RESUMEN
INTRODUCTION: To date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that provides real-time, objective and quantifiable kinetic data, including changes in the lung area (Rs), tracheal diameter, diaphragmatic kinetics and pulmonary ventilation during respiration, at a lower radiation dose than that used by fluoroscopic or CT imaging. However, the therapeutic effect of dual bronchodilators on respiratory kinetics, such as chest wall dynamics and respiratory muscle function, has not yet been prospectively evaluated using DCR. AIM: This study aims to evaluate the effects of bronchodilator therapy on respiratory kinetics in patients with COPD using DCR. METHODS AND ANALYSIS: This is an open-label, prospective, single-centre, non-controlled, comparative study. A total of 35 patients with COPD, aged 40-85 years, with a forced expiratory volume in the first second of 30-80%, will be enrolled. After a 2-4 weeks washout period, patients will receive tiotropium/olodaterol therapy for 6 weeks. Treatment effects will be evaluated based on DCR findings, pulmonary function test results and patient-related outcomes obtained before and after treatment. The primary endpoint is the change in Rs after therapy. The secondary endpoints include differences in other DCR parameters (diaphragmatic kinetics, tracheal diameter change and maximum pixel value change rate), pulmonary function test results and patient-related outcomes between pre-therapy and post-therapy values. All adverse events will be reported. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Ethics Committee of Chiba University Hospital. The results of this trial will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs032210543.
Asunto(s)
Benzoxazinas , Broncodilatadores , Combinación de Medicamentos , Enfermedad Pulmonar Obstructiva Crónica , Bromuro de Tiotropio , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Bromuro de Tiotropio/administración & dosificación , Bromuro de Tiotropio/uso terapéutico , Estudios Prospectivos , Broncodilatadores/uso terapéutico , Broncodilatadores/administración & dosificación , Anciano , Benzoxazinas/uso terapéutico , Benzoxazinas/administración & dosificación , Persona de Mediana Edad , Masculino , Anciano de 80 o más Años , Femenino , Adulto , Radiografía Torácica , Volumen Espiratorio Forzado/efectos de los fármacos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Pulmón/efectos de los fármacosRESUMEN
Purpose: SHR6390 is an oral, potent and selective small-molecule CDK4/6 inhibitor for the treatment of human breast, ovarian and colon cancer. Previous studies have shown that SHR6390 in combination with rifampicin, a potent inducer of CYP3A4, significantly reduces exposure levels. Therefore, we further investigated the effect of efavirenz, a moderate CYP3A4 inducer, on a single oral dose of SHR6390 in healthy volunteers. Patients and Methods: Twenty healthy subjects were enrolled in this single-center, open, single-dose, self-controlled DDI study. On Day 1, subjects received a single oral dose of 150mg SHR6390; on Day 8-26, subjects received 600 mg efavirenz orally at night, with a single dose of 150 mg SHR6390 on Day 22. Blood samples for pharmacokinetic analyses were collected. Results: The geometric mean ratios of the maximum concentration(Cmax) and the area under the concentration curve from zero to infinity (AUC0-inf) between combination therapy and SHR6390 monotherapy (combination therapy/SHR6390 monotherapy) and their 90% confidence intervals were 0.562 (0.482, 0.654) and 0.328 (0.278, 0.386), respectively. This indicates that the Cmax and AUC0 inf of SHR6390 decreased by approximately 43.8% and 67.2%, respectively. Oral administration of 150 mg SHR6390 alone or together with efavirenz was safe and tolerable in healthy subjects. Conclusion: It is suggested that under the action of the moderate CPY3A4 inducer efavirenz, the exposure AUC of SHR6390 exhibits a moderate level of induction. It is recommended to avoid concomitant administration of moderate inducers of CYP3A4 during treatment with SHR6390. Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20211571/ https://classic.clinicaltrials.gov, NCT04973020.
