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The UMB Digital Archive is a service of the Health Sciences and Human Services Library (HS/HSL) that collects, preserves, and distributes the academic works of the University of Maryland, Baltimore. It is a place that digitally captures the historical record of the campus.
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From Data to Decisions: Utilizing Pharmacometrics to Optimize Clinical Therapeutics and Drug Development in NeuropsychiatryAt least 50% of clinical trials of neuropsychiatric compounds fail due to an unclear understanding of disease pathophysiology and drug pharmacology. Further, lack of dosing information in special patient populations for approved neuropsychiatric drugs could contribute to suboptimal outcomes. The current research highlights the role of pharmacometrics in (i) optimizing therapeutics in patients receiving antiepileptics and continuous renal replacement therapy (CRRT) and (ii) informing efficient trial design for binge eating disorder (BED). Currently, no dosing recommendations exist for CRRT patients receiving antiepileptics. Real-world clinical studies were conducted to characterize the pharmacokinetics of levetiracetam and lacosamide in patients (N=18) receiving CRRT at the University of Maryland Medical Center. Major determinants for drug clearance were drug-specific extraction coefficient (EC) approximated to fraction unbound (levetiracetam: 0.89, lacosamide: 0.80), effluent flow rate, and preserved non-renal clearance. Ex-vivo models of CRRT were developed using human plasma and normal saline containing albumin solutions. The developed ex-vivo in-vivo correlation model demonstrated an average bias of <15% in predicting in-vivo CRRT clearance for levetiracetam and lacosamide. Similarity in ECs justified the ability to bridge dosing information across CRRT modalities. This research, in combination with a priori knowledge of drug pharmacokinetics, confirms the use of ex-vivo CRRT models to establish dosing recommendations and alleviate the need for CRRT pharmacokinetic studies. The development of BED therapies are challenged by high placebo response and high dropout rates in clinical trials. A comprehensive disease-drug-trial (DDT) model was developed using data from 12 different investigator-led BED clinical trials (N = 578; 6 to 16-week duration) to inform optimal clinical trial design elements. Baseline BED severity metrics were predictors for placebo response and dropouts. Stimulants and anticonvulsants demonstrated 1.8 times higher effect differences as compared to antidepressants. Among the clinical trial designs (placebo run-in, drug run-in, sequential parallel comparison design) evaluated in-silico, placebo-controlled trial of shorter (6-week) duration with model-based analysis demonstrated superior trial design properties (40% lower sample size with 50% lower dropouts) as compared to current 12-week registration trials for BED. The proposed DDT framework can inform efficient trial design and potentially increase the number of therapeutic options for BED.
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Whole-genome analysis of Plasmodium falciparum isolates to understand allele-specific immunity to malariaAfter repeated P. falciparum infections, individuals in high-transmission areas acquire clinical immunity to malaria. However, the genes important in determining allele-specific immunity are not entirely known. Previous genome-wide approaches explored signatures of selection in the parasite genome to identify targets of clinical immunity; however, these approaches did not account for individual level allele-specific immunity. Here we take a whole-genome approach to identify genes that may be involved in acquisition of allele-specific immunity to malaria by analyzing parasite genomes collected from infected individuals in Malawi. However, obtaining whole genome sequence data from clinical samples is one of the major hurdles in the field of malaria genomics. In order to obtain whole genome sequence data from non-leukocyte depleted, low parasitemia samples, we optimized a selective-whole genome amplification (sWGA) by filtering the DNA prior to sWGA, to generate high coverage, whole genome sequence data from P. falciparum clinical samples with low amounts of parasite DNA. Using this optimized approach, we successfully performed whole-genome sequencing on 202 parasite isolates. We compared parasite genomes from individuals with varying levels of clinical immunity, defined using an individual’s proportion of symptomatic infections during the course of the study, hypothesizing that individuals with higher immunity become symptomatically ill due to infection with parasites with less common alleles. Using FST, we identified 161 SNPs to be genetically differentiated between the two groups and the median allele frequency was significantly lower at these sites in individuals in higher immunity group compared to the lower immunity group. We also examined pairs of parasites collected at different time points from the same individuals and identified 225 loci in 174 genes that vary within same individuals more often than expected by chance. Using both of these approaches, we identified 25 genes that encode likely targets of immunity, including a known antigen, CLAG8. Further analysis of clag8 global diversity showed evidence of immune selection in the C-terminal region, supporting the use of this approach in identification of new vaccine targets. Identifying and further analyzing these genomic regions will provide insights into mechanisms involved in allele-specific acquired immunity.
