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A fast,reliable,and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019,namely,Lianhua Qingwen granules,Huoxiang Zhengqi capsules,Jinhua Qinggan granules,Shufeng Jiedu capsules,and Angong Niuhuang pills,on the pharmacokinetics of lopinavir/ritonavir in rats.Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard(IS).Separation was performed on an Agilent ZORBAX eclipse plus C18(2.1 mm x 50 mm,1.8 μm)column using acetonitrile and water containing 0.1％formic acid as the mobile phase for gradient elution.The flow rate was 0.4 mL/min and the injection volume was 2 μL Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir,m/z 721.3→296.1 for rito-navir,and m/z 705.4→168.1 for the IS.The method showed good linearity in the concentration range of 25-2500 ng/mL(r=0.9981)for lopinavir and 5-500 ng/mL(r=0.9984)for ritonavir.The intra-day and inter-day precision and accuracy were both within±15％.Items,such as dilution reliability and residual effect,were also within the acceptable limits.The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats.The pharmaco-kinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approx-imately 1.5-to 2-fold relative to that in the control group.Similarly,the pharmacokinetic parameters of lopinavir were altered.Overall,the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.
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@#Introduction: The global pandemic of Corona Virus Disease 2019 (COVID-19) has led to the re-purposing of medications, such as hydroxychloroquine and lopinavir-ritonavir in the treatment of the earlier phase of COVID-19 before the recognized benefit of steroids and antiviral. We aim to explore the corrected QT (QTc) interval and ‘torsadogenic’ potential of hydroxychloroquine and lopinavir-ritonavir utilising a combination of smartphone electrocardiogram and 12-lead electrocardiogram monitoring. Materials and Methods: Between 16-April-2020 to 30-April2020, patients with suspected or confirmed for COVID-19 indicated for in-patient treatment with hydroxychloroquine with or without lopinavir-ritonavir to the Sarawak General Hospital were monitored with KardiaMobile smartphone electrocardiogram (AliveCor®, Mountain View, CA) or standard 12-lead electrocardiogram. The baseline and serial QTc intervals were monitored till the last dose of medications or until the normalization of the QTc interval. Results: Thirty patients were treated with hydroxychloroquine, and 20 (66.7%) patients received a combination of hydroxychloroquine and lopinavir-ritonavir therapy. The maximum QTc interval was significantly prolonged compared to baseline (434.6±28.2msec vs. 458.6±47.1msec, p=0.001). The maximum QTc interval (456.1±45.7msec vs. 464.6±45.2msec, p=0.635) and the delta QTc (32.6±38.5msec vs. 26.3±35.8msec, p=0.658) were not significantly different between patients on hydroxychloroquine or a combination of hydroxychloroquine and lopinavir-ritonavir. Five (16.7%) patients had QTc of 500msec or more. Four (13.3%) patients required discontinuation of hydroxychloroquine and 3 (10.0%) patients required discontinuation of lopinavirritonavir due to QTc prolongation. However, no torsade de pointes was observed. Conclusions: QTc monitoring using smartphone electrocardiogram was feasible in COVID-19 patients treated with hydroxychloroquine with or without lopinavir-ritonavir. The usage of hydroxychloroquine and lopinavir-ritonavir resulted in QTc prolongation, but no torsade de pointes or arrhythmogenic death was observed.
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Objective: Provide a timely, rigorous, and continuously updated summary of the evidence on the role of lopinavir/ritonavir in the treatment of patients with COVID-19. Methods: We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in PubMed, Embase, CENTRAL, and other 33 sources. We searched for randomized trials and non-randomized studies evaluating the effect of lopinavir/ritonavir versus placebo or no treatment in patients with COVID-19. Two reviewers independently evaluated potentially eligible studies, according to predefined selection criteria, and extracted data using a predesigned standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. Results: Our search strategy yielded 862 references. Finally, we identified 12 studies, including two randomized trials, evaluating lopinavir/ritonavir, in addition to standard care versus standard care alone in 250 adult inpatients with COVID-19. The evidence from randomized trials shows lopinavir/ritonavir may reduce mortality (relative risk: 0.77; 95% confidence interval: 0.45 to 1.3; low certainty evidence), but the anticipated magnitude of the absolute reduction in mortality, varies across different risk groups. Lopinavir/ritonavir also had a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization and may lead to an increase in the number of total adverse effects. The overall certainty of the evidence was low or very low. Conclusions: For severe and critical patients with COVID-19, lopinavir/ritonavir might play a role in improving outcomes, but the available evidence is still limited. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.