Asunto(s)
Alquinos , Benzoxazinas , Ciclopropanos , Voluntarios Sanos , Humanos , Benzoxazinas/administración & dosificación , Benzoxazinas/farmacología , Benzoxazinas/farmacocinética , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacología , Ciclopropanos/farmacocinética , Adulto , Masculino , Femenino , Adulto Joven , Administración Oral , Persona de Mediana Edad , Interacciones Farmacológicas , Inductores del Citocromo P-450 CYP3A/farmacología , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Área Bajo la Curva , Relación Dosis-Respuesta a DrogaRESUMEN
Optic neuritis is a rare presentation of vitamin B12 deficiency. We describe a 33-year-old female patient living with HIV presenting with progressive loss of vision for 1 week. She had a history of severe peripheral neuropathy that was managed with vitamin B12-containing tablets approximately three years before presenting with progressive loss of vision. On examination, she had no perception of light in the left eye and no perception of hand motion in the right eye. The fundus in her left eye had mild blurring of disc margins. Results from tests done showed a haemoglobin of 12.9g/dl, MCV 101fl, a serum vitamin B12 of 78pmol/l, and cytomegalovirus (CMV) test showed no active disease. She was diagnosed with optic neuritis and started on 30 mg tablets of prednisolone for 1 week with slight improvement. She was then started on vitamin B12 injections 1 mg daily for 10 days and thereafter, monthly for 6 months. She reported gradual improvement and regained her sight after 5 months treatment of with Vitamin B12 injections. Ophthalmic manifestations of vitamin B12 deficiency are not common and may present without haematological signs therefore, a high index of suspicion is required for early diagnosis and management of vitamin B12 deficiency.
Asunto(s)
Alquinos , Fármacos Anti-VIH , Benzoxazinas , Ceguera , Ciclopropanos , Infecciones por VIH , Neuritis Óptica , Deficiencia de Vitamina B 12 , Vitamina B 12 , Humanos , Femenino , Adulto , Deficiencia de Vitamina B 12/diagnóstico , Deficiencia de Vitamina B 12/tratamiento farmacológico , Deficiencia de Vitamina B 12/complicaciones , Vitamina B 12/administración & dosificación , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Benzoxazinas/administración & dosificación , Benzoxazinas/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Ceguera/etiología , Ciclopropanos/administración & dosificación , Neuritis Óptica/diagnóstico , Neuritis Óptica/tratamiento farmacológico , Prednisolona/administración & dosificación , Glucocorticoides/administración & dosificaciónRESUMEN
Enteral feeding tubes (EFTs) can be placed in children diagnosed with HIV which need nutritional support due to malnutrition. EFTs are the main route for medication administration in these patients, bringing up concerns about off label use of medicines, dose inaccuracy and tube clogging. Here we report for the first time the use of selective laser sintering (SLS) 3D printing to develop efavirenz (EFZ) dispersible printlets for patients with HIV that require EFT administration. Water soluble polymers Parteck® MXP and Kollidon® VA64 were used to obtain both 500 mg (P500 and K500) and 1000 mg printlets (P1000 and K1000) containing 200 mg of EFZ each. The use of SLS 3D printing obtained porous dosage forms with high drug content (20 % and 40 % w/w) and drug amorphization using both polymers. P500, K500 and K1000 printlets reached disintegration in under 230 s in 20 mL of water (25 ± 1 °C), whilst P1000 only partially disintegrated, possibly due to saturation of the polymer in the medium. As a result, the development of dispersible EFZ printlets using hydrophilic polymers can be explored as a potential strategy for drug delivery through EFTs in paediatrics with HIV, paving the way towards the exploration of more rapidly disintegrating polymers and excipients for SLS 3D printing.
Asunto(s)
Alquinos , Benzoxazinas , Ciclopropanos , Impresión Tridimensional , Comprimidos , Alquinos/química , Benzoxazinas/administración & dosificación , Benzoxazinas/química , Humanos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/química , Solubilidad , Nutrición Enteral/métodos , Niño , Excipientes/química , Polímeros/química , Intubación Gastrointestinal/métodos , Infecciones por VIH/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , PorosidadRESUMEN
Cytochrome P450 46A1 (CYP46A1) is the CNS-specific cholesterol 24-hydroxylase that controls cholesterol elimination and turnover in the brain. In mouse models, pharmacologic CYP46A1 activation with low-dose efavirenz or by gene therapy mitigates the manifestations of various brain disorders, neurologic, and nonneurologic, by affecting numerous, apparently unlinked biological processes. Accordingly, CYP46A1 is emerging as a promising therapeutic target; however, the mechanisms underlying the multiplicity of the brain CYP46A1 activity effects are currently not understood. We proposed the chain reaction hypothesis, according to which CYP46A1 is important for the three primary (unifying) processes in the brain (sterol flux through the plasma membranes, acetyl-CoA, and isoprenoid production), which in turn affect a variety of secondary processes. We already identified several processes secondary to changes in sterol flux and herein undertook a multiomics approach to compare the brain proteome, acetylproteome, and metabolome of 5XFAD mice (an Alzheimer's disease model), control and treated with low-dose efavirenz. We found that the latter had increased production of phospholipids from the corresponding lysophospholipids and a globally increased protein acetylation (including histone acetylation). Apparently, these effects were secondary to increased acetyl-CoA production. Signaling of small GTPases due to their altered abundance or abundance of their regulators could be affected as well, potentially via isoprenoid biosynthesis. In addition, the omics data related differentially abundant molecules to other biological processes either reported previously or new. Thus, we obtained unbiased mechanistic insights and identified potential players mediating the multiplicity of the CYP46A1 brain effects and further detailed our chain reaction hypothesis.
