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Background: Omicron subvariants questioned the efficacy of the approved therapies for the early COVID-19. In vitro data show that remdesivir (RDV), molnupiravir (MLN), and nirmatrelvir/ritonavir (NMV/r) all retained activity against all sub-lineages, while poor neutralizing activity was observed for Sotrovimab (SOT) and Tixagevimab/cilgavimab (TIX/CIL). No data about the risk of clinical failure or even in vivo antiviral activity are available. Method(s): Single-center observational comparison study enrolling all consecutive patients (pts) seen for care with a confirmed SARS-CoV-2 Omicron diagnosis and who met the AIFA criteria for eligibility for treatment with RDV, MLN, NMV/r, TIX/CIL, or SOT. Treatment allocation was subject to drug availability, time from symptoms onset, and comorbidities. Nasopharyngeal swab (NPS) VL was measured on day 1 (D1) and D7 and was expressed by log2 cycle threshold (CT) scale. Comparisons between treatment groups were made by Chi-square, and Wilcoxon paired tests. Primary endpoint was D1-D7 VL variation. Potential decrease in VL and average treatment effect (ATE) were calculated from fitting marginal linear regression models weighted for calendar month of drug initiation, duration of symptoms, and immunodeficiency using NMV/r as the comparator trial arm. Result(s): A total of 971 pts received treatments (SOT 321, MLN 231, NMV/r 211, TIX/CIL 70, and RDV 138): female 457 (47%), median age 67 yrs (IQR 56-78), 93% vaccinated;12% with negative baseline serology. At D1, median time from symptoms onset was 3 days (IQR 2,4). 379 (39%) pts were infected with BA.1, 215 (22%) with BA.2, 372 with BA.4/5 (38%), and 5 with BQ.1 (0,5%). D1 mean viral load was 4.02 log2. Adjusted analysis (ATE) showed that NMV/r significantly reduced VL compared to all the other drugs in pts infected with all sublineages, (Fig.1A-B) while less evidence for a difference vs. TIX/CIL was seen in those infected with BA.2 (p=0.05) (Fig.1 C-D). Conclusion(s): In this analysis of in vivo early VL reductions, NMV/r appears to be the drug showing the greatest antiviral activity, regardless of the underlying subvariant, perhaps with the exception of TIX/CIL in people infected with BA.2 for which there was less evidence for a difference. In the Omicron era, due to the high prevalence of vaccinated people and in absence of clinical events, VL is one of the possible alternative endpoints which guarantees adequate statistical power. Fig 1 SARS-CoV-2 RNA levels at D1 and D7 in patients treated with Nirmatrelvir/ ritonavir, Sotrovimab, Molnupiravir, Remdesivir, and Tixagevimab/cilgavimab. Dot-plots showing the comparison of viral loads detected at D1 and D7 and the variation of RNA levels observed between the two time-points by intervention in (A) all patients treated with Nirmatrelvir/ritonavir (n=211), Sotrovimab (n=321), or Molnupiravir (n=231), or Remdesivir (n=138), or Tixagevimab/ cilgavimab (n=136);(C) patients with Omicron BA.2 infection treated with Nirmatrelvir/ritonavir (n=58), Sotrovimab (n=81), or Molnupiravir (n=21), or Remdesivir (n=37), or Tixagevimab/cilgavimab (n=18);(D) patients with Omicron BA.4/5 infection treated with Nirmatrelvir/ritonavir (n=102), Sotrovimab (n=92), or Molnupiravir (n=110), or Remdesivir (n=16), or Tixagevimab/cilgavimab (n=52). Viral RNA levels are expressed as log2 CT values. The horizontal dashed line represents the limit of detection (CT: 40.0), values >=40 are considered negative. Mean of log2 CT values, and SD are shown in the graph. Statistical analysis of the differences in viral loads by intervention as compared to Nirmatrelvir/ritonavir was performed by Mann-Whitney test. Potential decrease in VL and average treatment effect (ATE) were calculated from fitting marginal linear regression models weighted for calendar month of drug initiation, duration of symptoms, and immunodeficiency using NMV/r as the comparator trial arm. Results are shown (B) for patients infected with all Omicron sublineages and (D) for those infected with Omicron BA.2 sublineage.
