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2.
Biomed Res Int ; 2022: 1522426, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35013710

RESUMO

Several therapeutic regimens for COVID-19 have been studied, such as combination antiviral therapies. We aimed to compare outcome of two types of combination therapies atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r) plus hydroxychloroquine among COVID-19 patients. 108 patients with moderate and severe forms of COVID-19 were divided into two groups (each group 54 patients). One group received ATV/r plus hydroxychloroquine, and the other group received hydroxychloroquine plus LPV/r. Then, both groups were evaluated and compared for clinical symptoms, recovery rates, and complications of treatment regimens. Our findings showed a significant increase in bilirubin in ATV/r-receiving group compared to LPV/r receivers. There was also a significant increase in arrhythmias in the LPV/r group compared to the ATV/r group during treatment. Other findings including length of hospital stay, outcome, and treatment complications were not statistically significant. There is no significant difference between protease inhibitor drugs including ATV/r and LPV/r in the treatment of COVID-19 regarding clinical outcomes. However, some side effects such as hyperbilirubinemia and arrhythmia were significantly different by application of atazanavir or lopinavir.


Assuntos
Sulfato de Atazanavir/uso terapêutico , COVID-19/tratamento farmacológico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Idoso , Antivirais/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Bilirrubina/análise , COVID-19/metabolismo , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Feminino , Hospitalização/tendências , Humanos , Hidroxicloroquina/uso terapêutico , Tempo de Internação/tendências , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Resultado do Tratamento
3.
Med Sci Monit ; 28: e935952, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34972812

RESUMO

On 4th November 2021, the first oral antiviral drug for COVID-19, molnupiravir (Lagevrio®), received full regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. Molnupiravir is an orally bioavailable antiviral drug for use at home when a SARS-CoV-2 test is positive. On 22nd December 2022, the FDA granted emergency use authorization (EUA) for the oral antiviral drug, nirmatrelvir/ritonavir (Paxlovid®) for adults and children with mild and moderate COVID-19 at increased risk of progression to severe COVID-19. These regulatory drug approvals come at a crucial time when new variants of concern of the SARS-CoV-2 virus are spreading rapidly. Although the FDA approved remdesivir (Veklury®) on 22nd October 2020 for use in adults and children for the treatment of COVID-19 requiring hospitalization, its use has been limited by the requirement for intravenous administration in a healthcare facility. The four FDA-approved therapeutic neutralizing monoclonal antibodies, imdevimab, bamlanivimab, etesevimab, and casirivimab are costly and also require medically-supervised intravenous administration. The availability of effective, low-cost oral antiviral drugs available in a community setting that can be used at an early stage of SARS-CoV-2 infection is now a priority in controlling COVID-19. An increasing number of repurposed antiviral drugs are currently under investigation or in the early stages of regulatory approval. This Editorial aims to present an update on the current status of orally bioavailable antiviral drug treatments for SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Citidina/análogos & derivados , Hidroxilaminas/uso terapêutico , Administração Oral , Anticorpos Monoclonais/uso terapêutico , Citidina/uso terapêutico , Aprovação de Drogas , Reposicionamento de Medicamentos/tendências , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Estados Unidos , United States Food and Drug Administration
4.
J Hazard Mater ; 425: 127901, 2022 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-34906870

RESUMO

The aim of this work was to evaluate the adsorption capacity and mechanism of two antiviral drugs AVDs (lopinavir (LOP) and ritonavir (RIT)) on three various sewage sludges (SSLs). The results showed that SSLs differed in the structure and chemical composition and LOP and RIT had a high affinity to the studied SSLs (Kd in ranges 2076-3449 L/kg). The adsorption capacities differed between SSLs and ranged 7.55-8.71 mg/g (RIT) and 8.10-8.64 mg/g (LOP). The Freundlich model provided a best fitting of adsorption isotherms of all AVDs-SSLs. The adsorption kinetics were best described by pseudo-second order kinetic model. The adsorption of LOP and RIT on SSLs was exothermic, spontaneous, and thermodynamically feasible. The sorption of LOP and RIT to SSLs was complex due to the diverse chemical composition of SSLs and the differences in the chemical structure of AVDs. Analysis of binary solution of both AVDs showed the competition effect between AVDs and a decrease in adsorption efficiency (3-17%) compared to single solutions. The amount of desorbed AVDs from all SSLs was low (less than 15%). The findings of the present work are significant in the prediction of fate and persistence of AVDs on SSLs in the context of their further transmission and possible environmental contamination.