Asunto(s)
Alquinos , Benzoxazinas , Encéfalo , Colesterol 24-Hidroxilasa , Ciclopropanos , Animales , Colesterol 24-Hidroxilasa/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ratones , Benzoxazinas/farmacología , Benzoxazinas/administración & dosificación , Ciclopropanos/farmacología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Ratones Transgénicos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a DrogaRESUMEN
The efficacy of 400mg efavirenz (EFV) once daily is reported to be similar to that of 600mg EFV. However, EFV-related toxic and side effects of 400mg EFV are significantly reduced. Here, the feasibility of reducing EFV to 400mg once a day in HIV-infected/AIDS patients was evaluated. Fifty patients were included. Patients were given 3TC+TDF+400mg EFV (n=25) or 3TC+TDF+600mg EFV (n=25). The proportion of patients with HIV RNA < 40 copies/mL and the adverse events served as the primary and secondary outcomes, respectively. HIV inhibition rates of the 3TC+TDF+400mg EFV group and 3TC+TDF+600mg EFV group were both 56.52% at week 24 and respectively 100%, 91.3% at week 48. During 48 weeks, 27 cases of adverse events were reported in the 3TC+TDF+400mg EFV group, lower than those in the 3TC+TDF+600mg EFV group, which had 39 cases. Compared with the 3TC+TDF+400mg EFV group, the incidence of transaminase, dizziness, hyperlipidemia and rashes all increased in the 3TC+TDF+600mg EFV group (P>0.05). No serious adverse events of the central nervous system occurred. The incidence of depression, sleep disturbance, and vertigo were similar (P>0.05). The efficacy of 400mg EFV is comparable to 600mg EFV. However, patients receiving 400mg EFV have fewer adverse events.
Asunto(s)
Alquinos , Fármacos Anti-VIH , Benzoxazinas , Ciclopropanos , Infecciones por VIH , Humanos , Benzoxazinas/efectos adversos , Benzoxazinas/administración & dosificación , Benzoxazinas/uso terapéutico , Ciclopropanos/administración & dosificación , Masculino , Femenino , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Persona de Mediana Edad , Resultado del Tratamiento , Lamivudine/administración & dosificación , Lamivudine/efectos adversos , Lamivudine/uso terapéutico , Tenofovir/efectos adversos , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , Quimioterapia Combinada , Carga Viral/efectos de los fármacos , ARN Viral , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológicoRESUMEN
BACKGROUND: Concomitant use of efavirenz-based antiretroviral therapy and a standard-dose etonogestrel contraceptive implant led to 82% lower etonogestrel exposure when compared with women who do not receive antiretroviral therapy. The clinical impact of this reduced exposure is supported by retrospective cohort evaluations that demonstrated higher rates of unintended pregnancies when contraceptive implants were combined with efavirenz. We hypothesized that placement of 2 etonogestrel implants in those taking efavirenz-based antiretroviral therapy could increase etonogestrel exposure and improve measures of contraceptive efficacy. OBJECTIVE: This study compared the rate of ovulation and etonogestrel pharmacokinetics among women on efavirenz-based antiretroviral therapy who received 2 etonogestrel implants (136 mg; double implant group) in comparison with those who received 1 etonogestrel implant (68 mg; control group). STUDY DESIGN: This randomized, open-label study enrolled Ugandan women with regular menstrual periods who were receiving efavirenz-based antiretroviral therapy for the treatment of HIV. Participants were randomized 1:1 to the double implant or control group, and the etonogestrel implant(s) were placed in the same arm at enrollment. All participants used a copper intrauterine device to prevent pregnancy. Ovulation was evaluated by weekly serum progesterone concentrations measured over 4 consecutive weeks at months 3 (weeks 9-12), 6 (weeks 21-24), and 12 (weeks 45-48). Progesterone concentrations >3 ng/mL were interpreted as ovulation. The ovulation rate in each group was compared using Fisher's exact tests for each month and generalized estimating equations over 48 weeks. Plasma was collected at day 3 and weeks 1, 4, 12, 24, 36, and 48 after implant placement and analyzed using a validated liquid chromatography-triple quadrupole mass spectrometry method for etonogestrel. Etonogestrel concentrations were summarized as median (interquartile range) and compared between groups by geometric mean ratio