Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma.

BACKGROUND: In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China and quickly spread into a worldwide pandemic. Prior to the development of specific drug therapies or a vaccine, more immediately available treatments were sought including convalescent plasma. A potential improvement from convalescent plasma could be the preparation of anti-SARS-CoV-2 hyperimmune globulin (hIVIG). STUDY DESIGN AND METHODS: Convalescent plasma was collected from an existing network of plasma donation centers. A caprylate/chromatography purification process was used to manufacture hIVIG. Initial batches of hIVIG were manufactured in a versatile, small-scale facility designed and built to rapidly address emerging infectious diseases. RESULTS: Processing convalescent plasma into hIVIG resulted in a highly purified immunoglobulin G (IgG) product with more concentrated neutralizing antibody activity. hIVIG will allow for the administration of greater antibody activity per unit of volume with decreased potential for several adverse events associated with plasma administration. IgG concentration and IgG specific to SARS-CoV-2 were increased over 10-fold from convalescent plasma to the final product. Normalized enzyme-linked immunosorbent assay activity (per mg/ml IgG) was maintained throughout the process. Protein content in these final product batches was 100% IgG, consisting of 98% monomer and dimer forms. Potentially hazardous proteins (IgM, IgA, and anti-A, anti-B, and anti-D) were reduced to minimal levels. CONCLUSIONS: Multiple batches of anti-SARS-CoV-2 hIVIG that met regulatory requirements were manufactured from human convalescent plasma. The first clinical study in which the hIVIG will be evaluated will be Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) [NCT04546581].

A single-dose, randomized, double-blind, double dummy, placebo and positive-controlled, five-way cross-over study to assess the pharmacodynamic effects of lorediplon in a phase advance model of insomnia in healthy Caucasian adult male subjects.

OBJECTIVE: A 5-h phase advance model of insomnia was used to evaluate the efficacy of lorediplon, a new non-benzodiazepine hypnotic. METHODS: Thirty-five male, healthy subjects were included in a five-way randomized cross-over study. During each of the periods, sleep was recorded, and residual effects were measured. All subjects received lorediplon 1, 5, and 10 mg, placebo, and zolpidem 10 mg (i.e., active control). RESULTS: Polysomnographic evaluation revealed that lorediplon (5 and 10 mg) significantly decreased wake after sleep onset (WASO) and increased total sleep time. Analysis by quarters of the night showed a progressive increasing effectiveness of lorediplon 10 mg across the first three quarters. Lorediplon increased non-rapid eye movement slow wave sleep and stage N2 sleep in the second and third quarters. The magnitude of these effects was dose related, with minimal effects seen with 1 mg. No residual effects were observed 13 h post dose. CONCLUSIONS: Lorediplon demonstrated a dose-dependent improvement in sleep, whereas zolpidem showed a more sustained WASO effect. No next-day hangover effects were observed. These sleep effects are also consistent with the pharmacokinetic profile of lorediplon. These results warrant clinical trials in patients with insomnia.

Photoinduced polarization enhancement on biased bilayer graphene in the Landau level regime.

We investigate the charge carrier dynamics in bilayer graphene subject to monochromatic laser irradiation within the Landau level quantization regime. Even though the radiation field does not lift the energy degeneracy of the lowest Landau levels (LLs), it nevertheless has a strong effect on the photoinduced pseudospin polarization response for higher LLs ([Formula: see text]). Our results show that the photoinduced bandgaps lead to a finite response of the averaged pseudospin polarization with nontrivial oscillating behavior. It is shown that the contribution from these higher LL transitions turns out to be crucial to achieve an enhanced photoinduced polarization in radiated bilayer graphene. The experimental feasibility of our findings is also discussed.

Spin-orbit effects on the spin and pseudospin polarization in ac-driven silicene.

We study the pseudospin and spin dynamical effects in single-layer silicene due to a perpendicular electric field periodically driven and its interplay with the intrinsic and extrinsic (Rashba) spin-orbit interaction. We find that the spin nonconserving processes of the real spin of the quasiparticles in silicene, induced by the rather weak spin-orbit mechanisms, manifest themselves as shifts of the resonances of its quasienergy spectrum in the low coupling regime to the driving field. We show that there is an interesting cooperative effect among the, in principle, competing Rashba and intrinsic spin-orbit contributions. This is explicitly illustrated by exact and approximated analytical solutions of the dynamical equations. In addition, we show that a finite Rashba spin-orbit interaction is indeed necessary in order to achieve a nonvanishing spin polarization. As additional feature, trivial and nontrivial topological phases might be distinguished from each other as fast or slow dynamical fluctuations of the spin polarization. We mention the possible experimental detection schemes of our theoretical results and their relevance in new practical implementation of periodically driven interactions in silicene physics and related two-dimensional systems.

Randomized, open-label, blinded-endpoint, crossover, single-dose study to compare the pharmacodynamics of torasemide-PR 10 mg, torasemide-IR 10 mg, and furosemide-IR 40 mg, in patients with chronic heart failure.