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Background: SARS-CoV-2 evolution has contributed to successive waves of infections and severely compromised the efficacy of available SARS-CoV-2 monoclonal antibodies. Decaying vaccine-induced immunity, vaccine hesitancy, and limited vaccine protection in older and immunocompromised populations further compromises vaccine efficacy at the population level. Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease due to COVID-19. An orally bioavailable RDV analog could facilitate earlier widespread administration to non-hospitalized COVID-19 patients. Method(s): We synthesized monoalkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. We evaluated the in vivo efficacy of our lead compound, 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (V2043), in an oral treatment model of murine SARS-CoV-2 infection. We then synthesized numerous phospholipid analogs of RVn and determined which modifications enhanced in vitro antiviral activity and selectivity. The most effective compounds against SARS-CoV-2 were then evaluated for antiviral activity against other RNA viruses. Result(s): Oral treatment of SARS-CoV-2 infected BALB/c mice with V2043 (60 mg/kg once daily for 5 days, starting 12 hrs after infection) reduced lung viral load by more than 100-fold versus vehicle at day 2 and to below the LOD at day 5. V2043 inhibited previous and contemporary SARS-CoV-2 Variants of concern to a similar degree, as measured by the half maximal effective concentration (EC50) in a human lung epithelial cell line (Calu-3). Evaluation of multiple RVn analogs with hydrophobic esters at the sn-2 of glycerol revealed that in vitro antiviral activity was improved by the introduction of a 3-fluoro-4-methoxysubstituted benzyl or a 3-or 4-cyano-substituted benzyl. These compounds showed a 2-to 6-fold improvement in antiviral activity compared to analogs having an unsubstituted benzyl, such as V2043, and were more active than RDV. These compounds also showed enhanced antiviral activity against multiple contemporary and emerging RNA viruses. Conclusion(s): Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections and as preparation for future outbreaks of pandemic RNA viruses.
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Garlic (Allium sativum) has been known for its potent medicinal activities and its interesting culinary role since ancient times. With over 200 phytochemicals and flavoring compounds elucidated and many others yet to, garlic promises to improve human health and vitality. Just like other phytochemical classes, essential oils for garlic have been reported to show interesting medical activities delving across diverse antimicrobial, cardio-protective, anti-cancer, anti-Alzheimer, anti-diabetic, and immunomodulatory activities. Garlic essential oils contain mainly volatile and non-volatile allyl-sulphur-based compounds, which are a product of the stream decomposition of Allicin (a major component of garlic extract). Although a lot of work has been done on Allicin, there is little substantive work on the bio-availability and toxicities of its essential oil. This study, however, reviewed the methods that in recent times have been used to extract essential oils from garlic, recent studies on composition and therapeutic activities of Garlic essential oils, and a predictive overview of their bioavailability and toxicity. Finally, recommendations for future studies and other interesting prospects of garlic were also highlighted.Copyright © 2022
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AIFA Monitoring Registries (wMRs) constitute a collection of drug registries (product registries) deployed to physicians and pharmacists through a national web platform. They have been adopted in the clinical practice since 2005 and are used to define the population for which the drug is available under the umbrella of the National Health Service (NHS - Servizio Sanitario Nazionale SSN), monitor prescription appropriateness and ensure the rapid access to potentially priority medicines allowing the implementation of patient-based managed entry agreements (MEAs). Each registry consists of specific data entry forms, collecting data at the patient level and filled in by authorized clinicians and pharmacists. The required information includes: 1. Registration form with patient personal data (anonymized after registration);2. Eligibility and clinical data form;3. Prescription and administration forms;4. Evaluation of disease status and treatment update form;and 5. End-of-treatment form. Evaluation and end-of-treatment forms provide main safety and effectiveness data at a patient level. Moreover, since entry forms are the same throughout the nation, this platform allows access to treatment in a homogeneous manner throughout the country. Recently, a new type of registry has been released, with the primary aim of monitoring the pregnancy prevention programme (PPP) following the prescription of potentially teratogenic medicinal products. All this information is collected in a national database that represents a key source of postmarketing evidence that is frequently exploited to answer both administrative and clinical questions, such as drug utilization among a specific pharmacological class or the effectiveness of a drug in a census consisting of all Italian patients treated with that medicinal product. For example, given the prospective nature of the data contained inside the wMRs, AIFA together with members of the relevant scientific associations were able to evaluate the effect of the COVID- 19 pandemic and lockdown measures on the new prescription (i.e. first prescription) of some cardiovascular drugs in Italy and suggest new studies to analyse the occurrence of new cardiovascular- related events resulting from the decline in the activation of these treatments. Equally important is the work assessing the effectiveness of tyrosine kinase inhibitors in chronic myeloid leukaemia (CML) patients in Italian clinical practice, which was able to highlight important aspects on both expected mortality and consequential use in first and second line TKIs in Italy. Finally, the wMRs were also a critical instrument in the management of the COVID-19 medicinal products since 29 October 2020, providing essential evidence on drug availability through the country, predicting possible shortages and publishing hundreds of freely available reports on the utilization trend of COVID-19 drugs in the different Italian Regions. In conclusion, the wMRs represent a key tool to generate pharmaco-epidemiological evidences in the Real-world setting and monitoring drug appropriateness for expensive, innovative drug.