with 90% confidence intervals. RESULTS: All participants (n=72) were cisgender Ugandan women with a median age of 31 years (interquartile range, 29-36), and 36 participants were enrolled in each study group. Two participants in the control group discontinued the trial; 1 at week 1 because of undetected pregnancy at entry and another at week 45 because of clinically significant depression. There were 47 ovulations over 104 person-months (45%) in 25 of 34 participants in the control group, and 2 ovulations over 108 person-months (2%) in 2 of 36 participants in the double implant group (month 3: 11 [31%] vs 0 [0%]; month 6: 17 [49%] vs 0 [0%]; month 12: 19 [56%] vs 2 [6%], respectively; all P<.001). The odds of ovulation were reduced by 97.7% (95% confidence interval, 90.1-99.5) in the double implant group over 48 weeks. At each time point, etonogestrel concentration was more than 2-fold higher in the double implant group than in the controls (geometric mean ratio, 2.30-2.83) with a geometric mean ratio of 2.83 (90% confidence interval, 1.89-3.35) at week 48. There were no differences in the adverse events between groups and no participant discontinued because of adverse events. CONCLUSION: Over 48 weeks of combined use, placing 2 etonogestrel implants suppressed ovulation and increased plasma etonogestrel exposure when compared with 1 etonogestrel implant among women on efavirenz-based antiretroviral therapy. Doubling the dose of etonogestrel during efavirenz-based antiretroviral therapy could improve contraceptive effectiveness.
Asunto(s)
Alquinos , Benzoxazinas , Anticonceptivos Femeninos , Ciclopropanos , Desogestrel , Implantes de Medicamentos , Infecciones por VIH , Humanos , Desogestrel/administración & dosificación , Femenino , Ciclopropanos/administración & dosificación , Benzoxazinas/administración & dosificación , Adulto , Anticonceptivos Femeninos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Embarazo , Ovulación/efectos de los fármacos , Interacciones Farmacológicas , Adulto Joven , Agentes Anticonceptivos Hormonales/administración & dosificación , UgandaRESUMEN
INTRODUCTION: Although dolutegravir (DTG) is deemed stable, safe, cost-effective, and clinically beneficial, it also carries the risk of side effects, including observed weight gain among patients on DTG-based antiretroviral therapy (ART) regimens. We compared weight changes among adults (≥18 years) initiating tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE) regimens and those switching from TEE to TLD (TEE-to-TLD switchers) in three large primary care facilities in South Africa METHODS: We conducted a retrospective longitudinal record review using patient medical records, extracting relevant demographic and clinical data from October 2018 to June 2021 from randomly selected adults who initiated TLD or TEE (initiators) and adult TEE-to-TLD switchers. We assessed weight, body mass index (BMI), and percentage weight changes for both groups and fitted linear regression and generalized linear models to determine factors associated with weight and BMI change and percentage weight change ≥10%, respectively, among treatment initiators. We fitted linear mixed-effect models among TEE-to-TLD switchers to consider repeated measures. RESULTS: Of 860 initiators, 450 (52.3%) initiated on TEE and 410 (47.7%) on TLD, with median follow-up of 1.4 years and 1.0 year, respectively. At initiation, 43.3% on TEE and 40.8% on TLD were overweight or obese. TLD initiators had an adjusted higher mean weight gain of 1.6 kg (p < 0.001) and mean BMI gain of 0.51 kg/m2 (p < 0.001) than TEE initiators. Independent risk factors for higher mean weight and BMI included age ≥50 years, male, on ART for >12 months, initial BMI of <18.5 kg/m2, and CD4 counts <200 cells/µL. Of 298 TEE-to-TLD switchers, 36.6% were overweight or obese at TEE initiation. Comparing before and after TLD switch, TEE-to-TLD switchers had an adjusted mean weight of 1.2 kg less while on TLD (p = 0.026). Being overweight and CD4 counts >350 cells/µL were independent risk factors for lower weight gain after TLD switch. CONCLUSIONS: We report more weight gain among TLD than among TEE initiators, although to a lesser extent than previously reported. TEE-to-TLD switchers experienced less weight gain after TLD switch; return to health before receiving TLD may be a contributory factor. The current findings are reassuring for those switching to a DTG-based regimen.
