Bioavailability enhancement of atazanavir sulphate using mixed micelles: in vitro characterization and in vivo pharmacokinetic study.

This study aims to enhance the oral bioavailability of atazanavir sulphate, a human immunodeficiency virus-1 protease inhibitor known for its poor oral absorption, by formulating mixed micelles using Soluplus® and Kolliphor HS 15. Mixed micelles were prepared through the thin film hydration technique. The micelles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, and confirmed for atazanavir sulphate encapsulation via FTIR studies. In vitro release studies were conducted, and the morphology of the micelles was examined using TEM. Atazanavir sulphate mixed micelles exhibited a particle size of 62.92 nm, PDI of 0.221, zeta potential of - 17.8 mV, high entrapment efficiency (99.76 ± 1.06), and drug loading (14 ± 0.82). In vitro release studies demonstrated sustained release up to 12 h, with maximum solubility observed at 2 h under pH 1.2 conditions. TEM analysis revealed spherical micelle morphology. Oral administration of atazanavir sulphate mixed micelles showed a 1.23-fold increase in relative bioavailability compared to pure drug suspension. The formulation of mixed micelles using Soluplus® and Kolliphor HS 15 offers a promising strategy to improve the oral bioavailability of atazanavir sulphate. These findings suggest the potential utility of mixed micelles as an effective delivery system for atazanavir sulphate, offering enhanced therapeutic outcomes for patients.

Serum uric acid and high-sensitivity C-reactive protein levels among people living with HIV on dolutegravir and ritonavir-boosted atazanavir-based antiretroviral therapy: a comparative cross-sectional study.

Background: After the introduction of antiretroviral therapy, the care given to people living with HIV has become complicated by the appearance of comorbidities as a result of HIV and HAART toxicities, in which cardiovascular disease got the most attention. So, this study aimed to assess serum uric acid and high-sensitivity C-reactive protein levels among people living with HIV on dolutegravir (DTG) and ritonavir-boosted atazanavir (ATV/r)-based therapy. Methods: An institutional-based comparative cross-sectional study was conducted from November 4, 2021, to January 4, 2022. An equal number of dolutegravir- and ritonavir-boosted atazanavir-treated patients (n = 86 each) were enrolled. A consecutive sampling method was used to select participants. Data were entered into Epidata version 4.6, exported to SPSS version 25.0, and analyzed using Chi-square, Student's t-test, Mann-Whitney U-test, and logistic regression. Statistical significance was set at p < 0.05. Results: The prevalence of hyperuricemia and high-sensitivity C-reactive protein levels ≥2 mg/L were 46.5% (40/86) and 24.4% (21/86) in the DTG group, and 30.2% (26/86) and 44.2 (38/86) in the ATV/r group, respectively. When compared to ATV/r, a higher mean level of uric acid was found among DTG-based regimens (5.38 mg/dL). Duration of ART (AOR = 2, 95% CI: 1.2, 4.4) and DTG-based regimen (AOR = 1.9, 95% CI: 1.04, 3.8) were significant predictors of developing hyperuricemia. ATV/r-based regimen (AOR = 3, 95% CI: 1.5, 8.3) and high waist circumference (AOR = 2.5, 95% CI: 1, 3.5) were significantly associated with increased high-sensitivity C-reactive protein levels. Conclusion: It is observed that DTG-based and ATV/r-based ART are associated with hyperuricemia and increased high-sensitivity C-reactive protein levels, respectively. Therefore, it is important to consider and evaluate serum uric acid and high-sensitivity C-reactive protein levels in patients taking DTG and ATV/r-based ART, as well as among those on HAART for years and with a higher waist circumference, so as to detect and prevent early the risk of having CVD.

Synthetic and Clinical Perspectives of Evotaz: An Overview.

Viruses cause a variety of diseases in the human body. Antiviral agents are used to prevent the production of disease-causing viruses. These agents obstruct and kill the virus's translation and replication. Because viruses share the metabolic processes of the majority of host cells, finding targeted medicines for the virus is difficult. In the ongoing search for better antiviral agents, the USFDA approved EVOTAZ, a new drug discovered for the treatment of Human Immunodeficiency Virus (HIV). It is a once-daily (OD) fixed-dose combination of Cobicistat, a cytochrome P450 (CYP) enzyme inhibitor, and Atazanavir, a protease inhibitor. The combination drug was created in such a way that it can inhibit both CYP enzymes and proteases at the same time, resulting in the virus's death. The drug is not effective in children under the age of 18; however, it is still being studied for various parameters. This review article focuses on EVOTAZ's preclinical and clinical aspects, as well as its efficacy and safety profiles.

