Distinct Uroplakin II Staining Pattern in Apocrine Breast Carcinoma.

Uroplakin II (UPII) has been shown as a highly specific marker of urothelial carcinoma; however, it can also stain subtypes of apocrine-differentiated breast carcinoma. Given that urothelium and breast epithelium share other common immunohistochemical markers, such as CK7 and GATA3, this can lead to a potential diagnostic pitfall. We stained a cohort of triple-negative breast cancer with UPII. Compared with the diffuse, cytoplasmic staining in urothelial carcinoma, UPII was positive in 38.9% of apocrine carcinoma (7/18) with a course, granular cytoplasmic staining pattern and negative in all nonapocrine triple-negative breast cancer cases. Furthermore, the same staining pattern was present in all apocrine metaplasia of the breast (4/4) and apocrine sweat glands in normal skin (6/6). This distinct subcellular localization of UPII staining in breast carcinoma can offer a potential solution to the above diagnostic pitfall.

In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents.

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents.

Steady-state pharmacokinetics of gabapentin after administration of a novel gastroretentive extended-release formulation in postmenopausal women with vasomotor symptoms.

BACKGROUND AND OBJECTIVE: Approximately 75% of postmenopausal women experience vasomotor symptoms (hot flashes). Currently, hormone replacement therapy is the only approved treatment for hot flashes. However, its use has been associated with an increased risk of invasive breast cancer, coronary heart disease, stroke and venous thromboembolic disease. Gabapentin has also been demonstrated to be efficacious in the treatment of vasomotor symptoms in postmenopausal women when administered three times a day. A gastroretentive extended-release formulation of gabapentin (gabapentin-ER) has recently been demonstrated to be efficacious in the treatment of postmenopausal hot flashes. The objective of this paper is to report the steady-state pharmacokinetics and safety of gabapentin with different dosing regimens of gabapentin-ER in postmenopausal women with hot flashes. METHODS: This was a multicentre, randomized, double-blind, dose-escalating, placebo-controlled, parallel group study in 124 postmenopausal women experiencing ≥7 moderate to severe hot flashes per day. The study consisted of two 5-week treatment periods, with each one preceded by a 1-week titration to the assigned dose. Groups A, B and C received gabapentin-ER 600 mg evening (pm), 600 mg morning (am)/600 mg pm and 1200 mg pm in the first period, and then 600 mg am/1200 mg pm, 600 mg am/1800 mg pm and 1200 mg am/1800 mg pm in the second period, respectively. The tablets were taken after a non-specified meal. Pharmacokinetic sampling was conducted over a 24-hour period at the end of each study period. Plasma samples were analysed by a validated liquid chromatography tandem mass spectrometry method. Non-compartmental pharmacokinetic analysis was performed on the concentration-time data to determine area under the plasma concentration versus time curve from time zero to 24 hours (AUC(24)). Maximum (C(max)), minimum (C(min)) and average (C(avg)) drug concentration and time to reach C(max) (t(max)) were determined by inspection of the data. Tolerability was evaluated by physical examination, clinical laboratory measurements and adverse events monitoring. RESULTS: Gabapentin exposure at steady state, as measured by AUC(24), increased with doses from 600 mg/day to 3000 mg/day, although there was a slight decrease in gabapentin's relative bioavailability with increasing dose compared with the 600 mg dose. The relative bioavailability compared with the 600 mg dose was 86-88% for the 1200 mg/day doses, 75% for the 1800 mg/day dose, 84% for the 2400 mg/day dose, and 73% for the 3000 mg/day dose. C(max) generally increased with increasing dose as did C(min) and C(avg) for the various treatments in a manner that was consistent with the dosing regimen. The values of t(max) were not different between the various doses, with the median t(max) values relative to the most recent dose ranging from 6 to 8 hours for all dose levels. Gabapentin-ER was generally well tolerated at all doses studied. The most common AEs were headache, dizziness and somnolence, with most being mild in intensity. Seven patients withdrew from the study due to AEs. CONCLUSION: The pharmacokinetic profile of gabapentin-ER may allow for once- or twice-daily dosing while maintaining bioavailability and thus efficacy. Gabapentin-ER was well tolerated. CLINICAL TRIAL REGISTRATION: Registered as ClinicalTrials.gov Identifier: NCT00511953.

Prognostic use of circulating plasma nucleic acid concentrations in patients with acute stroke.

BACKGROUND: At present there is no simple, accurate blood test that may be used to determine the severity of stroke or to predict mortality and morbidity in stroke patients presenting to emergency departments. METHODS: Patients with stroke-like symptoms who presented to an emergency department of a university hospital in Hong Kong were recruited for the study. DNA extracted from patients' plasma was analyzed for the beta-globin gene with a fluorescent-based PCR test. The primary outcome measures were in-hospital and 6-month mortality and morbidity using the post-stroke modified Rankin Score. RESULTS: Among the 88 consecutive patients recruited to the study, 70 (80%) had ischemic stroke, 11 (13%) had intracerebral hemorrhage, and 7 (8%) had transient ischemic attacks. Median plasma DNA concentrations taken within 3 h of symptom onset were higher in patients who died compared with those who survived at discharge (6205 vs 1334 kilogenome-equivalents/L; P = 0.03). Among patients with NIH Stroke Scale scores >8, median plasma DNA concentrations were higher in patients who died compared with those who survived to 6 months (2273 vs 968 kilogenome-equivalents/L; P = 0.002). Plasma DNA concentrations correlated with the volume of cerebral hematoma (r = 0.66; P = 0.03). Plasma DNA concentrations >1400 kilogenome-equivalents/L had a sensitivity of 100% and a specificity of 74.4% for predicting hospital mortality after stroke, and the area under the ROC curve was 0.89 (95% confidence interval, 0.80-0.94). The adjusted odds ratio for plasma DNA concentrations predicting 6-month mortality was 1.6 (1.1-2.4; P = 0.03) and for predicting 6-month post-Rankin Score >2 was 1.8 (1.0-3.3; P = 0.05). CONCLUSION: Plasma DNA concentrations correlate with stroke severity and may be used to predict mortality and morbidity in the emergency room.

Gastric retentive dosage forms: a review.

Gastric retentive dosage forms have been investigated to provide controlled release therapy for drugs with reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the stomach or upper GI tract. Gastric retentive dosage forms rely on either natural GI physiology, such as floating or large tablets that depend on delayed emptying from the fed stomach, or those dosage forms that are designed to fight the physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or without flotation or bioadhesion. To understand the behavior of the dosage forms, an introduction to GI motility and its measurement is provided. Because the fed mode underlies the successful development of dosage forms that rely on size or flotation, the emptying of these dosage forms in the fed mode and identification of the key factors influencing the variability of gastric retention are discussed. The design and limitations of size or density-based fed mode, and mucoadhesive and expandable fasting-state gastric retentive systems are presented.