Asunto(s)
Alquinos , Benzoxazinas , Ciclopropanos , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piridonas , Aumento de Peso , Humanos , Masculino , Femenino , Aumento de Peso/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Adulto , Sudáfrica , Estudios Retrospectivos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Oxazinas/uso terapéutico , Benzoxazinas/uso terapéutico , Benzoxazinas/efectos adversos , Benzoxazinas/administración & dosificación , Persona de Mediana Edad , Piperazinas , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Estudios Longitudinales , Índice de Masa Corporal , Lamivudine/uso terapéutico , Lamivudine/efectos adversos , Lamivudine/administración & dosificación , Tenofovir/uso terapéutico , Tenofovir/efectos adversos , Tenofovir/administración & dosificación , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificaciónRESUMEN
Over the last 4 decades, significant advances in the care of HIV during pregnancy have successfully reduced, and nearly eliminated, the risk of perinatal HIV transmission. The baseline risk of transmission without intervention (25% to 30%) is now <1% to 2% in the United States with contemporary antepartum, intrapartum, and postnatal interventions. In this review, we discuss 3 landmark clinical trials that substantially altered obstetric practice for pregnant individuals with HIV and contributed to this extraordinary achievement: 1) the Pediatric AIDS Clinical Trials Group 076 Trial determined that antepartum and intrapartum administration of antiretroviral drug zidovudine to the pregnant individual, and postnatally to the newborn, could reduce the risk of perinatal transmission by approximately two-thirds; 2) the European Mode of Delivery Collaboration Trial demonstrated performance of a prelabor cesarean birth before rupture of membranes among pregnant people with viremia reduced the risk of perinatal transmission compared with vaginal birth; and 3) the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 Trial identified that dolutegravir-containing, compared with efavirenz-containing, antiretroviral regimens during pregnancy achieved a significantly higher rate of viral suppression at delivery with shorter time to viral suppression, with fewer adverse pregnancy outcomes. Collectively, these trials not only advanced obstetric practice but also advanced scientific understanding of the timing, mechanisms, and determinants of perinatal HIV transmission. For each trial, we will describe key aspects of the study protocol and outcomes, insights gleaned about the dynamics of perinatal transmission, how each study changed clinical practice, and relevant updates to current practice since the trial's publication.
Asunto(s)
Alquinos , Fármacos Anti-VIH , Infecciones por VIH , Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo , Piridonas , Zidovudina , Humanos , Embarazo , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Infecciones por VIH/prevención & control , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Piridonas/uso terapéutico , Zidovudina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Ciclopropanos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Ensayos Clínicos como Asunto , Benzoxazinas/uso terapéutico , Benzoxazinas/administración & dosificación , Recién Nacido , CesáreaRESUMEN
This study intended to investigate the impact of long-term tenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine ß2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood ß2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood ß2 microglobulin was statistically significant at month 6 and months 12-30 (P < .05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine ß2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P < .05). The abnormal concentration proportion of urine ß2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood ß2 microglobulin, urine ß2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P > .05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine ß2 microglobulin levels may be helpful in screening for renal dysfunction.
Asunto(s)
Alquinos , Fármacos Anti-VIH , Ciclopropanos , Tasa de Filtración Glomerular , Infecciones por VIH , Tenofovir , Microglobulina beta-2 , Humanos , Tenofovir/efectos adversos , Tenofovir/administración & dosificación , Tenofovir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Masculino , Femenino , Microglobulina beta-2/orina , Microglobulina beta-2/sangre , Adulto , Persona de Mediana Edad , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Benzoxazinas/efectos adversos , Benzoxazinas/administración & dosificación , Benzoxazinas/uso terapéutico , Lamivudine/efectos adversos , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Riñón/efectos de los fármacos , Riñón/fisiopatologíaRESUMEN
LINE1 retrotransposons, which are thought to be the remnants of ancient integrations of retrovirus-like elements, are aberrantly (re)activated in many cancer cells. Due to LINE1-induced alterations in target gene expression and/or chromosomal rearrangements, they may be important drivers of tumorigenesis. Moreover, LINE1 encoded proteins, Open Reading Frame (ORF)1 and ORF2, may have pro-oncogenic potential through inductors of oncogenic transcription factors or inhibitors of cell cycle suppressors. The current study therefore aimed to investigate in vitro and in vivo anti-tumorigenic effects of two well-known antiretroviral drugs, zidovudine, a nucleoside analogue inhibitor of RT (NRTI), and efavirenz, a non-nucleoside RT inhibitor (NNRTI). Our data demonstrate that both drugs in clinically relevant doses significantly reduced the proliferation of murine and human cancer cell lines, as well as growth of tumors in a murine subcutaneous model. Intriguingly, we found that the combination of both zidovudine and efavirenz almost entirely blocked tumorigenesis in vivo. Because both drugs are FDA-approved agents and the combination was very well tolerated in mice, the combination therapy as presented in our paper might be an opportunity to treat colorectal tumors and metastasis to the liver in an inexpensive way.