Assuntos
Esgotos , Poluentes Químicos da Água , Adsorção , Antivirais , Cinética , Lopinavir , Ritonavir , Poluentes Químicos da Água/análise
5.
J Med Virol ; 94(1): 291-297, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34491575

RESUMO

Due to current advances and growing experience in the management of coronavirus Disease 2019 (COVID-19), the outcome of COVID-19 patients with severe/critical illness would be expected to be better in the second wave compared with the first wave. As our hospitalization criteria changed in the second wave, we aimed to investigate whether a favorable outcome occurred in hospitalized COVID-19 patients with only severe/critical illness. Among 642 laboratory-confirmed hospitalized COVID-19 patients in the first wave and 1121 in the second wave, those who met World Health Organization (WHO) definitions for severe or critical illness on admission or during follow-up were surveyed. Data on demographics, comorbidities, C-reactive protein (CRP) levels on admission, and outcomes were obtained from an electronic hospital database. Univariate analysis was performed to compare the characteristics of patients in the first and second waves. There were 228 (35.5%) patients with severe/critical illness in the first wave and 681 (60.7%) in the second wave. Both groups were similar in terms of age, gender, and comorbidities, other than chronic kidney disease. Median serum CRP levels were significantly higher in patients in the second wave compared with those in the first wave [109 mg/L (interquartile range [IQR]: 65-157) vs. 87 mg/L (IQR: 39-140); p < 0.001]. However, intensive care unit admission and mortality rates were similar among the waves. Even though a lower mortality rate in the second wave has been reported in previous studies, including all hospitalized COVID-19 patients, we found similar demographics and outcomes among hospitalized COVID-19 patients with severe/critical illness in the first and second wave.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/mortalidade , Cuidados Críticos/estatística & dados numéricos , Índice de Gravidade de Doença , Idoso , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azitromicina/uso terapêutico , Proteína C-Reativa/análise , COVID-19/epidemiologia , COVID-19/patologia , Comorbidade , Combinação de Medicamentos , Enoxaparina/uso terapêutico , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Hidroxicloroquina/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lopinavir/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Pirazinas/uso terapêutico , Estudos Retrospectivos , Ritonavir/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento , Turquia/epidemiologia
6.
J Med Case Rep ; 15(1): 624, 2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34920744

RESUMO

BACKGROUND: Human immunodeficiency virus-infected patients are 100 times more likely to develop aseptic osteonecrosis compared with the general population. While 90% of cases concern the femoral head, the involvement of humeral bone remains rare. CASE PRESENTATION: We report a case of aseptic osteonecrosis of the left humeral head complicating antiretroviral therapy in a female, 46-year-old, Bissau-Guinean human immunodeficiency virus-infected patient received in a context of progressive pain in the left shoulder followed by limitation of articular movements. Standard x-ray of the shoulder allowed us to make the diagnosis by showing a typical image of osteonecrosis. The treatment was medical combined with physiotherapy. CONCLUSIONS: Aseptic osteonecrosis should be systematically looked for in human immunodeficiency virus patients on antiretroviral treatment. In addition to femoral head aseptic necrosis, the involvement of the humeral bone should also be considered.


Assuntos
Infecções por HIV , Osteonecrose , Emtricitabina , Feminino , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Cabeça do Úmero/diagnóstico por imagem , Lopinavir , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico por imagem , Ritonavir , Tenofovir/efeitos adversos
7.
Trials ; 22(1): 831, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814933

RESUMO

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Assuntos
Fármacos Anti-HIV , Lamivudina , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Sulfato de Atazanavir , Voluntários Saudáveis , Humanos , Oligopeptídeos , Piridinas , Ritonavir , Tenofovir , Uganda
10.
Viruses ; 13(10)2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34696490

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family, which is responsible for the COVID-19 pandemic followed by unprecedented global societal and economic disruptive impact. The innate immune system is the body's first line of defense against invading pathogens and is induced by a variety of cellular receptors that sense viral components. However, various strategies are exploited by SARS-CoV-2 to disrupt the antiviral innate immune responses. Innate immune dysfunction is characterized by the weak generation of type I interferons (IFNs) and the hypersecretion of pro-inflammatory cytokines, leading to mortality and organ injury in patients with COVID-19. This review summarizes the existing understanding of the mutual effects between SARS-CoV-2 and the type I IFN (IFN-α/ß) responses, emphasizing the relationship between host innate immune signaling and viral proteases with an insight on tackling potential therapeutic targets.