Antiretroviral action of Rosemary oil-based atazanavir formulation and the role of self-nanoemulsifying drug delivery system in the management of HIV-1 infection.

Atazanavir or ATV is an FDA-approved, HIV-1 protease inhibitor that belongs to the azapeptide group. Over time, it has been observed that ATV can cause multiple adverse side effects in the form of liver diseases including elevations in serum aminotransferase, indirect hyper-bilirubinemia, and idiosyncratic acute liver injury aggravating the underlying chronic viral hepatitis. Hence, there is an incessant need to explore the safe and efficacious method of delivering ATV in a controlled manner that may reduce the proportion of its idiosyncratic reactions in patients who are on antiretroviral therapy for years. In this study, we assessed ATV formulation along with Rosemary oil to enhance the anti-HIV-1 activity and its controlled delivery through self-nanoemulsifying drug delivery system or SNEDDS to enhance its oral bioavailability. While the designing, development, and characterization of ATV-SNEDDS were addressed through various evaluation parameters and pharmacokinetic-based studies, in vitro cell-based experiments assured the safety and efficacy of the designed ATV formulation. The study discovered the potential of ATV-SNEDDS to inhibit HIV-1 infection at a lower concentration as compared to its pure counterpart. Simultaneously, we could also demonstrate the ATV and Rosemary oil providing leads for designing and developing such formulations for the management of HIV-1 infections with the alleviation in the risk of adverse reactions.

Eficácia da ivermectina e atazanavir no tempo de recuperação dos sintomas de covid-19: uma coorte prospectiva / Effectiveness of ivermectin and atazanavir on time to resolution from covid-19 symptoms: a prospective cohort / Eficacia de ivermectina y atazanavir en el tiempo hasta lá resolución de los síntomas de covid-19: una cohorte prospectiva

Objetivo: avaliar a eficácia da Ivermectina e do Atazanavir em comparação com placebo no tempo de resolução dos sintomas e no tempo de duração da doença por COVID-19. Método: estudo observacional, de coorte prospectivo, longitudinal, descritivo e analítico com pacientes sintomáticos ambulatoriais, acompanhados por 06 meses em duas Unidades Básicas de Saúde para atendimento de COVID-19 em Teresina- Piauí, Brasil, no período de novembro a abril de 2021 identificados por amostragem aleatória 1:1:1. Foram realizados exames Reverse transcription polymerase chain reaction (RT-PCR) para confirmação laboratorial da suspeita de infecção pelo novo coronavírus e avaliação sociodemográfica e clínica. Resultados: dos 87 pacientes randomizados, 62,1% (n=54) eram do sexo masculino, com média de idade de 35,1 anos, possuíam companheira (53,9%), baixa renda (50,6%), eutróficos (40,7%) e sem comorbidades de saúde (78,2%). Não houve diferença entre o tempo médio para resolução dos sintomas, que foi de 21 dias (IQR, 8-30) no grupo atazanavir, 30 dias (IQR, 5-90) no grupo ivermectina em comparação com 14 dias (IQR, 9-21) no grupo controle. No dia 180, houve resolução dos sintomas em 100% no grupo placebo, 93,9% no grupo atazanavir e 95% no grupo ivermectina. A duração mediana da doença foi de 08 dias em todos os braços do estudo. Conclusão: o tratamento com atazanavir (6 dias) e ivermectina (3 dias) não reduziu o tempo de resolução dos sintomas e nem o tempo de duração da doença entre os pacientes ambulatoriais com COVID-19 leve em comparação com o grupo placebo. Os resultados não suportam o uso de ivermectina e atazanavir para tratamento de COVID-19 leve a moderado.