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We report in silico studies of pyridoxal, which is of interest both as a precursor for further functionalization due to the presence of the aldehyde functionality, as well as a bioactive compound. So far, the crystal structure of pyridoxal has not been reported and, thus, we have optimized its structure both under water solvation and in gas phase using the DFT calculations. Under water solvation conditions the optimized structure of pyridoxal is 7.62 kcal/mol more favorable in comparison to that in gas phase. The DFT calculations were also applied to verify optical and electronic properties of the optimized structure of pyridoxal in water. The HOMO and LUMO were revealed to subtract a set of descriptors of the so-called global chemical reactivity as well as to probe pyridoxal as a potential corrosion inhibitor for some important metals used in implants. The title compound exhibits the best electron charge transfer from the molecule to the surface of Ni and Co. Some biological properties of pyridoxal were evaluated using the respective on-line tools. Molecular docking was additionally applied to study interaction of pyridoxal with some SARS-CoV-2 proteins as well as one of the monkeypox proteins. It was established that the title compound is active against all the applied proteins with the most efficient interaction with nonstructural protein 15 (endoribonuclease) and Omicron Spike protein of SARS-CoV-2. Pyridoxal was found to be also active against the studied monkeypox protein. Interaction of pyridoxal with nonstructural protein 15 (endoribonuclease) was further studied using molecular dynamics simulation.Copyright © 2023 Indian Chemical Society
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Introduction: Biologics (biopharmaceuticals) present new promising therapies for many diseases such as cancers, chronical inflammatory diseases and today's biggest challenge - COVID-19. Research: Today, most biologics have been synthetized using modern methods of biotechnology, in particular DNA recombinant technology. Current pharmaceutical forms of protein/peptide biopharmaceuticals are intended for parenteral route of administration due to their instability and large size of molecules. In order to improve patient compliance, many companies are working on developing adequate forms of biopharmaceuticals for alternative, non-invasive routes of administration. The aim of this work is to review current aspirations and problems in formulation of biopharmaceuticals for alternative (non-parenteral) routes of administration and to review the attempts to overcome them. These alternative routes of administration could be promising in prevention and treatment of COVID-19, among other serious diseases. Conclusion(s): The emphasis is on stabilizing monoclonal antibodies into special formulations and delivery systems;their application should be safer, more comfortable and reliable. When it comes to hormones, vaccines and smaller peptides, some companies have already registered drugs intended for nasal and oral delivery.Copyright © 2022 Sciendo. All rights reserved.
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Partitioning and effect of antiviral GC376, a potential SARS-CoV-2 inhibitor, on model lipid membranes was studied using dynamic light scattering (DLS), UV–VIS spectrometry, Excimer fluorescence, Differential scanning calorimetry (DSC) and Small- and Wide-angle X-ray scattering (SAXS/WAXS). Partition coefficient of GC376 between lipid and water phase was found to be low, reaching KP = 46.8 ± 18.2. Results suggest that GC376 partitions into lipid bilayers at the level of lipid head-groups, close to the polar/hydrophobic interface. Changes in structural and thermodynamic properties strongly depend on the GC376/lipid mole ratio. Already at lowest mole ratios GC376 induces increase of lateral pressures, mainly in the interfacial region of the bilayer. Hereby, the pre- and main-transition temperature of the lipid system increases, what is attributed to tighter packing of acyl chains induced by GC376. At GC376/DPPC ≥ 0.03 mol/mol we detected formation of domains with different GC376 content resulting in the lateral phase separation and changes in both, main transition temperature and enthalpy. The observed changes are attributed to the response of the system on the increased lateral stresses induced by partitioning of GC376. Obtained results are discussed in context of liposome-based drug delivery systems for GC376 and in context of indirect mechanism of virus replication inhibition.
