PCOM Library / Hot Topics in Research / Archive for "Pharmaceutical Sciences"

Category: Pharmaceutical Sciences

Hot Topics: Liquid Lab-on-a-Chip 3D Printed

Jackie Werner Biomedical Sciences, Hot Topics in Research, Pharmaceutical Sciences

Harnessing liquid-in-liquid printing and micropatterned substrates to fabricate 3-dimensional all-liquid fluidic devices

Feng W, Chai Y, Forth J, Ashby PD, Russell TP, Helms BA. Harnessing liquid-in-liquid printing and micropatterned substrates to fabricate 3-dimensional all-liquid fluidic devices. Nature Communications. 2019;10(1):1095. https://doi.org/10.1038/s41467-019-09042-y.

Systems comprised of immiscible liquids held in non-equilibrium shapes by the interfacial assembly and jamming of nanoparticle−polymer surfactants have significant potential to advance catalysis, chemical separations, energy storage and conversion. Spatially directing functionality within them and coupling processes in both phases remains a challenge. Here, we exploit nanoclay−polymer surfactant assemblies at an oil−water interface to produce a semi-permeable membrane between the liquids, and from them all-liquid fluidic devices with bespoke properties. Flow channels are fabricated using micropatterned 2D substrates and liquid-in-liquid 3D printing. The anionic walls of the device can be functionalized with cationic small molecules, enzymes, and colloidal nanocrystal catalysts. Multi-step chemical transformations can be conducted within the channels under flow, as can selective mass transport across the liquid−liquid interface for in-line separations. These all-liquid systems become automated using pumps, detectors, and control systems, revealing a latent ability for chemical logic and learning.

Hot Topics: Bioluminescence Sensors Evaluate Drug Pathways

Jackie Werner Biomedical Sciences, Hot Topics in Research, Pharmaceutical Sciences

Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors

Namkung Y, LeGouill C, Kumar S, et al. Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors. Sci Signal. 2018;11(559). http://dx.doi.org/10.1126/scisignal.aat1631

G protein–coupled receptors (GPCRs) are important therapeutic targets that exhibit functional selectivity (biased signaling), in which different ligands or receptor variants elicit distinct downstream signaling. Understanding all the signaling events and biases that contribute to both the beneficial and adverse effects of GPCR stimulation by given ligands is important for drug discovery. Here, we report the design, validation, and use of pathway-selective bioluminescence resonance energy transfer (BRET) biosensors that monitor the engagement and activation of signaling effectors downstream of G proteins, including protein kinase C (PKC), phospholipase C (PLC), p63RhoGEF, and Rho. Combined with G protein and β-arrestin BRET biosensors, our sensors enabled real-time monitoring of GPCR signaling at different levels in downstream pathways in both native and engineered cells. Profiling of the responses to 14 angiotensin II (AngII) type 1 receptor (AT1R) ligands enabled the clustering of compounds into different subfamilies of biased ligands and showed that, in addition to the previously reported functional selectivity between Gαq and β-arrestin, there are also biases among G protein subtypes. We also demonstrated that biases observed at the receptor and G protein levels propagated to downstream signaling pathways and that these biases could occur through the engagement of different G proteins to activate a common effector. We also used these tools to determine how naturally occurring AT1R variants affected signaling bias. This suite of BRET biosensors provides a useful resource for fingerprinting biased ligands and mutant receptors and for dissecting functional selectivity at various levels of GPCR signaling.

Hot Topics: New Drug Found Effective for Influenza

Jackie Werner Hot Topics in Research, Infectious Disease, Pharmaceutical Sciences

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913-923. https://doi.org/10.1056/NEJMoa1716197.

BACKGROUND

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

METHODS

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

RESULTS

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

CONCLUSIONS

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed.

Hot Topics: New Sensor Speedily Detects Receptor Activation

Jackie Werner Hot Topics in Research, Pharmaceutical Sciences

A universal bioluminescence resonance energy transfer sensor design enables high-sensitivity screening of GPCR activation dynamics

Schihada H, Vandenabeele S, Zabel U, Frank M, Lohse MJ, Maiellaro I. A universal bioluminescence resonance energy transfer sensor design enables high-sensitivity screening of GPCR activation dynamics. Communications Biology. 2018;1(1):105. https://doi.org/10.1038/s42003-018-0072-0.