Assuntos
COVID-19/imunologia , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , SARS-CoV-2/imunologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/patologia , Citocinas/metabolismo , Combinação de Medicamentos , Humanos , Interferon Tipo I/biossíntese , Lopinavir/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Transdução de Sinais/imunologia
11.
J Infect Dev Ctries ; 15(9): 1257-1262, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34669593

RESUMO

Severe COVID-19 infection management for a recipient of kidney transplant has debatable prognosis and treatment. We described the case of a COVID-19 infected 70 year old female, previously had renal transplantation in 2017. The patient took immunosuppressive agents as routine drugs for transplant recipient status and received lopinavir/ritonavir, hydroxychloroquine, and dexamethasone daily at the hospitalization. Specific question arises about renal transplant recipients being infected by COVID-19 - whether the infection will get worse compared to those without immunosuppresive agent. In this case, author decided to stop the immunosuppressive agent followed administration of combination lopinavir/ritonavir, hydroxychloroquine, and dexamethasone that gives a good clinical impact change to patient's condition after once getting worsened and mechanically ventilated. Nevertheless, the assessment of risk and benefit in continuing immunosuppressive drugs is concurrently essential due to the prevention of transplant rejection.


Assuntos
COVID-19/tratamento farmacológico , Dexametasona/uso terapêutico , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Idoso , Combinação de Medicamentos , Feminino , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim , Transplantados
12.
J Infect Dev Ctries ; 15(9): 1273-1276, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34669595

RESUMO

INTRODUCTION: An outbreak of coronavirus disease-19 (COVID-19) has occurred in different parts of the world. Although a large piece of information regarding the epidemiology, clinical features, and management of COVID-19 has been reported in the general population, there is very limited data regarding organ transplant recipients, particularly regarding the management of maintenance immunosuppressive agents during infection. METHODOLOGY: We described a case of kidney transplant recipient from Thailand who had COVID-19 pneumonia and severe acute kidney injury. RESULTS: The patient's serum creatinine peaked at 7.0 mg/dL on day 15 of illness and returned to baseline value of 2.0 mg/dL on day 26 of illness. We have shown how we modified tacrolimus, mycophenolate, and steroids in the patient who had received favipiravir and lopinavir/ritonavir for COVID-19 pneumonia. CONCLUSIONS: In this case, successful modification of this immunosuppressive regimen was accomplished to reduce drug interaction complications, aiming to avoid calcineurin inhibitor nephrotoxicity while maintaining appropriate levels of immunosuppression to prevent organ rejection and to promote the patient's recovery from infection.


Assuntos
Injúria Renal Aguda/virologia , COVID-19/tratamento farmacológico , Imunossupressores/administração & dosagem , Injúria Renal Aguda/tratamento farmacológico , Adulto , Amidas/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Transplante de Rim , Lopinavir/uso terapêutico , Masculino , Ácido Micofenólico/administração & dosagem , Pirazinas/uso terapêutico , Ritonavir/uso terapêutico , Esteroides/administração & dosagem , Tacrolimo/administração & dosagem , Tailândia , Transplantados
13.
BMC Infect Dis ; 21(1): 952, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521365

RESUMO

BACKGROUND: Robust evidenced treatment strategy for Coronavirus disease 2019 (COVID-19) has not been established yet. Early, targeted, comprehensive management approach can be essential. METHODS: A lopinavir/ritonavir (LPV/r)-based antiviral treatment was administered to the patients with computed tomography (CT)-documented pneumonia. Medical records of patients with COVID-19, previously discharged or hospitalized for ≥ 21 days at the Seoul Medical Center from January 29 to April 15, 2020 were reviewed to analyze clinical and virological outcomes. Patients were divided into two groups (PCR-Negative conversion group vs. Non-negative conversion group and requiring oxygen group vs. Non-requiring oxygen group). RESULTS: In total, 136 patients with a mean age of 41.8 ± 18.2 years were included with median 3-day delay of hospitalization after illness. Thirteen (9.56%) were initially asymptomatic, and 5 (3.67%) were persistently asymptomatic. Eighty-five (62.5%) had CT-documented pneumonia, 94% of whom received LPV/r treatments. A total of 53 patients (38.97%) had negative polymerase chain reaction (PCR) results within 28 days. Eight (9.4%) out of 85 pneumonic patients received oxygen supplementation. Patients with initial lower respiratory symptoms showed significant delay in PCR negative conversion (> 28 days) (odds ratio [OR] 0.166; 95% confidence interval [CI] 0.067-0.477; P < 0.001). However, antiviral treatment for pneumonic patients was significantly related with early conversion within 28 days (OR 3.049; 95% CI 1.128-8.243; P = 0.028). Increasing age increased the likelihood of oxygen supplementation requirement in the pneumonic patient group (OR 1.108; 95% CI 1.021-1.202; P = 0.014). CONCLUSIONS: Early, pneumonia targeted LPV/r-based antiviral therapy resulted in a significantly higher probability of negative conversion of PCR within 28 days compared to symptomatic treatment.


