Interview with Diana Chow

Diana Shu-Lian Chow, Ph.D., is an outstanding researcher at the University of Houston College of Pharmacy, where she began her career in 1981. She has authored or co-authored more than 50 peer-reviewed journal articles, three book chapters and more than 200 abstracts presented at national and international scientific conference or meetings. She is the editor of the British Journal of Pharmacology, editorial board member for the Journal of Drug Development and Industrial Pharmacy and a reviewer for more than a dozen journals. She holds more than 10 U.S. and international patents, and in 2009, the Houston Intellectual Property Law Association bestowed its “Inventor of the Year” Award to Dr. Chow. She has worked with collaborators across the Texas Medical Center and the world on drugs that fight cancer and strive to help those with spinal cord injuries. She has received the Outstanding Alumni Achievement Award from the National Taiwan University School of Pharmacy in Taipei, Taiwan, awards as a Faculty Scholar-Minority Serving Institution Awards from the American Association for Cancer Research, and the UHCOP Faculty Service Excellence Award. In 2016, she was inducted as a Fellow of the National Academy of Inventors at the U.S. Patent & Trademark Office headquarters in Washington, D.C. She is a demure woman who is hesitant to boast of her awards, but pursuing research that has an impact on patients’ lives has been her professional passion

Pharmacokinetic Variability of Mycophenolic Acid in Pediatric and Adult Patients with Hematopoietic Stem Cell Transplantation

The aim of this study was to evaluate the pharmacokinetic variations of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in both pediatric and adult patients following hematopoietic stem cell transplantation (HSCT). Twenty pediatric patients with a median age of 3 years (range 0.2-12 years) and 13 adult patients with a median age of 54 years (range 18-63 years) were enrolled. Blood samples were collected on days 0, 7, 14, 21, and 30 after allogeneic HSCT. Total and free (unbound) MPA as well as MPA 7-O-glucuronide (MPAG) were quantified using a validated LC-MS/MS assay. The plasma protein binding of MPA and MPAG did not change significantly in pediatric patients over the 1-month sampling period post-HSCT. However, it increased in adult patients from day 7 to day 30 post-HSCT, from 97.3 ± 0.8% to 98.3 ± 0.6% for MPA (P < .05), and 74.6 ± 9.4% to 82.9 ± 8.1% for MPAG (P < .05). The plasma protein binding of MPA was significantly higher in males compared to females in both pediatric (98.3 ± 1.1% vs 97.4 ± 1.1%) and adult (98.1 ± 0.7% vs 97.4 ± 1.2%) patients (P < .05). The MPAG/MPA ratios on a milligram-per-kilogram dose basis in adult patients were significantly higher than those in pediatric patients (4.3 ± 3.4 vs 2.4 ± 2.6; P < .05). Time-dependent plasma protein binding and age-related differences in MPA metabolism at least in part impact the reported large intra- and interindividual variability in MPA pharmacokinetics. These patient and pharmacologic factors, if incorporated into MMF regimen design and modification, may contribute to the rational dose selection of MMF in HSCT patients

Impact of Gender on Pharmocokinetics of Intranasal Scopolamine

Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS), which is commonly experienced by astronauts during space missions. The bioavailability and pharmacokinetics (PK) were evaluated under IND guidelines. Since information is lacking on the effect of gender on the PK of Scopolamine, we examined gender differences in PK parameters of INSCOP at three dose levels of 0.1, 0.2 and 0.4 mg. Methods: Plasma scopolamine concentrations as a function of time data were collected from twelve normal healthy human subjects (6 male/6 female) who participated in a fully randomized double blind crossover study. The PK parameters were derived using WinNonlin. Covariate analysis of PK profiles was performed using NONMEN and statistically compared using a likelihood ratio test on the difference of objective function value (OFV). Statistical significance for covariate analysis was set at P<0.05(OFV=3.84). Results: No significant difference in PK parameters between male and female subjects was observed with 0.1 and 0.2 mg doses. However, CL and Vd were significantly different between male and female subjects at the 0.4 mg dose. Results from population covariate modeling analysis indicate that a onecompartment PK model with first-order elimination rate offers best fit for describing INSCOP concentration-time profiles. The inclusion of sex as a covariate enhanced the model fitting (OFV=-4.1) owing to the genderdependent CL and Vd differences after the 0.4 mg dose. Conclusion: Statistical modeling of scopolamine concentration-time data suggests gender-dependent pharmacokinetics of scopolamine at the high dose level of 0.4 mg. Clearance of the parent compound was significantly faster and the volume of distribution was significantly higher in males than in females, As a result, including gender as a covariate to the pharmacokinetic model of scopolamine offers the best fit for PK modeling of the drug at dose of 0.4 mg or higher