G-protein-coupled receptors (GPCRs) represent one of the most important classes of drug targets. The discovery of new GCPR therapeutics would greatly benefit from the development of a generalizable high-throughput assay to directly monitor their activation or de-activation. Here we screened a variety of labels inserted into the third intracellular loop and the C-terminus of the α2A-adrenergic receptor and used fluorescence (FRET) and bioluminescence resonance energy transfer (BRET) to monitor ligand-binding and activation dynamics. We then developed a universal intramolecular BRET receptor sensor design to quantify efficacy and potency of GPCR ligands in intact cells and real time. We demonstrate the transferability of the sensor design by cloning β2-adrenergic and PTH1-receptor BRET sensors and monitored their efficacy and potency. For all biosensors, the Z factors were well above 0.5 showing the suitability of such design for microtiter plate assays. This technology will aid the identification of novel types of GPCR ligands.

Hot Topics: Drug Effectiveness Predicted by Brain “Fingerprint”

Jackie Werner Hot Topics in Research, Neurology, Pharmaceutical Sciences

Multimodal imaging-based therapeutic fingerprints for optimizing personalized interventions: Application to neurodegeneration

Iturria-Medina Y, Carbonell FM, Evans AC. Multimodal imaging-based therapeutic fingerprints for optimizing personalized interventions: Application to neurodegeneration. NeuroImage. 2018;179:40-50. http://dx.doi.org/10.1016/j.neuroimage.2018.06.028.

Personalized Medicine (PM) seeks to assist the patients according to their specific treatment needs and potential intervention responses. However, in the neurological context, this approach is limited by crucial methodological challenges, such as the requirement for an understanding of the causal disease mechanisms and the inability to predict the brain’s response to therapeutic interventions. Here, we introduce and validate the concept of the personalized Therapeutic Intervention Fingerprint (pTIF), which predicts the effectiveness of potential interventions for controlling a patient’s disease evolution. Each subject’s pTIF can be inferred from multimodal longitudinal imaging (e.g. amyloid-β, metabolic and tau PET; vascular, functional and structural MRI). We studied an aging population (N = 331) comprising cognitively normal and neurodegenerative patients, longitudinally scanned using six different neuroimaging modalities. We found that the resulting pTIF vastly outperforms cognitive and clinical evaluations on predicting individual variability in gene expression (GE) profiles. Furthermore, after regrouping the patients according to their predicted primary single-target interventions, we observed that these pTIF-based subgroups present distinctively altered molecular pathway signatures, supporting the across-population identification of dissimilar pathological stages, in active correspondence with different therapeutic needs. The results further evidence the imprecision of using broad clinical categories for understanding individual molecular alterations and selecting appropriate therapeutic needs. To our knowledge, this is the first study highlighting the direct link between multifactorial brain dynamics, predicted treatment responses, and molecular alterations at the patient level. Inspired by the principles of PM, the proposed pTIF framework is a promising step towards biomarker-driven assisted therapeutic interventions, with additional important implications for selective enrollment of patients in clinical trials.

Hot Topics: New Drug Improves Bladder Function After Spinal Cord Injury

Jackie Werner Hot Topics in Research, Neurology, Pharmaceutical Sciences

Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury

Ryu JC, Tooke K, Malley SE, et al. Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest. 2018;128(5):1772-1786. https://doi.org/10.1172/JCI97837

Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro–nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase–positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Hot Topics: Opioids Overprescribed After Joint and Spine Surgery

Jackie Werner Hot Topics in Research, Pharmaceutical Sciences, Rheumatology, Surgery

Opioid Oversupply After Joint and Spine Surgery: A Prospective Cohort Study

Bicket MC, White E, Pronovost PJ, Wu CL, Yaster M, Alexander GC. Opioid oversupply after joint and spine surgery: A prospective cohort study. Anesth Analg. 2018. doi: 10.1213/ANE.0000000000003364.

