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

Category: Pharmaceutical Sciences

Hot Topics – Remdesivir for Compassionate Use in Severe Covid

Jackie Werner Covid-19, Hot Topics in Research, Pharmaceutical Sciences

Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe covid-19. N Engl J Med. 2020;382(24):2327-2336. https://doi.org/10.1056/NEJMoa2007016.

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BACKGROUND

Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.

METHODS

We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.

RESULTS

Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

CONCLUSIONS

In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy.

Hot Topics: Ivermectin Inhibits Covid in Vitro

Jackie Werner Covid-19, Hot Topics in Research, Pharmaceutical Sciences

Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. 2020;178:104787. https://doi.org/10.1016/j.antiviral.2020.104787.

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Abstract:

Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.

Hot Topics: Reports of Drug Side Effects Inconsistent

Jackie Werner Hot Topics in Research, Lung, Oncology, Pharmaceutical Sciences

Variation in toxicity reporting methods for early phase lung cancer treatment trials at oncology conferences

Simons EA, Smith DE, Gao D, Camidge DR. Variation in toxicity reporting methods for early phase lung cancer treatment trials at oncology conferences. Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2020.04.020.

Introduction

Phase I and II trials provide the initial human safety and tolerability data for new drugs. However, the methods for presenting toxicity data are not standardized. Clinicians often first encounter these data at professional conferences. We sought to characterize how the burden of adverse events (AE) is reported at the largest professional conference in clinical oncology.

Methods

We collected toxicity data from all lung cancer-associated phase I and II trial presentations and posters at the American Society for Clinical Oncology annual meetings 2017-2019. We captured AE features including the minimum incidence utilized for reporting; whether AEs shown were treatment-emergent or treatment-related, grouped by organ system or separated by individual descriptors; whether combined or separated across dose levels when a dose escalation component was included; and whether dose-limiting toxicities, serious AE, dose reduction rules and denominators for laboratory tests were described.

Results

209 trials were analyzed. There was wide variability in toxicity reporting practices. Six different thresholds for reporting AE of any grade were used. Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. Toxicities were as likely to be reported across dose level as by dose level. Terms such as dose-limiting toxicity and serious AE were rarely defined. Dose reduction rules and denominators for laboratory tests were never defined.

Conclusion

Standardization of methods for reporting toxicities could improve the quality and ease of comparability of data on adverse effects in early phase therapeutic trials. A minimal AE data disclosure template is proposed.

Hot Topics: Novel Target for Addiction Treatment

Jackie Werner Hot Topics in Research, Neurology, Pharmaceutical Sciences, Substance Use Disorders

Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity

Corkrum M, Covelo A, Lines J, et al. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron. 2020. https://doi.org/10.1016/j.neuron.2019.12.026.

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson’s disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

Hot Topics: ACE Inhibitors Less Effective for Hypertension

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

Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis

Suchard, M. A., Schuemie, M. J., Krumholz, H. M., You, S. C., Chen, R., Pratt, N., . . . Ryan, P. B. (2019). Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: A systematic, multinational, large-scale analysis https://doi.org/10.1016/S0140-6736(19)32317-7

Background

Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice.

Methods

We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested.

Findings

Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75–0·95), hospitalisation for heart failure (0·83, 0·74–0·95), and stroke (0·83, 0·74–0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes.

Interpretation

This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension—in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers.

Hot Topics: Drug Release Controlled with Artificial DNA

Jackie Werner Hot Topics in Research, Pharmaceutical Sciences

Engineering an orchestrated release avalanche from hydrogels using DNA-nanotechnology

Kimna C, Lieleg O. Engineering an orchestrated release avalanche from hydrogels using DNA-nanotechnology. Journal of Controlled Release. 2019;304:19-28. http://doi.org/10.1016/j.jconrel.2019.04.028.

Most medical therapies require repeated, sequential administration of therapeutic agents in well-defined intervals and over extended time windows. Typically, the patient is in charge of applying the individual drug doses, and insufficient patient compliance reduces the efficiency of the treatment. Therefore, the development of a smart delivery mechanism releasing therapeutic agents in a pre-defined, time-controlled fashion would be beneficial for many medical treatments. Here, we present a DNA-mediated release cascade which allows for precisely controlling the sequential delivery of several different nanoparticles. By using complementary DNA sequences, nanoparticle aggregates are created, embedded into distinct layers of a hydrogel and released by triggering aggregate dispersal. This mechanism is compatible with physiological conditions as the release cascade is initiated by exposing the nanoparticle-loaded gel to physiological salt concentrations. Moreover, we show that the reservoir hydrogel can be enriched with biopolymers to receive charge-selective release properties towards small molecules – without interfering with the DNA-based release cascade. Owing to the excellent reproducibility, precision and effectiveness of the presented mechanism, a similar DNA-mediated release avalanche may lead to the development of autonomous and robust delivery systems, which minimize the possibility of pharmaceutical therapy failure due to patient non-compliance.

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.