Assuntos
COVID-19 , Pneumonia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Combinação de Medicamentos , Humanos , Recém-Nascido , Lopinavir/uso terapêutico , Pneumonia/tratamento farmacológico , Estudos Retrospectivos , Ritonavir/uso terapêutico , SARS-CoV-2
14.
Sci Rep ; 11(1): 17810, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497279

RESUMO

Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antivirais/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Comorbidade , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Fígado/patologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Lopinavir/química , Lopinavir/metabolismo , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ritonavir/química , Ritonavir/metabolismo , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/isolamento & purificação , Especificidade por Substrato
15.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502033

RESUMO

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Lactamas/farmacologia , Leucina/farmacologia , Nitrilas/farmacologia , Prolina/farmacologia , Antivirais/uso terapêutico , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/uso terapêutico , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
16.
Exp Clin Transplant ; 19(9): 977-980, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34545780

RESUMO

One year after COVID-19 was declared a pandemic, the management of the disease in kidney transplant patients remains uncertain. The interruption of immunosuppressive therapy is frequently suggested in kidney transplant recipients with COVID-19; however, such an interruption potentially increases the risk of allograft rejection and hyperimmune response. We here report the successful treatment of COVID-19 pneumonia in a kidney transplant recipient who received a sirolimus-based regimen. The course of COVID-19 management was favorable for maintaining sirolimus treatment. Nevertheless, the patient showed signs of extreme overexposure to sirolimus because of drug interaction with antiviral treatment. This case illustrates the advantages and related adverse events of sirolimus-based immunosuppression in the management of COVID-19 in kidney transplant recipients.


Assuntos
COVID-19/terapia , Transplante de Rim , Sirolimo/administração & dosagem , Antivirais/uso terapêutico , Combinação de Medicamentos , Humanos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ritonavir/uso terapêutico , Transplantados
18.
Int J Pharm ; 608: 121119, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34560205

RESUMO

The present study was designed to investigate the contribution of solid-state and the impact of composite drug-rich phase generated as a consequence of pH shift on the maximum achievable supersaturation of co-amorphous formulations. The co-amorphous phases of weak base-weak base-pair i.e. Ritonavir and Darunavir were prepared in anticipation of studying the effect of drug-rich phase consequent to pH shift. While the co-amorphous phases of weak base-Weak acid pair i.e. Darunavir and Indomethacin were studied to understand the manifestation of the solid-state drug: co-former miscibility in the absence of drug rich phase. Thermodynamically, the lowering of the supersaturation was found commensurate with the mole fraction of the respective component (Drug/Co-former) within the co-amorphous materials for both Darunavir: Ritonavir and Darunavir: Indomethacin pair. Kinetically, for Darunavir: Ritonavir co-amorphous materials, the shift in the pH from acidic to the neutral side led to the generation of drug-rich phase and subsequent LLPS. The free drug concentration achieved in the bulk of the solution was found dependent upon the mole fraction of the respective component within the drug-rich phase. The relative mole fraction of each component within the composite drug-rich phase is dictated by pH-dependent solubility and molecular weight of the individual components.


Assuntos
Preparações Farmacêuticas , Ritonavir , Darunavir , Indometacina , Solubilidade
19.
J Laryngol Otol ; 135(9): 755-758, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34387182

RESUMO

BACKGROUND: There are significant drug-drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. METHOD: All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. RESULTS: A literature search and further cross-referencing yielded a total of seven reports on drug-drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. CONCLUSION: The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.


Assuntos
Corticosteroides/efeitos adversos , Síndrome de Cushing/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , HIV , Administração Intranasal , Corticosteroides/administração & dosagem , Adulto , Cobicistat/administração & dosagem , Cobicistat/efeitos adversos , Interações Medicamentosas , Fluticasona/administração & dosagem , Fluticasona/efeitos adversos , Inibidores da Protease de HIV/administração & dosagem , Humanos , Masculino , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos
20.
Sci Transl Med ; 13(607)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408078

RESUMO

Dystonias are a group of chronic movement-disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.


Assuntos
Distonia , Inibidores da Protease de HIV , Animais , Encéfalo/diagnóstico por imagem , Distonia/tratamento farmacológico , Camundongos , Chaperonas Moleculares , Fenótipo , Ritonavir
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