Objetivo: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y constantemente actualizado de la evidencia disponible sobre los efectos de lopinavir/ritonavir en pacientes con COVID-19. Métodos: Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) y otras 33 fuentes. Se buscaron ensayos aleatorios y estudios no aleatorios que evaluaran el uso de lopinavir/ritonavir versus placebo o ningún tratamiento en pacientes con COVID-19. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará disponible durante la pandemia de COVID-19. Resultados: La búsqueda inicial arrojó 862 referencias. Finalmente, identificamos 12 estudios incluyendo 2 ensayos aleatorios, que evaluaban lopinavir/ritonavir adicionado al tratamiento estándar versus tratamiento estándar en 250 pacientes adultos hospitalizados con COVID-19. Los resultados provenientes de los ensayos aleatorios muestran que el uso de lopinavir/ritonavir puede reducir la mortalidad (riesgo relativo: 0,77; intervalo de confianza 95%: 0,45 a 1,3; certeza de evidencia baja), pero la magnitud de la reducción absoluta de la mortalidad varía según los diferentes grupos de riesgo. El uso de lopinavir/ritonavir mostró además una ligera reducción en el riesgo de requerir ventilación mecánica invasiva, desarrollar insuficiencia respiratoria o síndrome de dificultad respiratoria aguda. No se observó diferencias en la duración de la hospitalización y su uso puede producir un aumento en el número de efectos adversos totales. La certeza global de la evidencia fue baja o muy baja. Conclusiones: Para pacientes graves y críticos con COVID-19, el uso de lopinavir/ritonavir podría desempeñar un papel en la mejora de los resultados, pero la evidencia disponible aún es limitada. La gran cantidad de estudios en curso deberían proporcionar evidencia valiosa para informar a los investigadores y los tomadores de decisiones en el futuro cercano.
Subject(s)
Humans , Adult , Antiviral Agents/administration & dosage , Ritonavir/administration & dosage , Lopinavir/administration & dosage , COVID-19/drug therapy , Antiviral Agents/adverse effects , Randomized Controlled Trials as Topic , Treatment Outcome , Ritonavir/adverse effects , Drug Combinations , Pandemics , Lopinavir/adverse effectsABSTRACT
No hay tratamiento antiviral específico para el COVID-19. Sin embargo, conocimientos adquiridos durante los brotes del SARS y el MERS, en conjunto con la información obtenida con COVID-19, han permitido detectar varios objetivos terapéuticos en el ciclo de replicación del virus, y en su patogénesis. Se incluye la evidencia actual con respecto a los principales tratamientos propuestos para COVID-19, reutilizados o experimentales, mediante una revisión de la literatura científica a la fecha. Debido a la falta de ensayos controlados aleatorios, se incluyeron: informes de casos, series de casos y artículos de revisión. Globalmente se están llevando a cabo múltiples estudios con el fin de identificar agentes que sean efectivos ante COVID-19, en los siguientes objetivos estratégicos: inhibición de la entrada/fusión del virus (anticuerpos neutralizantes, inhibidores de proteasa de serina transmembrana 2, cloroquina, hidroxicloroquina y umifenovir); interrupción de la replicación viral (remdesivir, favipiravir, lopinavir/ritonavir e ivermectina) y supresión de la respuesta inflamatoria excesiva (corticosteroides, tocilizumab, e inmunoglobulina). Aún no existe un tratamiento efectivo y seguro contra COVID-19; los fármacos descritos en esta revisión se administran como uso compasivo de drogas, o bien, como parte de un ensayo clínico. La terapia de soporte continúa siendo el pilar del manejo de COVID-19.(AU)
