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1.
Eur Rev Med Pharmacol Sci ; 26(1): 54-58, 2022 01.
Article in English | MEDLINE | ID: covidwho-1636663

ABSTRACT

OBJECTIVE: Direct-acting oral anticoagulants (DOACs) have established indications, according to recent guidelines for the treatment and prevention of venous thromboembolism (VTE), including pulmonary embolism (PE), with a safer profile compared to vitamin K antagonist (VKA) in terms of a lower risk for major bleeding and no need of blood coagulation tests. However, DOACs are not indicated in the treatment of patients with triple-positive antiphospholipid syndrome (APS). This limitation is often extended in clinical practice to patients with isolated positivity. The COVID-19 pandemic has sometimes made it difficult to maintain a safe VKA treatment, due to the practical difficulties of performing INR. PATIENTS AND METHODS: We evaluated 39 patients with a previous unprovoked VTE/PE, who were no longer eligible for VKA treatment due to the difficulty of performing INR during the COVID-19 pandemic lockdown, in Italy. All patients had a positive LAC and refused a long-term anticoagulation with low molecular weight heparin. They were shifted to edoxaban. RESULTS: Any recurrence of VTE/PE occurred during the observation period (up to eight months of treatment), while only one minor bleeding event was recorded (Hazard ratio=0.06, 95% confidence interval 0.03-0.11, p=0.094). No arterial events occurred during the observation period. Hemoglobin, platelets, and creatinine were unchanged during the observation period. CONCLUSIONS: Edoxaban treatment may be safe and effective in preventing the recurrence of VTE/PE in patients with isolated LAC positivity, without the occurrence of arterial events.


Subject(s)
COVID-19/epidemiology , Factor Xa Inhibitors/therapeutic use , Lupus Coagulation Inhibitor/drug effects , Pandemics , Pulmonary Embolism/drug therapy , Pyridines/therapeutic use , Thiazoles/therapeutic use , Venous Thromboembolism/drug therapy , Adult , COVID-19/prevention & control , Factor Xa Inhibitors/adverse effects , Female , Humans , Italy , Male , Middle Aged , Pyridines/adverse effects , Quarantine , Thiazoles/adverse effects
2.
Clin Pharmacol Ther ; 111(3): 585-594, 2022 03.
Article in English | MEDLINE | ID: covidwho-1482119

ABSTRACT

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , Nitro Compounds/administration & dosage , Nitro Compounds/adverse effects , Nitro Compounds/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Drug Repositioning , Female , Healthy Volunteers , Humans , Male , Middle Aged , Young Adult
3.
Sci Rep ; 11(1): 19998, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462031

ABSTRACT

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/metabolism , Adenine/pharmacology , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Amides/adverse effects , Amides/metabolism , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/metabolism , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Chloroquine/pharmacology , Drug Design , Humans , Metabolic Networks and Pathways , Molecular Docking Simulation , Nitro Compounds/adverse effects , Nitro Compounds/metabolism , Nitro Compounds/pharmacology , Pyrazines/adverse effects , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Ribavirin/adverse effects , Ribavirin/metabolism , Ribavirin/pharmacology , SARS-CoV-2/metabolism , Thiazoles/adverse effects , Thiazoles/metabolism , Thiazoles/pharmacology
4.
Pharmacotherapy ; 40(5): 416-437, 2020 05.
Article in English | MEDLINE | ID: covidwho-1449937

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Coronavirus Infections/drug therapy , Immunomodulation , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adrenal Cortex Hormones , Alanine/administration & dosage , Alanine/adverse effects , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , Betacoronavirus , COVID-19 , Chloroquine/administration & dosage , Chloroquine/adverse effects , Coronavirus Infections/therapy , Drug Combinations , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Immunization, Passive , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Lopinavir/administration & dosage , Lopinavir/adverse effects , Nelfinavir/administration & dosage , Nelfinavir/adverse effects , Nitro Compounds , Pandemics , Purines , Pyrazoles , Ribavirin/administration & dosage , Ribavirin/adverse effects , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2 , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Thiazoles/administration & dosage , Thiazoles/adverse effects
5.
Trials ; 22(1): 3, 2021 Jan 04.
Article in English | MEDLINE | ID: covidwho-1007149