PURPOSE: Diuretics are the primary treatment for the management of chronic heart failure (HF) symptoms and for the improvement of acute HF symptoms. The rate of delivery to the site of action has been suggested to affect diuretic pharmacodynamics. The main objective of this clinical trial was to explore whether a prolonged release tablet formulation of torasemide (torasemide-PR) was more natriuretically efficient in patients with chronic HF compared to immediate-release furosemide (furosemide-IR) after a single-dose administration. Moreover, the pharmacokinetics of torasemide-PR, furosemide-IR, and torasemide-IR were assessed in chronic HF patients as well as urine pharmacodynamics. METHODS: Randomized, open-label, blinded-endpoint, crossover, and single-dose Phase I clinical trial with three experimental periods. Torasemide-PR and furosemide-IR were administered as a single dose in a crossover fashion for the first two periods, and torasemide-IR 10 mg was administered for the third period. Blood and urine samples were collected at fixed timepoints. The primary endpoint was the natriuretic efficiency after administration of torasemide-PR and furosemide-IR, defined as the ratio between the average drug-induced natriuresis and the average drug recovered in urine over 24 hours. RESULTS: Ten patients were included and nine completed the study. Here, we present the results from nine patients. Torasemide-PR was more natriuretically efficient than furosemide-IR (0.096 ± 0.03 mmol/µg vs 0.015 ± 0.0007 mmol/µg; P < 0.0001). Mictional urgency was lower and more delayed with torasemide-PR than with furosemide-IR. CONCLUSION: In a study with a limited sample size, our results suggest that 10 mg of torasemide-PR is more natriuretically efficient than 40 mg of furosemide-IR after single-dose administration in patients with chronic HF over a 24-hour collection period. Further studies are necessary to evaluate potential pharmacodynamic differences between torasemide formulations and to assess its impact on clinical therapeutics.

In vitro percutaneous absorption and metabolism of ozenoxacin in excised human skin.

In vitro studies using excised human skin samples were conducted to evaluate the percutaneous absorption and skin metabolism of ozenoxacin. The formulations studied were 1% ointment, 1% cream and 2% cream. Permeation assays met the conditions for infinite dose experiments. In all but one case, ozenoxacin concentrations in receptor fluid samples of Franz diffusion cells were below the limits of quantification (0.04 µg/ml) by liquid chromatography/mass spectrometry/electrospray ionization at the designated time points. Across all four absorption studies, ≤ 0.015% of the applied ozenoxacin dose permeated through the skin over the course of 24 or 48 h. Ethnic origin had no influence on absorption. Ozenoxacin at concentrations of 7, 35 and 70 µM was metabolically stable in the presence of freshly prepared human skin discs.

Systemic bioavailability, safety and tolerability of topical ozenoxacin in healthy adult volunteers.

A series of Phase I studies was conducted in healthy volunteers to examine the systemic bioavailability and safety of topical ozenoxacin. Study 1 examined increasing single doses (relating to quantity and body surface area) of ozenoxacin 1% ointment. Study 2 compared multiple doses of ozenoxacin 1% ointment and placebo applied for 7 days. Study 3 investigated multiple doses of ozenoxacin 2% cream and placebo applied for 7 days. Study 4 examined multiple doses of ozenoxacin 2% cream applied to intact and abraded skin for 8 days. No systemic absorption was observed in any study and ozenoxacin was well tolerated. The most common treatment-related adverse events were application-site reactions (erythema and pruritus), but the differences in local tolerability between ozenoxacin and placebo were not clinically significant.

Skin tissue exposure of once- versus twice-daily topical ozenoxacin 2% cream: a Phase I study in healthy volunteers.

In this Phase I study, healthy volunteers (n = 24) were randomly allocated to receive either one or two 0.2-g applications per day (12 h apart) of ozenoxacin 2% cream on three different areas of the back for 3 consecutive days. Ozenoxacin concentrations were measured in tape stripping samples (from the stratum corneum) and in skin punch biopsy samples (from the epidermis and dermis) taken predose from selected dosing areas on study days 2, 3 and 4. Ozenoxacin concentrations were high in the stratum corneum and were approximately twofold greater for the twice- versus once-daily application. Ozenoxacin concentrations were low in the epidermis and were higher for the twice- versus once-daily application. Ozenoxacin concentrations in the dermis were below the limit of quantitation on most study days.

Systemic bioavailability and safety of twice-daily topical ozenoxacin 1% cream in adults and children with impetigo.

In this Phase I open-label study, the systemic absorption, clinical response, safety and tolerability of multiple-dose ozenoxacin 1% cream were evaluated in children (≥ 2 months of age) and adults with impetigo. A single (evening) dose of ozenoxacin 1% cream on day 1 was followed by twice-daily application for 4 days (every 12 h), and then a final single (morning) dose on day 6. A total of 46 patients were enrolled in the study. The majority of ozenoxacin plasma samples were below the limit of quantification (no systemic absorption). Approximately half (22/45) of the evaluable patients achieved clinical success (skin lesions were cured). No patients were withdrawn from the study because of a lack of healing or worsening of a lesion. Ozenoxacin was well tolerated in all patients.