Objective: to evaluate the effectiveness of Ivermectin and Atazanavir compared to placebo in the time to resolution of symptoms and duration of illness due to COVID-19. Method: observational, prospective, longitudinal, descriptive and analytical cohort study with symptomatic outpatients, followed for 06 months in two Basic Health Units for COVID-19 care in Teresina-Piauí, Brazil, from November to April 2021 identified by 1:1:1 random sampling. Reverse transcription polymerase chain reaction (RT-PCR) tests were performed for laboratory confirmation of suspected infection with the new coronavirus and sociodemographic and clinical evaluation. Results: of the 87 randomized patients, 62.1% (n=54) were male, with a mean age of 35.1 years, had a partner (53.9%), low income (50.6%), eutrophic (40.7%) and without health comorbidities (78.2%). There was no difference between the median time to resolution of symptoms, which was 21 days (IQR, 8-30) in the atazanavir group, 30 days (IQR, 5- 90) in the ivermectin group compared with 14 days (IQR, 9- 21) in the control group. At day 180, there was resolution of symptoms in 100% in the placebo group, 93.9% in the atazanavir group, and 95% in the ivermectin group. The median duration of illness was 8 days in all study arms. Conclusion: Treatment with atazanavir (6 days) and ivermectin (3 days) did not reduce the time to symptom resolution or the duration of illness among outpatients with mild COVID-19 compared to the placebo group. The results do not support the use of ivermectin and atazanavir for the treatment of mild to moderate COVID-19.

Objetivo: evaluar la efectividad de Ivermectina y Atazanavir en comparación con placebo en el tiempo de resolución de los síntomas y duración de la enfermedad por COVID-19. Método: estudio de cohorte observacional, prospectivo, longitudinal, descriptivo y analítico con pacientes ambulatorios sintomáticos, seguidos durante 06 meses en dos Unidades Básicas de Salud para atención de COVID-19 en Teresina-Piauí, Brasil, de noviembre a abril de 2021 identificados por 1:1:1 muestreo aleatorio. Se realizaron pruebas de reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR) para confirmación de laboratorio de sospecha de infección por el nuevo coronavirus y evaluación sociodemográfica y clínica. Resultados: de los 87 pacientes aleatorizados, 62,1% (n=54) eran del sexo masculino, con una edad media de 35,1 años, tenían pareja (53,9%), bajos ingresos (50,6%), eutróficos (40,7%) y sin comorbilidades de salud (78,2%). No hubo diferencia entre la mediana de tiempo hasta la resolución de los síntomas, que fue de 21 días (RIC, 8-30) en el grupo de atazanavir, 30 días (RIC, 5- 90) en el grupo de ivermectina en comparación con 14 días (RIC, 9 - 21) en el grupo control. En el día 180, hubo una resolución de los síntomas del 100 % en el grupo de placebo, del 93,9 % en el grupo de atazanavir y del 95 % en el grupo de ivermectina. La mediana de duración de la enfermedad fue de 8 días en todos los brazos del estudio. Conclusión: El tratamiento con atazanavir (6 días) e ivermectina (3 días) no redujo el tiempo de resolución de los síntomas ni la duración de la enfermedad entre los pacientes ambulatorios con COVID-19 leve en comparación con el grupo placebo. Los resultados no respaldan el uso de ivermectina y atazanavir para el tratamiento de la COVID-19 de leve a moderada.

In situ gastric floating gel of atazanavir sulphate for sustained release: formulation, optimization and evaluation.

Aim: Atazanavir sulphate belongs to BCS class II drug, its oral bioavailability is limited due to its rapid first-pass metabolism and P-gp efflux. Materials & methods: The in situ floating gel using the complexed drug was prepared by ion gelation method and optimized the formulation as per 32 full factorial design. Results: Floating lag time of optimized formulation was found to be 18 s and percentage drug release of 94.18 ± 0.18 % at the end of 16 h. The concentration of gelling polymer affects drug release and a floating lag time and vice versa. Conclusion: In situ floating gel of atazanavir sulphate was found promising to sustain drug release due to an increased gastric residence time, which leads to enhanced potential therapy.

In our study, we wanted to create a gel for a medicine called atazanavir sulphate. This gel can float in the stomach for a long time and slowly release the medicine. We mixed atazanavir sulphate with something called ß-cyclodextrin, and this mixture made the medicine dissolve better in water. We used this mixture to make our floating gel, which can stay in the stomach without sinking. Our gel can make the medicine work better because it dissolves well and stays in the stomach for a long time. This means the medicine can help people for a longer period.

Pharmacokinetics and safety of twice-daily ritonavir-boosted atazanavir with rifampicin.

BACKGROUND: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial.