Asunto(s)
Alquinos/administración & dosificación , Antirretrovirales/administración & dosificación , Antineoplásicos/administración & dosificación , Benzoxazinas/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Ciclopropanos/administración & dosificación , Zidovudina/administración & dosificación , Animales , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/fisiopatología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.516G>T and patient demographics on plasma efavirenz (EFV) and 8-hydroxyefavirenz (8OH-EFV) concentrations, metabolic ratio (8OH-EFV/EFV) (MR), and their association with adverse effects, in PNG patients with HIV/AIDS. For 156 PNG patients with HIV/AIDS taking EFV 600 mg/day (for 3-156 months), plasma EFV and 8OH-EFV concentrations were quantified, CYP2B6 c.516G>T genotyped, and demographic and self-reported adverse effects data recorded. Genotype differences in EFV and 8OH-EFV concentrations, MR, and percent within therapeutic range (1000-4000 ng/ml) were examined, in addition to EFV and 8OH-EFV concentration differences between patients experiencing adverse effects. CYP2B6 c.516T allele frequency was 53%. Plasma EFV (p < 0.0001), 8OH-EFV (p < 0.01), and MR (p < 0.0001) differed significantly between genotypes, with genotype explaining 38%, 10%, and 50% of variability, respectively. Plasma EFV concentrations were significantly higher in T/T (median = 5168 ng/ml) than G/G (1036 ng/ml, post hoc p < 0.0001) and G/T (1502 ng/ml, p < 0.0001) genotypes, with all patients above therapeutic range (n = 23) being T/T genotype (p < 0.0001). EFV and 8OH-EFV concentrations were not significantly higher in patients experiencing adverse effects. In PNG HIV/AIDS population where the 516T frequency is very high, it explains a substantial portion of variability (38%) in EFV disposition; however, at least for the patients receiving EFV long term, this does not translate into significant side effects.
Asunto(s)
Alquinos/sangre , Benzoxazinas/sangre , Ciclopropanos/sangre , Inductores del Citocromo P-450 CYP2B6/sangre , Citocromo P-450 CYP2B6/sangre , Citocromo P-450 CYP2B6/genética , Frecuencia de los Genes , Infecciones por VIH , Adolescente , Adulto , Anciano , Alquinos/administración & dosificación , Benzoxazinas/administración & dosificación , Ciclopropanos/administración & dosificación , Inductores del Citocromo P-450 CYP2B6/administración & dosificación , Femenino , Genotipo , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Papúa Nueva Guinea/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Our group previously proved that the human enteric nervous system can be visualized with confocal laser endomicroscopy after topical application of cresyl violet using surgically resected intestine specimens. The present report documents the first in vivo visualization of the human enteric nervous system with confocal laser endomicroscopy using local cresyl violet staining. The aim of this study was to evaluate the technical feasibility and clinical efficiency of confocal laser endomicroscopy in patients with Hirschsprung's disease and allied disorders in vivo. METHODS: Confocal laser endomicroscopy was performed in vivo in two patients to confirm the presence of the enteric nervous system during surgery in patients with Hirschsprung's disease and allied disorders. Cresyl violet was gently injected from the serosal side into the muscular layer of the intestine, and scanning was performed within 30 min. Then, the scanned intestines were resected, and the visualized area of the specimens was pathologically evaluated. RESULTS: The ganglion cell nuclei and the enteric nervous system network were clearly visualized intraoperatively in both cases. The morphological findings were similar to the pathological findings of the enteric nervous system in both cases although the period of visibility was brief. CONCLUSION: This study demonstrated the first, real-time observation of the enteric nervous system in humans using confocal laser endomicroscopy and suggest the potential to identify the enteric nervous system intra-operatively during surgery for Hirschsprung's disease and allied disorders.