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Background: In December 2019, a respiratory illness due to a novel coronavirus, SARS-CoV-2, was first identified in Wuhan, China. SARS-CoV-2, termed COVID-19, is now a worldwide pandemic and has been identified in 216 countries and areas or territories (WHO, 2020). As of May 15th, 2020, there have been more than 4.2 million confirmed cases and 294,190 deaths worldwide. Purpose(s): Ensure patient safety, drug availability, and therapeutic efficacy for all COVID-19 patients. Implement a number of changes to urgently meet the institution's patient care needs. Method(s): Data were collected from a 62-year-old male patient admitted with severe COVID-19 to the intensive care unit in April 2020. The following pharmacy services were then provided: first, constant review and interpretation of new clinical data;second, patient eligibility assessment and obtaining medication through compassionate use protocols;third, evidence-based interventions (e.g. drug-drug interaction, drug-disease interaction, and dose adjustments);fourth, limit unnecessary nebuliser use. Last but not least, educate patients and the public on effective strategies to prevent acquisition and further spread of infection (e.g. social distancing, optimal hand hygiene, and personal protective equipment). Result(s): With standard care and the compassionate use of Hydroxychloroquine, Azithromycin, Zn supplements, and Tocilizumab under close monitoring, the patient successfully recovered and was discharged on May 4th, 2020. Conclusion(s): Pharmacists play a vital role within a multi-disciplinary healthcare team to optimise patient care during this COVID-19 pandemic.
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Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health hazard due to its rapid dissemination and limited treatment options. Identification of possible treatments that may kill the virus, speed up the recovery, or reduce the case fatality rate is a need of hour. However, developing and producing particular COVID-19 medicines and vaccines is a time-consuming process with possibilities of clinical failures due to safety or efficacy issue. Medication repositioning is a safer and quicker approach for dealing with the COVID-19 worldwide threat right now. Out of 48 FDA-approved medicines tested against SARS-CoV-2, niclosamide is one amongst few that has shown potential in vitro antiviral activity against SARS-CoV-2. However, the currently available oral conventional formulation of niclosamide results in systemic medication levels those are unsatisfactory to inhibit SARS-CoV-2. Hence, various formulation strategies have been adapted in order to achieve an optimum therapeutic outcome of niclosamide when delivered via oral, inhalation, and intranasal routes. Some of these formulations are presently undergoing clinical trials. The current review focuses on the mechanisms of action of niclosamide and its repurposing effectiveness against COVID-19. The delivery strategies to improve its bioavailability have been overviewed. The recently completed and ongoing clinical trials have also been summarized. Copyright © 2023 The Authors.
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Objectives: To identify stakeholders' understanding of drug shortage and the internal process of reporting a drug shortage to the Saudi Food & Drug Authority (SFDA). Evaluate the clarity of the communication channels and the stakeholder's satisfaction. A secondary objective was to explore the impact of COVID-19 on drug shortage in Saudi Arabia. Method(s): A cross-sectional study consisting of three separate surveys targeting: Health care providers, National Unified Procurement Company (NUPCO) registered in Saudi-vigilance, and pharmaceutical companies/storage that are registered in (RSD). Descriptive analysis such as percentages and frequencies was preformed to describe the knowledge and the practice of the targeted stakeholders Results: Drug shortages was defined by healthcare institutions as the unavailability of the product in the agent's stocks and by NUPCO as zero stock, and confirmation by pharmaceutical companies of product unavailability. Positive Feedback on drug availability services;55% supplying agents compliance, 69% drug availability improvement and 89% SFDA contribution to facilitate drug availability. Satisfaction on reporting system was reported by (47%) of healthcare institutions and (43%) of pharmaceutical companies' .COVID-19 pandemic impact on drug shortages: Most pharmaceutical company identified highest impact on different medication groups (39.7%) and antibiotics (22.2%). Most Healthcare institutions identified highest impact on antiviral medications (80%). Conclusion(s): Most of the stakeholders had a positive feedback and satisfaction rate on services of SFDA drug availability department. For the COVID-19, as expected, COVID-19 had a noticeable impact on drug shortages and demands in Saudi Arabia. Copyright © 2022