There is no specific antiviral treatment for COVID-19. However, knowledge acquired during the SARS and MERS outbreaks, together with the information obtained with COVID-19, have allowed the detection of various therapeutic targets in the virus replication cycle, and in its pathogenesis. The current evidence regarding the leading treatments proposed for COVID-19, reused or experimental, is included through a review of the scientific literature to date. Due to the lack of randomized controlled trials, the following were involved: case reports, case series and review articles. Globally, multiple studies are being carried out in order to identify agents that are effective against COVID-19, upon the following strategic objectives: inhibition of viral entry/fusion (neutralizing antibodies, transmembrane serine protease 2 inhibitors, chloroquine, hydroxychloroquine, and umifenovir); interruption of viral replication (remdesivir, favipiravir, lopinavir/ritonavir and ivermectin), and suppression of excessive inflammatory response (corticosteroids, tocilizumab, and immunoglobulin). There is still no effective and safe treatment against COVID-19; the medications described in this review are given as compassionate drug use, or as part of a clinical trial. Support therapy continues to be COVID-19 management cornerstone.(AU)
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Humans , El SalvadorABSTRACT
AIM: To study the regularity and characteristics of side effects of lopinavir/ritonavir for COVID-19. METHODS: The type of side effects, general information, medical history and prognosis in 61 confirmed and suspected COVID-19 patients with lopinavir/ritonavir were analyzed. RESULTS: Among the 61 patients, 41(67.21%) had lopinavir/ritonavir related side effects, mainly manifested as gastrointestinal reactions (82.93%) and liver function damage (53.66%). Old age, long course of disease and chronic gastrointestinal disease are independent risk factors for side effects. CONCLUSION: Lopinavir/ritonavir has a high incidence of side effects and can be used in COVID-19 patients under the condition of close observation of the patient's symptoms and test results. Special population should improve pharmaceutical care to ensure the safety of drug use.
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Objective@#To evaluate the efficacies of lopinavir/ritonavir and abidol in the treatment of NCP.@*Methods@#The clinical data of 134 patients with NCP receiving treatment at Shanghai Public Health Clinical Center during Jan 20 to Feb 6, 2020 were retrospectively collected. All the patients received interferon-α2b spray and symptomatic supportive treatment, and 52 cases received oral lopinavir/ritonavir treatment, 34 cases received oral abidol treatment, the remaining 48 cases did not take any antiviral drugs. The efficacies at median day 7 among the three groups were compared by using Kruskal-Wallis or chi-square tests.@*Results@#The 134 patients included 69 males (51.5%) and 65 females, aged 35-62 years with the average of 48 years. The median time to temperature normalization in patients receiving abidol or lopinavir/ritonavir treatment was both 6 days after admission, and that was 4 days in the control group, with no significant difference (χ2=2.37, P=0.31). The median time to PCR negative in the respiratory specimens in the three groups was all 7 days after admission, and the PCR negative rates at day 7 after admission in lopinavir/ritonavir, abidol and control groups were 71.8% (28/39), 82.6% (19/23) and 77.1% (27/35), respectively, which were not significantly different (χ2=0.46, P=0.79). Radiological worsening at day 7 was observed in comparable proportions of patients in the three groups, which were 42.3% (n=22), 35.3% (n=12) and 52.1% (n=25), respectively (χ2=2.38, P=0.30) . Adverse reactions occurred in 17.3% (n=9), 8.8% (n=3) and 8.3% (n=4) patients, respectively in the three groups (χ2=2.33, P=0.33).@*Conclusions@#This study did not find any effects of lopinavir/ritonavir and abidol on relieving symptoms or accelerating virus clearance. The efficacies of these two drugs in NCP treatment need further investigation.