BACKGROUND: The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N-acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID-19. METHODS: Two 30-person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study. RESULTS: At the end of the study, a further decrease in C-reactive protein was observed in the NAC group (P = 0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O2 saturation at the end of the study and a significant rise in O2 saturation following intervention commencement, including NAC (P > 0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and lower mortality in hospitalized patients with COVID-19. CONCLUSION: The NAC could be more effective as prophylactic or adjuvant therapy in stable non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation or could be effective for better controlling of COVID-19 or its therapy-related side effects.

Biterapia con atazanavir/ritonavir más raltegravir versus terapia triple en segunda línea: Ensayo ARTE / ATV/r+RAL (DT) after failure with NNRTI

Antecedentes: La terapia dual ha surgido como un nuevo concepto para el tratamiento del VIH. Este estudio tenía como objetivo comparar un régimen dual basado en ATV/r + RAL (TD) frente a estándar de tres drogas con ATV/r + TDF/FTC (TT) luego del fracaso de un primer esquema ba-sado en INNTR.ClinicalTrials.gov, Número: NCT01829802.Método: Estudio piloto abierto, multicéntrico y aleatoriza-do. Resultado primario: proporción de sujetos con ARN del VIH-1 menor a 50 copias/mL en semana 48 (S48). Resulta-dos secundarios: discontinuaciones asociadas a eventos adversos (EA), tiempo transcurrido hasta la supresión viral, desarrollo de mutaciones de resistencia a la integrasa y proteasa, cambio en recuento de CD4. Resultados: De los 57 participantes seleccionados, 34 fue-ron asignados aleatoriamente para recibir: TD (n: 18) o TT (n: 16). En semana 48, 67% (n: 12/18) en TD tuvo respues-ta virológica y 88% (n: 14/16) en rama según el análisis FDA, intención de tratamiento/expuestos (p = NS) y 73% (TD) y 93% (TT) según análisis por protocolo (p = NS). El cambio de CD4 entre basal - S48: +119 y +52 células/µL en DT y TT, respectivamente. Cuatro participantes en TD y uno en TT presentaron fracaso virológico en la semana 48. Un participante desarrolló una mutación de resistencia a integrasa (155H).Conclusión: ATV/r+RAL como terapia dual de segunda línea mostró una tendencia al fracaso virológico más frecuente, en comparación con TT, aunque el estudio piloto no tenía potencia para demostrar esta diferencia. Este estudio está registrado en ClinicalTrials.gov, Número: NCT01829802

Background: Dual therapy has emerged as a novel concept for HIV treatment. This study was aimed at comparing a nucleoside-sparing dual regimen consisting of ATV/r + RAL (DT) vs standard therapy of ATV/r + TDF/FTC (TT) among individuals failing first NNRTI-containing treatment.Methods: Randomized multicenter open-label pilot study. Primary outcome: proportion of subjects with plasma HIV-1 RNA below the limit of detection (<50 copies/mL) at 48 weeks (W48). Secondary outcomes: proportion of discontinuation due to adverse events (AEs), time until viral suppression, time until loss of virological response, development of integrase resistance mutations, and absolute change in CD4 counts. The primary outcome was analyzed using the FDA snapshot analysis.Results: Out of 57 participants screened, 34 were randomized to receive: DT (n: 18) or TT (n: 16). At W48, virological response was achieved in 67% (n: 12/18) of participants receiving DT and 88% (n: 14/16) receiving TT by FDA snapshot analysis (p = NS) and 73% and 93% by per-protocol analysis (p = NS). CD4 cell count median change from baseline to W48 was +119 and + 52 cell/µL in DT and TT, respectively. Four participants receiving DT and one TT presented virological failure at W48, with low pVL. One participant developed an integrase resistance mutation (155H) and suppressed later on TT.Conclusion: ATV/r+RAL as second-line therapy showed a trend to more frequent virological failure, compared to TT, although the study was unpowered to prove this difference. No major differences were seen in tolerance or toxicity.This study is registered with ClinicalTrials.gov, Number: NCT01829802

Microparticles of Sericin-Dextran Conjugate for Improving the Solubility of Antiviral Drug.

A novel sericin-dextran conjugate (SDC) and self-assembled microparticles has been prepared for improving solubility of atazanavir. Microparticles of SDC were assembled by the reprecipitation method. The size and morphology of SDC microparticles could be adjusted by the concentration and solvents. Low concentration was conducive to the preparation of microspheres. Heterogeneous microspheres could be prepared in ethanol with the range of 85-390 nm, and hollow mesoporous microspheres in propanol with an average particle size of 2.5-22 µm. The aqueous solubility of atazanavir was improved to 2.22 mg/mL in buffer solutions at pH 2.0 and 1.65 mg/mL at pH 7.4 by SDC microspheres. In vitro release of atazanavir from hollow microspheres of SDC exhibited a slower release, had the lowest linear cumulative release in basic buffer (pH 8.0), and the most rapid double exponential diphase kinetic cumulative release in acid buffer (pH 2.0).