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Placebo Analgesia in Neuropathic Pain: A Translational Investigative Approach from Rodents to HumansPain is a complex phenomenon which can be influenced by various factors. Placebo analgesia (PA) is the experience of pain relief after the administration of a physiologically inert intervention via the expectation of benefit. However, adequate animal models of PA in chronic neuropathic pain were unavailable to determine how PA occurs in neuropathic pain. Neuropathic pain (NP) is a chronic pain condition characterized by a dysfunction of the peripheral or central nervous system. There is still limited progress in translating the findings of preclinical studies to address the clinical burden of chronic pain. This is thought to partly reflect difficulties in reliably assessing pain in animals. Hence, we employ a translational approach in both rodents and humans to explore the occurrence of PA in chronic NP. First, I tested the hypothesis that the facial grimace scale is a useful metric of spontaneous pain in rodents. We performed a chronic constriction injury of the infraorbital nerve (CCI-ION) and tested for changes in mechanical hypersensitivity and grimace scores. Results showed rodents with CCI-ION had significantly higher grimace scores and lower mechanical withdrawal thresholds compared to controls. These changes were reversed by an opioid, indicating the grimace scale as a sensitive metric for assessing ongoing pain in CCI-ION. Secondly, I tested the hypothesis that pharmacological conditioning with fentanyl would produce PA in a rat model of CCI-ION. Rats were pharmacologically conditioned with or without contextual cues. We administered a placebo and found marginally significant PA effect via the grimace scale but not in mechanical sensitivity. These findings suggest that PA may be more challenging to induce in rodents. Finally, in humans, I investigated how NP-like symptoms in Temporomandibular Joint Disorder alter PA. The effect of NP on PA is yet to be fully understood. I tested the hypothesis that the presence of NP-like symptoms would decrease PA in TMD. NP assessment was carried out both in the orofacial region and across the whole body using validated screening tools. Our results showed that the presence of co-occurring NP-like symptoms increased PA in TMD. We also show that this effect is mediated by reinforced expectation.
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Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodologyPurpose: Trustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine’s risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and inaccurately described the formulation that the control arms received. Under the Restoring Invisible and Abandoned Trials initiative (RIAT), we aim to restore the public record regarding the content and rationale of the controls used in the trials. Methods: We assembled a cohort (five randomised controlled trials) described as placebo-controlled using clinical study reports (CSRs) obtained from the European Medicines Agency. We extracted the content and rationale for the choice of control used in each trial across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms. Results: Across data sources, the controlwas inconsistently reported as ‘placebo’- containing aluminium adjuvant (sometimes with dose information). Amorphous aluminium hydroxyphosphate sulfate (AAHS) was not mentioned in any trial registry entry, but was mentioned in all publications and CSRs. In three of five trials, consent forms described the control as an ‘inactive’ substance. No rationale for the selection of the control was reported in any trial publication, register, consent form, CSR synopsis or protocol. Three trials reported the rationale for choice of control in CSRs: to preserve blinding and assess the safety of HPV virus-like particles as the ‘safety profile of (AAHS) is well characterised’. Conclusions: The stated rationale of using AAHS control—to characterise the safety of the HPV virus-like particles—lacks clinical relevance. A nonplacebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns. Trial registration numbers NCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.
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COVID-19 Can't Stop the UMB CURE ScholarsThe article describes the mentorship between Ayishat Yussef, a high-school student at City College, and Kat Coburn, an MD/PhD student at the University of Maryland School of Medicine, through the UMB CURE Scholars program. The mentorship has been helpful for both students through the COVID-19 pandemic and the social unrest.