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Objectives: Assess how transparency and independence in health technology assessment (HTA), pricing, reimbursement and access procedures influence drug availability and time to market. Method(s): Secondary research to analyze the independence and transparency of the Spanish, French, German and Italian national pricing, reimbursement and access processes (scale: high, medium, low) and how those impact drug availability and time to market. For each country, HTA, final decision and timing from European Commission (EC) approved medicines (January 2019-December 2021) were analyzed. Biosimilars, generics, hybrids, vaccines, and covid-19 medicines were excluded. Result(s): On the one hand, France and Germany are the most independent systems (medium), both driven by (1) separated clinical and economic evaluations, with some differences: (2) these are assessed by autonomous agencies in Germany and (3) France has different procedures for pricing and reimbursement. Spain and Italy achieved lower scores. On the other hand, the German system is the most transparent (high) as (1) drug added value is defined using objective scales, (2) publication of detailed decisions and (3) participation of external entities in the evaluation process. France and Italy obtained medium scores;Spain got a low score. Of 138 medicines EC approved, 135 (98%) accessed Germany, 81 (58%) France, 59 (42%) Italy and 37 (26%) Spain. The mean time from EC approval to national access was 9,9+/-5.9 months in Germany (HTA outcome), France 13+/-7.1 months, Italy 17.4+/-7.2 months and Spain 19+/-7.5 months. Excluding Germany (reimbursement is automatic), France is the country with the most rapid reimbursement decisions. Conclusion(s): Higher rates of independence/ transparency seem to lead to higher availability and faster drug access to the market, providing a stable framework for all stakeholders. Best practices for improving independence include the establishment of separate evaluations for clinical and economic. Additionally, include objective scales and the active participation of external stakeholders support transparency. Copyright © 2022
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Background: Atypical Hemolytic-uremic syndrome (aHUS) is a rare clinical syndrome whose diagnosis is based on the combination of clinical evaluation, biochemical findings and genetic testing. It develops with thrombocytopenia, microangiopathic hemolytic anemia, renal injury and non-specific symptoms. Nowadays, Eculizumab is an specific treatment for aHUS that should be considered in case of renal failure and after exclusion of other Thrombotic Microangiopathies (TM), namely Thrombotic Thrombocytopenic Purpura and infection by Shiga-Toxin producing Escherichia Coli. Aim(s): This review intends to characterize the management of aHUS at our center aiming the optimization of early recognition, diagnosis and treatment of aHUS. Method(s): This retrospective study based on the evaluation of all the patents coded as aHUS at our hospital between 2017 and 2021. Result(s): Five presumed cases were identified -three females and two males, aged between 33-75 (mean of 48 years). In all cases the onset was abrupt, mainly identified by analytical changes and few clinical relavants signs, despite fluctuating neurological symptoms in two patients. One patient had a previous asymptomatic Coronavirus Disease 2019. Platelets ranged from 30.000-135.000/ microliter, hemoglobin ranged from 7,7-12,8 grams per deciliter and renal dysfunction occurred with creatinine levels between 2.8-6.9 miligram/deciliter. The therapeutic approach varied according to disease's severity and patient outcome. Three patients were submitted to Therapeutic Plasma Exchange (TPE). The number of TPE varied from 3-12 sessions. Eculizumab was administered in two patients, as the other three had substantial clinical improvement before molecular results that led to Eculizumab request. This drug availability has few obstacles at our center. No patient had died, however two patients are now hemodialysis dependent. Conclusion(s): Further characterization of future cases is imperative to better understand this condition and it urges the implementation of protocols to optimize general practice in TM assistance and to avoid misdiagnosis of such rare diseases that need a specific approach.
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Paxlovid™ is a combination of Nirmatrelvir and Ritonavir antiviral pills with good oral bioavailability. In clinical studies, treatment of the patients infected with SARS-CoV-2 with Paxlovid™ within three to five days of the appearance of symptoms significantly reduced the hospitalization rate as well as mortality. It is the first oral antiviral treatment for the COVID-19 which received USFDA approval for EUA on 22nd December, 2021. Nirmatrelvir inhibits the replication of SARS-CoV-2 while another antiviral drug, Ritonavir, is given in combination to enhance the bioavailability of Nirmatrelvir. Molecular interaction studies have shown that Nirmatrelvir binds covalently with the catalytic triad of the active site of the viral protease enzyme (3CLPRO). It, therefore, acts by stopping the SARS-CoV-2 replication by its ability to block the translation of the viral genetic materials. Research studies conducted have proven the efficacy of this oral anti-viral drug in mild to moderate COVID-19 patients beside its ease of oral administration and good oral bioavailability. Alternative synthetic methods to scale up the synthesis of this potent molecule are needed to reduce the treatment cost of the COVID-19. Extensive clinical research on a larger group population is also underway for ensuring the safety and efficacy of this medication in the battle against the COVID-19 pandemic.