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Objective@#Comparing the benefit of Abidor, lopinavir/ritonavir and recombinant interferon α-2b triple combination antiviral therapy and lopinavir/ritonavir and interferon dual combination antiviral therapy to hospitalized novel coronavirus pneumonia 2019 in Zhejiang province.@*Methods@#A multi-center prospective study was carried out to compare the effect of triple combination antiviral therapy with dual combination antiviral therapy in 15 medical institutions of Zhejiang Province. All patients were treated with recombinant interferon α-2b (5 million U, 2 times/d) aerosol inhalation. 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir / ritonavir (2 tablets, 1 time/12 h) as the triple combination antiviral treatment group. 41 patients were treated with lopinavir / ritonavir (2 tablets, 1 time/12 h) as the dual combination antiviral treatment group. The patients who received triple combination antiviral therapy were divided into three groups: within 48 hours, 3-5 days and > 5 days after the symptom onset. To explore the therapeutic effects of triple combination antiviral drugs and dual combination antiviral drugs, as well as triple combination antiviral drugs with different antiviral initiate time. SPSS17.0 software was used to analyze the data.@*Results@#The time of virus nucleic acid turning negative was (12.2 ± 4.7) days in the triple combination antiviral drug group, which was shorter than that in the dual combination antiviral drug group [(15.0 ± 5.0) days] (t = 6.159, P < 0.01 ). The length of hospital stay [12 (9, 17) d] in the triple combination antiviral drug group was also shorter than that in the dual combination antiviral drug group [15 (10, 18) d] (H = 2.073, P < 0.05). Comparing the antiviral treatment which was started within 48 hours, 3-5 days and > 5 days after the symptom onset of triple combination antiviral drug group, the time from the symptom onset to the negative of viral shedding was 13 (10,16.8), 17 (13,22) and 21 (18-24) days respectively (Z = 32.983, P < 0.01), and the time from antiviral therapy to the negative of viral shedding was (11.8±3.9) , (13.5±5.1) and (11.2±4.3) d. The differences among the three groups were statistically significant (Z=32.983 and 6.722, P<0.01 or<0.05).@*Conclusions@#The triple combination antiviral therapy of Abidor, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy. The earlier the time to initiate triple antiviral treatment, the shorter the time of virus shedding.
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Backgrounds: This randomised controlled, open-label, non-inferiority trial was conducted in antiretroviral-na飗e HIV-1-infected patients to assess the efficacy and safety of 48-week dual therapy of LPV/r plus 3TC (DT group) compared with Chinese first-line triple-therapy regimen (TT group). Methods: 198 were randomised to DT (n = 100) or TT (n = 98). Results: Ninety-two DT patients (92%) and 88 TT patients (89.8%) achieved HIV-1 RNA <50 copies/ml at week 48 (P = 0.629). Moreover, the safety profile was similar between two groups, and no secondary HIV resistance was observed. Conclusion: The results suggest that dual therapy of LPV/r plus 3TC is non-inferior to the first-line triple-therapy regimen in China.
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Background: Lopinavir/ritonavir (LPV/r) could be associated with adverse cardiac event. Antiretroviral drugs containing LPV/r are used concurrently with sulfamethoxazole/trimethoprim (SMX/TMP) which may also be associated with adverse cardiac events in the management of human immunodeficiency virus and co-infection. The concurrent use of these drugs may precipitate synergistic adverse cardiac events. This work, therefore, evaluates the possible toxicological interaction of co administered LPV/r and SMX/TMP on cardiac function and architecture of albino rats. Methods: Seventy five (75) animals which were divided into five groups (A-E) of fifteen (15) animals each were used in this study. Animals in Group A, which served as the control, were treated with 1% ethanol orally. Animals in Group (B-E) were treated with oral doses of SMX/TMP (11.2/2.3 mg/kg), LPV/r (11.4/2.9 mg/kg), and combine doses of SMX/TMP+LPV/r for 2-8 weeks, respectively. Blood sample was collected and evaluated for pack cell volume, hemoglobin, red blood cell and white blood cell. Cardiac tissues were evaluated for malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSHPX), and histopathological changes. Results: Treatment with SMX/TMP LPV/r and their combine doses produced no significant effect on cardiac weight. SMX/TMP significantly decreased red blood cell and hemoglobin while LPV/r produced no significant hematologic effect. Combine doses of these agents produced no synergistic hematologic effects. Treatment with a single and combine doses of these agents produced time-dependent decrease in SOD, GSHPX and increase in MDA, but no synergistic effects were produced by their combine doses. Normal cardiac myocytes with patchy collection of mononuclear inflammatory cells infiltration of the interstitium were observed after treatment with single and combined doses of these agents but without any synergistic effect when agents were co-administered. Conclusion: In this study, the co-administration of SMX/TMP and LPV/r did not produce any significant synergistic effects on all the evaluated parameters; hence, the concurrent use of these agents in the management of HIV and co-infections may be safe on cardiac function and structure.
