resulted in increases of all O-dealkylations measured in both strains of mouse. For both inbred strains of mouse, anion exchange chromatography revealed a P450 peak associated with BeP pretreatment that was not present in chromatograms generated with corn oil or TCDD pretreatments. Results of enzyme linked immunosorbant assays also indicated that the pattern of P450 isoenzyme expression associated with BeP pretreatment was distinct from that associated with TCDD pretreatment. Overall, these data show that treatment with a specific ligand of CBP induces changes the biochemical activities and chromatographic behavior of P450 isozymes in murine hepatic microsomes. Moreover, they indicate that changes in P450 occurring after treatment with a CBP ligand are distinct from those changes that are associated with treatment with an Ah receptor ligand (TCDD). Differences between B6 and D2 strains suggest that the hepatic P450 changes occurring in response to pretreatment with a CBP ligand may be influenced by the presence of Ah receptor.

Hepatic microsomes were prepared from immature C57BL/6J mice 24 h after receiving intraperitoneal injections of either corn oil, benzo[e]pyrene (BeP, 50 mg/kg) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 4 × 10−3mg/kg). The capacity of these hepatic microsomes to bioactivate aflatoxin b1 (AFB1), 2-aminoanthracene (AA), benzo[a]pyrene (BaP), 3-methylcholanthrene (MC), 7,12-dimethylbenzanthracene (DMBA), BeP and pyrene (PY) was measured using strain TA 100 in the Salmonella typhimurium/ microsome reversion assay. BeP pretreatment of mice resulted in a 33% increase in mutagenic potency (MP) of AFB1 over the corn oil controls and a 70% increase in MP relative to TCDD-pretreated microsomes. With AA, BaP and DMBA as promutagens, BeP pretreatment reduced MP an average of 24%, while TCDD pretreatment increased MP of these 3 promutagens 263% compared to controls. Since the general effects of BeP and TCDD on murine hepatic cytochrome P-450 (P450)-mediated activities in this study were discordant, it appears that changes in P450 activity by BeP pretreatment are not mediated through the Ah receptor.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ibudilast is an oral drug approved in Asia for asthma. • Tolerability of 10-mg regimens has been described previously. • Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers. WHAT THIS STUDY ADDS • Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers. • Higher-dose regimens are relevant for testing in new neurological indications. • LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast). AIMS To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen. METHODS Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite. RESULTS Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median Tmax was 4–6 h. Mean (SD) steady-state plasma Cmax and AUC0–24 were 60 (25) ng ml−1 and 1004 (303) ng h ml−1, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent. CONCLUSIONS Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day−1) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.

Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.

Strains of Mycobacterium and Nocardia isolated because of their ability to use di(2‒ethylhexyl) phthalate (DEHP) as sole carbon source also grew on diethyl, diisooctyl, and butyl benzyl phthalates. As the two bacteria grew on DEHP, they excreted products that increased the solubility of DEHP and diisooctyl, dihexyl, and diisodecyl but not butyl benzyl or di‒n‒butyl phthalates. The solubilizer was produced by Mycobacterium sp. even when grown on a water‒soluble substrate such as acetate. Addition of the solubilizer to culture media enhanced the degradation of DEHP and diisooctyl phthalate by Mycobacterium sp. and Nocardia sp. but not butyl benzyl phthalate. The extent of DEHP degradation by Mycobacterium sp. in media amended with the solubilizer was reduced and the initiation of degradation was delayed if the solubilizer was first treated with protease. The effect of protease was not a result of its toxicity to Mycobacterium or use of the enzyme preparation for growth of the organism. The results thus show that microbial products increase the solubility of certain phthalates and enhance their degradation.

Background and Objectives Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Methods A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). Results Coadministration of gemfibrozil increased the composite area under the plasma concentration–time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. Conclusions If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure. Electronic supplementary material The online version of this article (doi:10.1007/s40262-015-0283-1) contains supplementary material, which is available to authorized users.

The essay summarizes the results of a research carried out in the Italian community of Toronto, through the use of photographic observation in the field