Spherical crystal agglomeration technique for improved flow properties and oral bioavailability of atazanavir sulphate.

Aim: The current research focused on formulation of spherical crystal agglomerates (SCA) of atazanavir sulphate for improving flow property and solubility. Materials & methods: SCA were formulated by quasi-emulsification solvent diffusion. Methanol, water and dichloromethane were employed as a good solvent, bad solvent and bridging liquid respectively. Results & conclusion: SCA with improved solubility and micromeritic properties were directly compressed into a tablet. The SCA tablets had higher dissolution rates compared with plain drug and marketed product. In vivo pharmacokinetic studies revealed higher Cmax and AUC0-t of the SCA than marketed product with relative bioavailability of 1.74. The formulation was stable for more than 3 months, with insignificant difference in % drug content and % drug dissolution.

Atazanavir sulphate is a drug used for treatment of AIDS in which the patients are infected with HIV. Presently, it is available as a capsule. The amount of the drug reaching the blood after oral delivery is less due to the poor solubility of the drug. Compared with capsules, tablets are more preferred dosage forms due to its ease of manufacturing and tamper proof nature. In the present research work, we have developed a tablet formulation of the drug, which has improved solubility. The higher solubility leads to greater absorption after oral delivery. Thus the formulation is beneficial to the patients as the dose can be reduced and the treatment can be made more economic.

Atazanavir Resensitizes Candida auris to Azoles.

Candida auris represents an urgent health threat. Here, we identified atazanavir as a potent drug capable of resensitizing C. auris clinical isolates to the activity of azole antifungals. Atazanavir was able to significantly inhibit the efflux pumps, glucose transport, and ATP synthesis of all tested isolates of C. auris. In addition, the combination of itraconazole with atazanavir-ritonavir significantly reduced the burden of azole-resistant C. auris in murine kidneys by 1.3 log10 (95%), compared to itraconazole alone.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial.

Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

In silico-assisted development of supersaturable preconcentrated isotropic mixture of atazanavir for augmenting biopharmaceutical performance in the presence of H2-receptor antagonist.

The therapeutic potential of atazanavir (BCS Class II drug), a highly selective inhibitor of human immunodeficiency virus (HIV-1), has been largely limited due to its low intrinsic solubility at elevated pH resulting in low oral bioavailability. Thus, the current work describes the systematic development, optimization, and evaluation of hydroxypropyl methylcellulose acetate succinate (HPMC-AS)-based supersaturable preconcentrate isotropic mixture (SP-IM) containing long-chain triglyceride to improve intestinal lymphatic transport and augment oral bioavailability of atazanavir (ATZ). A D-optimal mixture design was employed for optimization of plain IM containing corn oil, oleic acid, Tween 80, and propylene glycol, evaluating various critical quality attributes (CQAs) like particle size, polydispersity index, self-emulsification time, % transmittance, and drug content. In silico analysis and in vitro supersaturation test facilitated the selection of HPMC-AS as a best suited polymeric precipitation inhibitor (PPI) for formulating ATZ loaded SP-IM (ATZ-SP-IM). In vitro dissolution data indicated that ATZ-SP-IM exhibits superior performance in 0.025 N HCl and pH 6.8 over pure drug. Ex vivo permeation and in vivo pharmacokinetic study of ATZ-SP-IM corroborated enhanced permeation (2.03 fold) and improved drug absorption via lymphatic transport in Wistar rats. Further, the pharmacokinetic performance of ATZ-SP-IM was not affected in presence of H2 receptor antagonist. Therefore, the results showed that ATZ-SP-IM can significantly improve the biopharmaceutical attributes of ATZ so as to lay a foundation of further research on the new dosage form of ATZ.