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Background: Trauma calls with substantial injuries are low volume;exposure per fellow is low. A pilot questionnaire demonstrated that fellows were unaware of colleagues' trauma workload. There was no standardized process for departmental case review. With COVID-19 precautions limiting face-to-face time with colleagues, we were concerned that learning may be affected. We aimed to improve education by identifying cases with high potential for shared learning or system improvement and instigating a triannual Coffee and Cases meeting. Method(s): We devised a feedback form for trainees to fill in following each trauma team activation. These data were combined with trauma registry data to provide an overall perspective on the anesthesia workload for trauma and presented via Teams to the entire department. Infographics were used to illustrate cases and highlight important learning points. These were combined with up-to-date literature regarding pediatric trauma management. Trainees were reaudited following the talk. Result(s): During the pilot questionnaire, just 14.3% of fellows agreed with the statement: I am aware of the number of trauma calls, mechanisms of trauma and injuries sustained, presenting to Sick Kids in the previous month. In total, 71.4% disagreed and 14.3% strongly disagreed. Reaudit in November 2020 following the Coffee and Cases meeting online via Teams showed 100% agreement, with 71.4% strongly agreeing. Because of clinical commitments, it is often not possible for all relevant and interested staff members to attend such meetings, so a supplementary update PDF was provided via hospital email. Issues were identified regarding communication (team briefing), billing and prompt drug availability. These issues were addressed and reaudited. Conclusion(s): The questionnaire allowed us to collect real-time feedback on our trauma service and collate learning points from cases. This was integrated with up-to-date literature. Trauma patients may present critically unwell, yet the environment may be unfamiliar to rotating staff. Education is vital. Infographics helped us to illustrate cases, highlighting important learning points. These are 30 times more likely to be read than text so can successfully improve readership and learning of information..
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The 2022 American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting held virtually, with "Disruptive innovation" as the motto, offered attendees an outstanding scientific program focused on clinical pharmacology, translational medicine, drug discovery and drug development. It is the most important event for scientists involved in clinical pharmacology and translational medicine. The ASCPT conference offers scientists from different professional scopes and around the world the perfect opportunity to discuss emerging science. It focuses on improving the understanding and use of existing drug therapies and developing safer and more effective treatments for the future. Oral and poster presentations were available for participants during the running of the conference to accommodate the different time zones. Presentations covered the latest research with the option to ask questions after each presentation via a chat function. Discussion boards were available to provide networking opportunities for virtual attendees.
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Background: The 3CL protease (3CLpro) of coronaviruses (CoV) is responsible for essential & early steps of viral replication. Early treatment of SARS-CoV2 infection with a 3CLpro inhibitor has shown to substantially reduce the rate of hospitalization & death from COVID-19. There is a need for a protease inhibitor that can be used as a stand-alone agent to treat and prevent SARS-CoV-2 infection globally, in the setting of remote testing & healthcare delivery, and as unsupervised outpatient use by a significant number of people who take other medications. Methods: PBI-0451 was assessed in cultures of inducible pluripotent stem cell-derived alveolar type II (iPS-AT2) cells, in nonclinical PK and toxicity studies, and an ongoing randomized, double-blind first-in-human (FIH) study evaluating the tolerability, safety, and PK of single and multiple doses administered as an oral suspension to healthy adult subjects. The effect of food and the potential for a drug-drug interaction (DDI) with ritonavir were also explored. Results: PBI-0451 potently inhibited SARS-CoV-2 replication in iPS-AT2 cells with multi-log reductions in viral titer and mean (SD) IC50 & EC90 values of 32 (25) & 106 (90) nM, respectively. No clinically relevant adverse effects of PBI-0451 were observed in 14-day GLP toxicity studies in mice and dogs, including on the cardiovascular, CNS, or respiratory systems. PBI-0451 was not genotoxic in Ames and micronucleus tests. In the ongoing FIH study to date, study treatments were generally well tolerated with no study drug or study discontinuations. No Grade 2, 3, 4, or severe adverse events were reported. Preliminary single-dose concentration-time profile of PBI-0451 following administration with food demonstrated a 2-compartment PK profile with a median terminal elimination t1/2 ranging from 11-14 hours. PBI-0451 demonstrated good oral bioavailability and a linear increase in exposure over a 10-fold dose range when administered with food, achieving concentrations >1-, 3-& 10-fold the plasma protein binding-adjusted EC90 value (374 ng/mL) against SARS-CoV-2 at doses of 100, 300 & 1050 mg, respectively. The PK of PBI-0451 was unaffected by coadministration with ritonavir. Conclusion: PBI-0451 has shown favorable nonclinical properties and early clinical safety & PK that supports its continued evaluation as a stand-alone agent. Ongoing multiple-dose evaluation will further elucidate its clinical profile and inform the dose & dosing regimen selection for potential Phase II/III studies.