Effect of diet and dietary fatty acids on the transformation and incorporation of C18 fatty acids in double-muscled Belgian Blue young bulls

Three groups of double-muscled Belgian Blue young bulls were fed during different stages of production diets differing in the proportions of linolenic and linoleic acid by including linseed in the concentrate or giving grass silage as main linolenic acid suppliers. Samples of rumen and abomasal contents and of the longissimus thoracis, subcutaneous fat, and liver were taken to analyze the fatty acid pattern with emphasis on the individual trans (t) C18:1 fatty acids and cis-9,trans-11 conjugated linoleic acid (c9t11CLA). Trans C18:1 isomers represented up to 20 g/100 g of total fatty acids in rumen and abomasal contents, whereas the accumulation of c9t11CLA was limited. Total trans C18:1 content in subcutaneous fat and intramuscular fat of the longissimus thoracis comprised 8.4 and 5.2 g/100 g of total fatty acids, respectively, with t11C18:1 being the most abundant one. Compared to rumen contents, subcutaneous and intramuscular fat were enriched in c9t11CLA and contained fewer tC18:1 isomers, resulting in a higher c9t11CLA/t11C18:1 ratio (0.04, 0.22, and 0.22, respectively). This result suggests that the endogenous synthesis of c9t11CLA in adipose tissue by the Delta(9)-desaturase was more important than its ruminal production

Sub-tenon Anaesthesia versus Intracameral Anaesthesia in Patients Undergoing Cataract Extraction: A Comparative Study of the Level of Pain, Visual Perception and Anxiety

Background: Phacoemulsification is a modern method of cataract extraction. Sub-tenon anaesthesia used to be the preferred anaesthetic technique for this procedure before intracameral anaesthesia gained its popularity in recent years. Nevertheless, many surgeons still believe that sub-tenon anaesthesia is better than topical anaesthesia. This study aimed to evaluate and compare the experiences of patients who were treated for cataract by phacoemulsification surgery using either sub-tenon or intracameral anaesthesia. Methods: Cross-sectional study conducted at Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia. Participants were asked to complete a questionnaire within 1-2 hours following surgery. The questionnaires were designed to gather information on the patient’s level of anxiety, visual perception and amount of pain experienced during cataract surgery. Results: A total of 62 patients were included in the study. Thirty-one patients received anaesthesia by sub-tenon injection, whereas another 31 patients received anaesthesia by intracameral injection. There were no significant differences in the level of pain experienced by the two groups of patients during instillation of anaesthesia and during surgery (p=0.205 and p=0.592, respectively). There were also no significant differences in terms of visual perception and anxiety levels during surgery between the two groups (p=0.178 and p=0.731, respectively). Conclusion: Intracameral anaesthesia obviates the need for an injection during cataract surgery and is as comfortable for patients as sub-tenon anaesthesia in terms of visual perception, level of pain, and anxiety

Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP

Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes

The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide) treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein)/PS1 (presenilin 1) Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein) and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group

Interplanetary CubeSats: Opening the Solar System to a Broad Community at Lower Cost

Interplanetary CubeSats could enable small, low-cost missions beyond low Earth orbit. This class is defined by mass < ~ 10 kg, cost < $30 M, and durations up to 5 years. Over the coming decade, a stretch of each of six distinct technology areas, creating one overarching architecture, could enable comparatively low-cost Solar System exploration missions with capabilities far beyond those demonstrated in small satellites to date. The six technology areas are: (1) CubeSat electronics and subsystems extended to operate in the interplanetary environment, especially radiation and duration of operation; (2) Optical telecommunications to enable very small, low-power uplink/downlink over interplanetary distances; (3) Solar sail propulsion to enable high !V maneuvering using no propellant; (4) Navigation of the Interplanetary Superhighway to enable multiple destinations over reasonable mission durations using achievable !V; (5) Small, highly capable instrumentation enabling acquisition of high-quality scientific and exploration information; and (6) Onboard storage and processing of raw instrument data and navigation information to enable maximum utility of uplink and downlink telecom capacity, and minimal operations staffing. The NASA Innovative Advanced Concepts (NIAC) program in 2011 selected Interplanetary CubeSats for further investigation, some results of which are reported here for Phase 1

Ensuring the Involvement of Children in the Evaluation of New Tuberculosis Treatment Regimens

William Burman and colleagues review the barriers to involving children in studies of new tuberculosis treatments and recommend strategies for overcoming these barriers