Uso de Ivermectina e Atazanavir no tratamento da Covid-19: uma revisão de escopo / Use of Ivermectin and Atazanavir in the treatment of Covid-19: a scoping review / Uso de Ivermectina y Atazanavir en el tratamiento de Covid-19: una revisión de alcance

Objetivo: Examinar e mapear as evidências científicas sobre a eficácia do uso de ivermectina e atazanavir no tratamento de COVID-19. Metodologia: Scoping Review, baseado nos procedimentos recomendados pelo Instituto Joanna Briggs. Estabeleceu-se a pergunta norteadora: "Quais são as evidências científicas sobre o uso de ivermectina e atazanavir no tratamento de pacientes com sintomas leves de COVID-19?". Foram realizadas buscas em seis bases de dados nacionais e internacionais, sobre trabalhos publicados até dezembro de 2022. Dos 357 estudos encontrados, 22 foram selecionados para leitura na íntegra, resultando em uma amostra final de 11 estudos analisados. Resultados: As 11 publicações analisadas foram publicadas de 2020 a 2022 durante período pandêmico, de âmbito nacional e internacional com delineamento de estudos experimentais, do tipo ensaio clínico com randomização. Apenas 03 estudos (25%) testaram o atazanavir como intervenção conjugada a outras drogas, não evidenciando melhorias significativas em relação ao seu uso. Já no tratamento com Ivermectina, dos oito (75%) estudos que a testaram, apenas três (37,5%) recomendaram seu uso e cinco (62,5%) não suportam seu uso para tratamento de COVID-19 leve. O tempo de resolução dos sintomas variou de 8 a 10 dias nos braços tratados com ivermectina e em média 07 dias no tratamento com atazanavir. Não se detectou eventos adversos graves relacionados ao uso das duas drogas. Conclusão: As evidências que recomendavam o uso de ivermectina datam do início do período pandêmico, 2020, mas posteriormente, com a realização de ensaios clínicos robustos e controlados, novas evidências não suportam o uso de ivermectina e atazanavir no tratamento de COVID-19 leve mostrando que não houve diferença no tempo de resolução dos sintomas, na taxa de mortalidade, taxa de internação na UTI e tempo de hospitalização.

Objective: To examine and map the scientific evidence on the effectiveness of using ivermectin and atazanavir in the treatment of COVID-19. Methodology: Scoping Review, based on the procedures recommended by the Joanna Briggs Institute. The guiding question was established, "What is the scientific evidence on the use of ivermectin and atazanavir in the treatment of patients with mild symptoms of COVID-19?" Searches were conducted in six national and international databases on papers published until December 2022. Of the 357 studies found, 22 were selected for reading in full, resulting in a final sample of 11 studies analyzed. Results: The 11 publications analyzed were published from 2020 to 2022 during pandemic period, of national and international scope with experimental study design, of clinical trial type with randomization. Only 03 studies (25%) tested atazanavir as a combined intervention with other drugs, showing no significant improvements in relation to its use. As for the treatment with Ivermectin, of the eight (75%) studies that tested it, only three (37.5%) recommended its use and five (62.5%) did not support its use for treating mild COVID-19. The time to symptom resolution ranged from 8 to 10 days in the ivermectin-treated arms and on average 07 days in the atazanavir treatment. No serious adverse events related to the use of the two drugs were detected. Conclusion: evidence recommending the use of ivermectin dates back to the beginning of the pandemic period, 2020, but subsequently, with robust controlled clinical trials, new evidence does not support the use of ivermectin and atazanavir in the treatment of mild COVID-19 showing that there was no difference in time to symptom resolution, mortality rate, ICU admission rate, and length of hospital stay.

Objetivo: Examinar y mapear la evidencia científica sobre la eficacia del uso de ivermectina y atazanavir en el tratamiento de COVID-19. Metodología: Scoping Review, basada en los procedimientos recomendados por el Instituto Joanna Briggs. La pregunta guía era: "¿Cuál es la evidencia científica sobre el uso de ivermectina y atazanavir en el tratamiento de pacientes con síntomas leves de COVID-19? Se realizaron búsquedas en seis bases de datos nacionales e internacionales, en artículos publicados hasta diciembre de 2022. De los 357 estudios encontrados, se seleccionaron 22 para su lectura completa, lo que dio lugar a una muestra final de 11 estudios analizados. Resultados: Las 11 publicaciones analizadas fueron publicadas entre 2020 y 2022 durante el periodo pandémico, de ámbito nacional e internacional con diseño de estudio experimental, de tipo ensayo clínico con aleatorización. Apenas 03 estudios (25%) probaron el atazanavir como intervención combinada con otras drogas, sin evidenciar mejoras significativas en relación con su uso. En cuanto al tratamiento con Ivermectina, de los ocho (75%) estudios que la probaron, sólo tres (37,5%) recomendaron su uso y cinco (62,5%) no apoyaron su uso para tratar la COVID-19 leve. El tiempo transcurrido hasta la resolución de los síntomas osciló entre 8 y 10 días en los brazos tratados con ivermectina y una media de 07 días en el tratamiento con atazanavir. No se detectaron acontecimientos adversos graves relacionados con el uso de los dos fármacos. Conclusión: las pruebas que recomiendan el uso de ivermectina se remontan al inicio del periodo pandémico, 2020, pero posteriormente, con ensayos clínicos controlados sólidos, las nuevas pruebas no apoyan el uso de ivermectina y atazanavir en el tratamiento de la COVID-19 leve, lo que demuestra que no hubo diferencias en el tiempo hasta la resolución de los síntomas, la tasa de mortalidad, la tasa de ingreso en la UCI y la duración de la estancia hospitalaria.

Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study.

Candida albicans is the chief etiological agent of candidiasis, a mycosis prevalent in individuals with acquired immunodeficiency syndrome (AIDS). In recent years, the introduction of human immunodeficiency virus (HIV) protease inhibitors (HIV-PI) has reduced the prevalence of candidiasis in these patients. Seeking new therapeutic strategies based on the perspective of drug repositioning, we evaluated the effects of two second-generation HIV-PIs, atazanavir (ATV) and darunavir (DRV), on virulence factors of C. albicans and experimental candidiasis. For this, clinical strains of C. albicans were subjected to in vitro and in vivo treatments with ATV or DRV. As a result, ATV and DRV exhibited antifungal activity against fungal cells at 512 µg/mL, reduced the viability and biomass of biofilms, and inhibited filamentation of C. albicans. In addition, these HIV-PIs downregulated the expression of SAP2 and BRC1 genes of C. albicans. In an in vivo study, prophylactic use of ATV and DRV prolonged the survival rate of Galleria mellonella larvae infected with C. albicans. Therefore, ATV and DRV showed activity against C. albicans by reducing cell growth, biofilm formation, filamentation, and expression of virulence genes. Furthermore, ATV and DRV decreased experimental candidiasis, suggesting the repurposing of HIV-PIs as antifungal treatments for C. albicans infections.

Atazanavir-Loaded Crosslinked Gamma-Cyclodextrin Nanoparticles to Improve Solubility and Dissolution Characteristics.

Objectives: Atazanavir sulfate (AS), a Biosafety Cabinet (BCS) class II antiretroviral drug, shows dissolution rate-limited bioavailability, therefore, it is necessary to improve its solubility and oral bioavailability. The present investigation is intended to improve the aqueous solubility by developing AS-loaded nanoparticles (ASNPs). Additionally, the immediate release formulation of AS capsules has gastrointestinal side effects such as nausea and abdominal pain, cardiovascular side effect, e.g. abnormal cardiac conduction, toxic effects on kidney and liver such as nephrolithiasis, hyperbilirubinemia, and jaundice. Therefore, ASNPs were designed to release the drug slowly for 12 h, so that these side effects could be reduced. Materials and Methods: ASNPs were prepared using gamma-cyclodextrin (γ-CD) and the crosslinker dimethyl carbonate were characterized by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) to check the crystal characteristics of AS upon entrapment in NPs. Entrapment efficiency (EE), particle size, morphology, solubility, and dissolution behavior were also determined. Results: EE%, particle size, and zeta potential varied from 14.38 ± 0.16 to 75.97 ± 0.28%, 65.4 ± 1.25 nm to 439.6 ± 2.21 nm, and 28.3 ± 0.1 mV to 41.0 ± 0.3 mV, respectively. XRD and DSC confirmed the transformation of the crystalline AS to amorphous in NPs. There was 11.717 folds rise in AS solubility in water from NPs. The formulation having AS: γ-CD, 1:1 at 10 mg/mL, depicted 88.55 ± 0.58, 91.23 ± 0.80, and 86.8 ± 0.65% drug release in water, acid buffer, and phosphate buffer, respectively, in 12 h. Conclusion: Solubility enhancement could be attributed to the decrease in crystallinity of atazanavir, when dispersed in NPs.

A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19.