ABSTRACT

OBJECTIVES: To investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in shortening the time to clinical improvement and achievement of SARS-CoV-2 polymerase chain reaction (PCR) negativity in patients diagnosed with moderate to severe COVID-19. TRIAL DESIGN: This is a pilot phase 2, multicentre 2-arm (1:1 ratio) open-label randomised controlled trial. PARTICIPANTS: Patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 PCR positive nasopharyngeal swab) will be recruited from four participating isolation and treatment centres in Nigeria: two secondary care facilities (Infectious Diseases Hospital, Olodo, Ibadan, Oyo State and Specialist State Hospital, Asubiaro, Osogbo, Osun State) and two tertiary care facilities (Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State and Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State). These facilities have a combined capacity of 146-bed COVID-19 isolation and treatment ward. INCLUSION CRITERIA: Confirmation of SARS-CoV-2 infection by PCR test within two days before randomisation and initiation of treatment, age bracket of 18 and 75 years, symptomatic, able to understand study information and willingness to participate. Exclusion criteria include the inability to take orally administered medication or food, known hypersensitivity to any of the study drugs, pregnant or lactating, current or recent (within 24 hours of enrolment) treatment with agents with actual or likely antiviral activity against SARS-CoV-2, concurrent use of agents with known or suspected interaction with study drugs, and requiring mechanical ventilation at screening. INTERVENTION AND COMPARATOR: Participants in the intervention group will receive 1000 mg of nitazoxanide twice daily orally and 300/100 mg of atazanvir/ritonavir once daily orally in addition to standard of care while participants in the control group will receive only standard of care. Standard of care will be determined by the physician at the treatment centre in line with the current guidelines for clinical management of COVID-19 in Nigeria. MAIN OUTCOME MEASURES: Main outcome measures are: (1) Time to clinical improvement (defined as time from randomisation to either an improvement of two points on a 10-category ordinal scale (developed by the WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection) or discharge from the hospital, whichever came first); (2) Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 2, 4, 6, 7, 14 and 28; (3) Temporal patterns of SARS-CoV-2 viral load on days 2, 4, 6, 7, 14 and 28 quantified by RT-PCR from saliva of patients receiving standard of care alone versus standard of care plus study drugs. RANDOMISATION: Allocation of participants to study arm is randomised within each site with a ratio 1:1 based on randomisation sequences generated centrally at Obafemi Awolowo University. The model was implemented in REDCap and includes stratification by age, gender, viral load at diagnosis and presence of relevant comorbidities. BLINDING: None, this is an open-label trial. NUMBER TO BE RANDOMISED (SAMPLE SIZE): 98 patients (49 per arm). TRIAL STATUS: Regulatory approval was issued by the National Agency for Food and Drug Administration and Control on 06 October 2020 (protocol version number is 2.1 dated 06 August 2020). Recruitment started on 9 October 2020 and is anticipated to end before April 2021. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov (July 7, 2020), with identifier number NCT04459286 and on Pan African Clinical Trials Registry (August 13, 2020), with identifier number PACTR202008855701534 . FULL PROTOCOL: The full protocol is attached as an additional file which will be made available on the trial website. In the interest of expediting dissemination of this material, the traditional formatting has been eliminated, and this letter serves as a summary of the key elements in the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/drug therapy , Ritonavir/administration & dosage , Thiazoles/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Atazanavir Sulfate/adverse effects , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , Clinical Trials, Phase II as Topic , Drug Administration Schedule , Drug Combinations , Drug Repositioning , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Humans , Male , Middle Aged , Multicenter Studies as Topic , Nigeria , Nitro Compounds , Pilot Projects , RNA, Viral/isolation & purification , Randomized Controlled Trials as Topic , Ritonavir/adverse effects , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Standard of Care , Thiazoles/adverse effects , Treatment Outcome , Viral Load/drug effects , Young Adult
7.
J Thromb Haemost ; 18(6): 1320-1323, 2020 06.
Article in English | MEDLINE | ID: covidwho-116313

ABSTRACT

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


Subject(s)
Antithrombins/blood , Antiviral Agents/adverse effects , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Dabigatran/blood , Factor Xa Inhibitors/blood , Pneumonia, Viral/drug therapy , Pyrazoles/blood , Pyridines/blood , Pyridones/blood , Thiazoles/blood , Administration, Oral , Aged , Aged, 80 and over , Antithrombins/administration & dosage , Antithrombins/adverse effects , Antiviral Agents/administration & dosage , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Dabigatran/administration & dosage , Dabigatran/adverse effects , Darunavir/adverse effects , Drug Interactions , Drug Monitoring , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Humans , Italy , Lopinavir/adverse effects , Male , Pandemics , Patient Safety , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Risk Assessment , Risk Factors , Ritonavir/adverse effects , SARS-CoV-2 , Severity of Illness Index , Thiazoles/administration & dosage , Thiazoles/adverse effects
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