Asunto(s)
Sistema Nervioso Entérico/diagnóstico por imagen , Enfermedad de Hirschsprung/diagnóstico por imagen , Microscopía Confocal/métodos , Administración Tópica , Benzoxazinas/administración & dosificación , Preescolar , Colon/inervación , Colorantes/administración & dosificación , Procedimientos Quirúrgicos del Sistema Digestivo , Estudios de Factibilidad , Femenino , Ganglios/diagnóstico por imagen , Enfermedad de Hirschsprung/cirugía , Humanos , Lactante , Cuidados Intraoperatorios , MasculinoRESUMEN
BACKGROUND: Virological failure during antiretroviral treatment (ART) may indicate the presence of drug resistance, but may also originate from nonadherence. Qualitative detection of ART components using drug level testing may be used to differentiate between these scenarios. We aimed to validate and implement qualitative point-of-care drug level tests for efavirenz (EFV), lopinavir (LPV), and dolutegravir (DTG) in rural South Africa. METHODS: Qualitative performance of immunoassays for EFV, LPV, and DTG was assessed by calculating limit of detection (LoD), region of uncertainty, and qualitative agreement with a reference test. Minimum duration of nonadherence resulting in a negative drug level test was assessed by simulation of treatment cessation using validated population pharmacokinetic models. RESULTS: LoD was 0.05 mg/L for EFV, 0.06 mg/L for LPV, and 0.02 mg/L for DTG. Region of uncertainty was 0.01-0.06 mg/L for EFV, 0.01-0.07 mg/L for LPV, and 0.01-0.02 mg/L for DTG. Qualitative agreement with reference testing at the LoD in patient samples was 95.2% (79/83) for EFV, 99.3% (140/141) for LPV, and 100% (118/118) for DTG. After simulated treatment cessation, median time to undetectability below LoD was 7 days [interquartile range (IQR) 4-13] for EFV, 30 hours (IQR 24-36) for LPV, and 6 days (IQR 4-7) for DTG. CONCLUSIONS: We demonstrate that qualitative ART drug level testing using immunoassays is feasible in a rural resource-limited setting. Implementation of this technology enables reliable detection of recent nonadherence and may allow for rapid and cost-effective differentiation between patients in need for adherence counseling and patients who require drug resistance testing or alternative treatment.
Asunto(s)
Alquinos/administración & dosificación , Fármacos Anti-VIH/sangre , Benzoxazinas/administración & dosificación , Ciclopropanos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Lopinavir/administración & dosificación , Cumplimiento de la Medicación , Oxazinas/administración & dosificación , Piperazinas/administración & dosificación , Pruebas en el Punto de Atención/normas , Piridonas/administración & dosificación , Alquinos/farmacocinética , Alquinos/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/farmacocinética , Benzoxazinas/uso terapéutico , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , VIH-1 , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Técnicas para Inmunoenzimas/métodos , Límite de Detección , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Pruebas en el Punto de Atención/economía , Piridonas/farmacocinética , Piridonas/uso terapéutico , Reproducibilidad de los Resultados , Población Rural , SudáfricaRESUMEN
Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor-targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (-23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.
Asunto(s)
Portadores de Fármacos/administración & dosificación , VIH-1/efectos de los fármacos , Receptores de Hialuranos , Macrófagos/efectos de los fármacos , Nanoestructuras/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Alquinos/administración & dosificación , Alquinos/síntesis química , Alquinos/metabolismo , Benzoxazinas/administración & dosificación , Benzoxazinas/síntesis química , Benzoxazinas/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Ciclopropanos/administración & dosificación , Ciclopropanos/síntesis química , Ciclopropanos/metabolismo , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Células HEK293 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , VIH-1/fisiología , Humanos , Receptores de Hialuranos/metabolismo , Lípidos/administración & dosificación , Lípidos/síntesis química , Macrófagos/metabolismo , Nanoestructuras/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/metabolismo , Células THP-1RESUMEN
BACKGROUND: Escalation to triple therapy (long-acting muscarinic antagonist/ß2-agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma. METHODS: In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy. RESULTS: For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy. CONCLUSIONS: ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.
Asunto(s)
Benzoxazinas/administración & dosificación , Puntaje de Propensión , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Bromuro de Tiotropio/administración & dosificación , Administración por Inhalación , Anciano , Antagonistas Colinérgicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Humanos , Japón/epidemiología , Masculino , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Estudios Retrospectivos , Factores de Tiempo , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R- and S-PZQ in healthy male participants. This was toward evaluating the risk of drug-drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non-randomized, open-label, single-dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC-MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2 , Cmin , and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4-fold (1213.15 vs. 281.35 h·ng/ml for R-PZQ and 5669 vs. 871.84 h·ng/ml for S-PZQ). Ritonavir had no significant effect on R-PZQ but increased the AUC 2-fold for S-PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively.