Background: The nitazoxanide plus atazanavir/ritonavir for COVID-19 (NACOVID) trial investigated the efficacy and safety of repurposed nitazoxanide combined with atazanavir/ritonavir for COVID-19. Methods: This is a pilot, randomized, open-label multicenter trial conducted in Nigeria. Mild to moderate COVID-19 patients were randomly assigned to receive standard of care (SoC) or SoC plus a 14-day course of nitazoxanide (1,000 mg b.i.d.) and atazanavir/ritonavir (300/100 mg od) and followed through day 28. Study endpoints included time to clinical improvement, SARS-CoV-2 viral load change, and time to complete symptom resolution. Safety and pharmacokinetics were also evaluated (ClinicalTrials.gov ID: NCT04459286). Results: There was no difference in time to clinical improvement between the SoC (n = 26) and SoC plus intervention arms (n = 31; Cox proportional hazards regression analysis adjusted hazard ratio, aHR = 0.898, 95% CI: 0.492-1.638, p = 0.725). No difference was observed in the pattern of saliva SARS-CoV-2 viral load changes from days 2-28 in the 35% of patients with detectable virus at baseline (20/57) (aHR = 0.948, 95% CI: 0.341-2.636, p = 0.919). There was no significant difference in time to complete symptom resolution (aHR = 0.535, 95% CI: 0.251-1.140, p = 0.105). Atazanavir/ritonavir increased tizoxanide plasma exposure by 68% and median trough plasma concentration was 1,546 ng/ml (95% CI: 797-2,557), above its putative EC90 in 54% of patients. Tizoxanide was undetectable in saliva. Conclusion: Nitazoxanide co-administered with atazanavir/ritonavir was safe but not better than standard of care in treating COVID-19. These findings should be interpreted in the context of incomplete enrollment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial. Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT04459286], identifier [NCT04459286].

Dose of ritonavir-boosted atazanavir for HIV patient: a reappraisal based on genetic polymorphism epidemiology in Southeast Asia.

Several anti-HIV medications are currently available and used in medical care for HIV-positive people all over the world. Drug resistance is a global problem that necessitates the development of a new treatment regimen to address it. In several countries, ritonavir (RTV)-boosted atazanavir (ATV) is now used. There is evidence that patients taking RTV-boosted ATV on a regular basis have a higher ATV exposure, increasing the risk of toxicity. A recent theory suggests that a smaller dose of ATV/r may be sufficient. In this article, the authors reevaluate the dose of ATV/r for HIV patients based on existing data on the genetic epidemiology of CYP3A5 6986 A > G. According to the research, the likelihood of an individual achieving the therapeutic range of ATV through concentrations in various ATV/r regimens differs depending on baseline sex and CYP3A5 6986 A > G type. With the exception of a normal dosing regimen for male subjects, all have a chance of reaching the therapeutic range of ATV through concentrations (overall probability greater than 1). As a result, the lowering of the ATV/r dose should be considered primarily for male HIV infected patients.

Atazanavir-Concentrate Loaded Soft Gelatin Capsule for Enhanced Concentration in Plasma, Brain, Spleen, and Lymphatics.

This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain, spleen, and lymphatics beneficial in the significant reduction of viral load in HIV infection. For this purpose, ATV-concentrate in the presence and absence of Soluplus with corn oil, oleic acid, tween 80, and propylene glycol was developed. The developed ATV-concentrate was found to have enhanced dispersibility with no signs of precipitation after dilution with simulated G.I fluid as evident from particle size (16.49±0.32 nm) and PDI (0.217±0.02) analysis. The rheological and molecular docking studies explainedthe reduction of viscosity of SuATV-C due to the intermolecular H-bond between ATV and Soluplus that helps to retard crystallization. The shell of the soft gelatin capsule retains its integrity when subjected to a folding endurance test on a texture analyzer depicting that the concentrate did not affect the integrity of the soft gelatin capsule shell. An ex vivo and in vivo pharmacokinetic study in rats revealed that the SuATV-C soft gelatin capsule (SuATV-C SGC) indicated 2.9 fold improvement in rate and extent of permeation and absorption than that of ATV-suspension. The tissue distribution study also exhibited higher drug concentration in the brain (2.5 fold), lymph nodes (2.7 fold), and spleen (1.2 fold) administered with SuATV-C SGC, revealing the overwhelming influence of Soluplus and corn oil. In a nutshell, these studies demonstrated that SuATV-C SGC seems to have the potential to deliver an anti-retroviral drug to the viral sanctuaries for the better management of HIV.