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Background: Human immunodeficiency virus/acquired immune deficiency syndrome is usually associated with co-infections which has allow the concurrent use of sulfamethoxazole/trimethoprim (SMX/TMP)+Lopinavir/ritonavir (LPV/r). The concurrent use of these drugs may have possible adverse effects on the kidney because they are individually associated with adverse renal events. This study, therefore evaluates the possible effect of co-administered SMX/TMP+LPV/r on kidney function and architecture of albino rats. Methods: Seventy five (75) animals which were divided into five groups were used in this study. Group A, which served as control, contained 15 animals which were treated with 1% ethanol orally. Group B-E, which contained 15 animals each, was further subdivided into three groups of five animals each. Animals in these groups were treated with oral doses of SMX/TMP (11.2/2.3 mg/kg), LPV/r (11.4/2.9 mg/kg), and combined doses of SMX/TMP+LPV/r for 2-8 weeks respectively. Serum levels of creatinine, urea, and uric acid were evaluated. Kidney tissue was evaluated for malondialdehyde (MDA), superoxide dismutase (SOD), and histopathological changes. Results: Treatment with single doses of SMX/TMP, and LPV/r, produced a time-dependent increase in serum creatinine and urea. But no significant synergistic effects on serum creatinine and urea were observed when these agents were co-administered. Treatment with single and combine doses of these agents had no significant effects on serum uric acid level. Treatment with single agents produced time-dependent increase in kidney MDA and decrease in SOD level but without any significant effects when these agents were co-administered. Kidney of animals treated with single doses of these agents showed hypercellarity of the interstitium of the glomeruli and vascular congestion with no synergistic effects when these agents were co-administered. Conclusion: Concurrent use of SMX/TMP+LPV/r in the management of HIV and co-infection may not have any deleterious effect on the renal system.
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Es común la interrogante del esquema antirretrovirala utilizar de inicio, si la combinación de 2 inhibidores nucleósidos de la transcriptasa reversa (INTR) con lopinavir/ritonaviro o con efavirenz. No existen conclusiones sobre la superioridad de algún esquema en niños. Comparar la respuesta virológica, inmunológica y clínica del tratamiento inicial de pacientes pediátricos con infección VIH con esquemas basados en lopinavir/ritonavir y con efavirenz. Estudio comparativo, retrospectivo incluyendo pacientes con infecciones VIH del Hospital de Niños "J.M. de Los Ríos" entre 2000-2008, mediante revisión de la base de datos de la Unidad. Se incluyeron pacientes con terapia triple de inicio, agrupándose en esquemas con 2INTR más lopinavir/ritonavir o más efavirenz, comparando la respuesta virológica, inmunológica y clínica. Se calcularon medidas de tendencia central y Chi cuadrado. Se incluyeron 35 pacientes, 71,4% con lopinavir/ritonavir, 28,6% con efavirenz. El 64% del grupo con lopinavir/ritonavir presentó cargas virales indetectables y con efavirenz, 70% (P > 0,05). La indetectabilidad a las 24 semanas se evidenció en 87,5% de pacientes con lopinavir/ritonavir y en 57,1% con efavirenz (P > 0,05). De los pacientes con falla virológica, 55,6% del grupo lopinavir/ritonavir presentaron <10000 copias/mL, mientras que en el grupo con efavirenz fue 66,7% (P > 0,05). El ascenso de linfocitos TCD4+ en 1 año se produjo en 60% en el grupo con lopinavir/ritonavir y en 70% con efavirenz (P > 0,05). Del grupo lopinavir/ritonavir 68% tenían categoría clínica B o C y con efavirenz 60% igual que al inicio de ambos esquemas (P> 0,05). No se establecieron diferencias significativas en respuestas virológicas, inmunológicas y clínicas entre el grupo con lapinavir/ritonavir y el grupo efavirenz en la población pediátrica. Se evidencio tendencia al logro indetectabilidad en menos tiempo en el grupo de lopinavir/ritonavir.
It is not uncommon for the clinician the question about what to use between combinations of lopinavir/ritonavir or efavirenz with 2 NRTI as initial antiretroviral therapy in children. Superiority of one or another regimen in children is not conclusive. To compare the clinical, virological, and immunological response to regimens containing lopinavir/ritonavir or efavirenz, in combination with 2 NRTI. Retrospective, comparative study including VIH infected patients from Children Hospiyal "J.M. de Los Ríos", from 2000-2008. Unit data base was revised to compare two groups of children receiving initial triple antiretroviral therapy that included lopinavir/ritonavir or efavirenz, in combination with 2 NRTI, in terms of virological, immunological and clinical response to treatment. Statiscal calculations included chi square, and trends.