BACKGROUND: Many patients receive prescription opioids at hospital discharge after surgery, yet little is known regarding how often these opioids go unused. We estimated the prevalence of unused opioids, use of nonopioid analgesics, and storage and disposal practices after same-day and inpatient surgery.

METHODS: In this prospective cohort study at a large, inner-city tertiary care hospital, we recruited individuals ≥18 years of age undergoing elective same-day or inpatient joint and spine surgery from August to November 2016. Using patient surveys via telephone calls, we assessed patient-reported outcomes at 2-day, 2-week, 1-month, and 6-month intervals, including: (1) stopping opioid treatment and in possession of unused opioid pills (primary outcome), (2) number of unused opioid tablets reported after stopping opioids, (3) use of nonopioid pain treatments, and (4) knowledge and practice regarding safe opioid storage and disposal.

RESULTS: Of 141 eligible patients, 140 (99%) consented (35% taking preoperative opioids; mean age 56 years [standard deviation 16 years]; 47% women). One- and 6-month follow-up was achieved for 115 (82%) and 110 patients (80%), respectively. Among patients who stopped opioid therapy, possession of unused opioids was reported by 73% (95% confidence intervals, 62%-82%) at 1-month follow-up and 34% (confidence interval, 24%-45%) at 6-month follow-up. At 1 month, 46% had ≥20 unused pills, 37% had ≥200 morphine milligram equivalents, and only 6% reported using multiple nonopioid adjuncts. Many patients reported unsafe storage and failure to dispose of opioids at both 1-month (91% and 96%, respectively) and 6-month (92% and 47%, respectively) follow-up.

CONCLUSIONS: After joint and spine surgery, many patients reported unused opioids, infrequent use of analgesic alternatives, and lack of knowledge regarding safe opioid storage and disposal. Interventions are needed to better tailor postoperative analgesia and improve the safe storage and disposal of prescription opioids.

Hot Topics: Animal Model May Show How to Reduce Chemotherapy Pain

Jackie Werner Hot Topics in Research, Oncology, Pharmaceutical Sciences

Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms

Wahlman C, Doyle TM, Little JW, et al. Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain. doi: 10.1097/j.pain.0000000000001177

Development of chemotherapy-induced neuropathic pain (CINP) compromises the use of chemotherapy and greatly impacts thousands of lives. Unfortunately, there are no Food and Drug Administration–approved drugs to prevent or treat CINP. Neuropathological changes within CNS, including neuroinflammation and increased neuronal excitability, are driven by alterations in neuro-glia communication; but, the molecular signaling pathways remain largely unexplored. Adenosine is a potent neuroprotective purine nucleoside released to counteract the consequences of these neuropathological changes. Adenosine signaling at its adenosine receptors (ARs) is dictated by adenosine kinase (ADK) in astrocytes, which provides a cellular sink for the removal of extracellular adenosine. We now demonstrate that chemotherapy (oxaliplatin) in rodents caused ADK overexpression in reactive astrocytes and reduced adenosine signaling at the A3AR subtype (A3AR) within the spinal cord. Dysregulation of ADK and A3AR signaling was associated with increased proinflammatory and neuroexcitatory interleukin-1β expression and activation of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, but not putative oxaliplatin-associated GSK3β transcriptional regulation. Intrathecal administration of the highly selective A3AR agonist MRS5698 attenuated IL-1β production and increased the expression of potent anti-inflammatory and neuroprotective IL-10. The effects of MRS5698 were blocked by attenuating IL-10 signaling in rats with intrathecal neutralizing IL-10 antibody and in IL-10−/− knockout mice. These findings provide new molecular insights implicating astrocyte-based ADK-adenosine axis and nucleotide-binding oligomerization domain-like receptor protein 3 in the development of CINP and IL-10 in the mechanism of action of A3AR agonists. These findings strengthen the pharmacological rationale for clinical evaluation of A3AR agonists already in advanced clinical trials as anticancer agents as an adjunct to chemotherapy.