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Background. The prompt recognition and treatment of Plasmodium falciparum is necessary to prevent death. We reviewed data from a cohort of patients presenting with malaria to Kings College Hospital NHS Trust, London. Methods. Retrospective review of electronic records and drug charts of patients diagnosed with malaria from Jan 2019- March 2021. Results. 109 cases of malaria were identified representing travellers from 11 Sub-Saharan African countries: Nigeria(38%), Sierra Leone(33%), Ivory Coast(10%). The age range varied from 4 to 76 years with a mean of 44, 66% of the cohort was male. 22 cases occurred during the COVID-19 Pandemic. The commonest symptoms were Fever (97%), Headache (92%) and malaise (72%). P. falciparum was present in 99% cases. A travel history was taken in 94% of cases. Malaria was considered by the first clinician in 82% of cases with the second highest differential being a viral illness. In 6 cases, it took 4 to 11 medical reviews before malaria was considered. 29 patients met the UK criteria for severe malaria. Door to antimalarial time varied from 1 to 128 hours, with a median of 7.4 hours. 46% of the cohort received intravenous Artesunate as their first antimalarial. Extreme delays occurred were clinicians did not consider malaria, patients had negative films or a patient did not declare a travel history when asked. 1 patient died of cerebral malaria with a door to needle time of 2hr 3min. Where a reason for delay is documented, drug availability represented the highest cause with mean delay from prescribing antimalarial to giving antimalarial of 2.7 hours. There was no difference in door to antimalarial administration during the COVID-19 Pandemic, but patients did have a delay in presentation to hospital from onset of symptoms, mean 6.2 days pre-pandemic, 10.5 days during pandemic, this was not statistically significant (P= 0.198). 3 patients presenting during the Pandemic had covid-19 swabs prior to admission and 10 had attended primary care services. Number of days between onset of malaria symptoms and presentation to the Emergency Department Box plot demonstrating that patients were waiting longer post symptom onset to access care in the Emergency Department. 3 patients had covid swabs in the community and 10 accessed care through their primary care physician. Conclusion. Our data show that malaria is being considered early in the emergency department however there remain significant delays in administration of treatment. In 6 cases where malaria was not considered early there were delays in diagnosis of up to 5 days. An audit cycle will be completed with the aim of reducing door to antimalarial time.
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Neutrophils, which are among the first immune cells to respond to both infection and injury, when activated can release pre-stored serine proteases such as neutrophil elastase, cathepsin G and proteinase 3. An abundant release of these proteolytic enzymes in the alveolar compartment as well as the airways can trigger collateral pulmonary tissue damage. Indeed, much of the tissue destruction that characterizes non-cystic fibrosis bronchiectasis appears to be caused by serine proteases. The transitory pharmacological inhibition of bone marrow dipeptidyl peptidase 1 (DPP1), which converts neutrophil proteolytic enzymes into their mature active form, is a therapeutic possibility to decrease the constitutively produced serine protease pool of neutrophils. Brensocatib (also called INS-1007 or AZD-7986) is a potent reversible DPP1 inhibitor that has been successfully evaluated in a phase II trial as a treatment for non-cystic fibrosis bronchiectasis and, consequently, has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and Priority Medicines (PRIME) designation by the European Medicines Agency.