Hot Topics: Ingestible Sensors Can Tell If Patients Are Taking Pills

Jackie Werner Hot Topics in Research, Pharmaceutical Sciences

Oxycodone Ingestion Patterns in Acute Fracture Pain With Digital Pills

Chai PR, Carreiro S, Innes BJ, et al. Oxycodone ingestion patterns in acute fracture pain with digital pills. Anesthesia & Analgesia. 2017;125(6). doi: 10.1213/ANE.0000000000002574

BACKGROUND: Opioid analgesics are commonly prescribed on an as-needed (PRN) basis for acute painful conditions. Uncertainty of how patients actually take PRN opioids, coupled with a desire to completely cover pain, leads to variable and overly generous opioid prescribing practices, resulting in a surplus of opioids. This opioid surplus becomes a source for diversion and nonmedical opioid use. Understanding patterns of actual opioid ingestion after acute painful conditions can help clinicians counsel patients on safe opioid use, and allow timely recognition and intervention when escalating opioid self-dosing occurs, to prevent tolerance and addiction.

METHODS: We used a novel oxycodone digital pill system (ingestible biosensor within a standard gelatin capsule combined with 5-mg oxycodone) that when ingested, is activated by the chloride ion gradient in the stomach thereby emitting a radiofrequency signal captured by a wearable reader. The reader relays ingestion data to a cloud-based server that displays ingestion events to the study team. We deployed the oxycodone digital pill among opioid-naive individuals discharged from the emergency department with acute fracture pain. Participants were trained on digital pill operation and discharged with twenty-one 5-mg oxycodone digital pills. They were instructed to take digital pills PRN for pain on discharge. We conducted a brief interview 7 days after study enrollment, at which point participants returned the digital pill system. We identified oxycodone ingestion events in real time by data from the digital pill system and performed pill counts at the return visit to validate digital pill reporting of medication ingestion.

RESULTS: In this study, 26 individuals were approached; 16 enrolled with 15 completing the study. Participants ingested a median of 6 (3–9.5) oxycodone digital pills over the course of 7 days, with 82% of the oxycodone dose ingested in the first 3 days. In individuals who required operative repair, 86% (N = 6) continued to ingest opioids at 1 week. There was substantial variability in ingestion patterns between individuals.

CONCLUSIONS: The utilization patterns of individuals with acute fracture pain could be captured using a digital pill system and revealed a median opioid ingestion of 45-mg morphine equivalents for acute pain over 7 days. Seven participants ceased using opioids within 4 days after discharge from the emergency department, although operative repair was associated with longer use. This digital pill system was able to measure changes in and patterns of opioid self-dosing, which varied between patients.

Hot Topics: Unnecessary Antibiotics in Hospitals Can Cause Adverse Events

Jackie Werner Hot Topics in Research, Internal Medicine, Pharmaceutical Sciences

Association of Adverse Events With Antibiotic Use in Hospitalized Patients

Tamma PD, Avdic E, Li DX, Dzintars K, Cosgrove SE. Association of Adverse Events With Antibiotic Use in Hospitalized Patients. JAMA Intern Med. Published online June 12, 2017. doi:10.1001/jamainternmed.2017.1938

Importance  Estimates of the incidence of overall antibiotic-associated adverse drug events (ADEs) in hospitalized patients are generally unavailable.

Objective  To describe the incidence of antibiotic-associated ADEs for adult inpatients receiving systemic antibiotic therapy.

Design, Setting, and Participants  Retrospective cohort of adult inpatients admitted to general medicine wards at an academic medical center.

Exposures  At least 24 hours of any parenteral or oral antibiotic therapy.

Main Outcomes and Measures  Medical records of 1488 patients were examined for 30 days after antibiotic initiation for the development of the following antibiotic-associated ADEs: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac, and neurologic; and 90 days for the development of Clostridium difficile infection or incident multidrug-resistant organism infection, based on adjudication by 2 infectious diseases trained clinicians.

Results  In 1488 patients, the median age was 59 years (interquartile range, 49-69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non–clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of C difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics.

Conclusions and Relevance  Although antibiotics may play a critical role when used appropriately, our findings underscore the importance of judicious antibiotic prescribing to reduce the harm that can result from antibiotic-associated ADEs.