Asunto(s)
Alquinos/administración & dosificación , Antihelmínticos/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/administración & dosificación , Ciclopropanos/administración & dosificación , Praziquantel/farmacocinética , Ritonavir/administración & dosificación , Adulto , Antihelmínticos/sangre , Antihelmínticos/química , Estudios Cruzados , Interacciones Farmacológicas , Humanos , Masculino , Praziquantel/sangre , Praziquantel/química , Estereoisomerismo , Adulto JovenRESUMEN
Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight because of species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologs were developed. The aim of this work was to investigate the utility of mouse models expressing human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz, and pioglitazone, which were employed to represent strong, moderate, and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. After the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction of clinic induction was recapitulated as rifampin yielded the greatest inductive effect followed by efavirenz and pioglitazone. Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity. Conversely, there was no difference between in vivo and in vitro CYP3A activity with efavirenz. These findings are consistent with the report that, although rifampin exhibits differential inductive effects between the intestines and liver, efavirenz does not. These data highlight the promise of transgenic models, such as Tg-Composite, to complement human hepatocytes to enhance the translatability of clinical induction as well as become a powerful tool to further study mechanisms of drug disposition. SIGNIFICANCE STATEMENT: Underprediction of the magnitude of clinical induction when using human hepatocytes has been reported, and transgenic models may improve clinical translatability. The work presented here showcases the human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 model, which was able to recapitulate the magnitude of clinical induction and to differentiate tissue-dependent induction observed with rifampin but not with efavirenz. These results not only foreshadow the potential application of such transgenic models in assessing clinical induction but also in further investigation of the mechanism of drug disposition.
Asunto(s)
Inductores del Citocromo P-450 CYP3A/farmacocinética , Alquinos/administración & dosificación , Alquinos/farmacocinética , Animales , Benzoxazinas/administración & dosificación , Benzoxazinas/farmacocinética , Receptor de Androstano Constitutivo/genética , Receptor de Androstano Constitutivo/metabolismo , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Evaluación Preclínica de Medicamentos/métodos , Interacciones Farmacológicas , Estudios de Factibilidad , Femenino , Humanos , Ratones , Ratones Transgénicos , Microsomas Hepáticos , Pioglitazona/administración & dosificación , Pioglitazona/farmacocinética , Receptor X de Pregnano/genética , Receptor X de Pregnano/metabolismo , Rifampin/administración & dosificación , Rifampin/farmacocinética , Especificidad de la Especie , Triazolam/administración & dosificación , Triazolam/farmacocinéticaRESUMEN
BACKGROUND: There is limited clinical trial and/or real-world evidence comparing differences among currently approved fixed-dose combination (FDC) long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) treatments. OBJECTIVE: To compare chronic obstructive pulmonary disease (COPD)-related and all-cause health care resource utilization (HCRU) and costs between COPD patients initiating tiotropium (TIO) + olodaterol (OLO) versus (a) other LAMA + LABA FDCs and (b) umeclidinium (UMEC) + vilanterol (VI), specifically. METHODS: In this retrospective observational study, patients initiating fixed-dose LAMA + LABA therapy (earliest fill date = index date) between January 1, 2014, and September 30, 2018, were identified using administrative claims data from the Optum Research Database. Patients were followed post-index for 1-12 months. Follow-up was censored at the earliest occurrence of index therapy discontinuation or switch, health plan disenrollment, study end date, or reaching the maximum 12-month allowed duration. Propensity score matching of 1:2 was used to balance differences in baseline characteristics between cohorts for each of the 2 comparisons. Annualized population averages of HCRU and costs were calculated for each cohort as [sum of visits (or costs) for all individuals during the follow-up period] ÷ [sum of follow-up on-treatment time for all individuals] × 365 days. RESULTS: After matching, compared with patients who initiated other LAMA + LABAs or UMEC + VI, patients who initiated TIO + OLO had 14.29% and 16.95% fewer mean annualized per-patient COPD-related emergency department (ED) visits (vs. other LAMA + LABAs: 0.49 vs. 0.59, P = 0.005; vs. UMEC + VI: 0.48 vs. 0.56, P = 0.026) and 3.07% and 3.14% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 12.66 vs. 13.07, P = 0.016; vs. UMEC + VI: 12.62 vs. 13.02, P = 0.022), leading to 17.39% and 21.47% lower mean annualized per-patient COPD-related ED costs (vs. other LAMA + LABAs: $289 vs. $368, P = 0.003; vs. UMEC + VI: $285 vs. $345, P = 0.027) and 4.56% and 5.67% lower mean annualized per-patient pharmacy spending (vs. other LAMA + LABAs: $3,570 vs. $3,741, P < 0.001; vs. UMEC + VI: $3,556 vs. $3,770, P < 0.001) in the follow-up period. Similarly, patients in the TIO + OLO cohort had 15.63% and 21.17% fewer mean annualized per-patient all-cause ED visits (vs. other LAMA + LABAs: 1.08 vs. 1.37, P < 0.001; vs. UMEC + VI: 1.08 vs. 1.28, P = 0.001), 8.29% fewer mean annualized per-patient outpatient visits (vs. UMEC + VI: 13.28 vs. 14.48, P = 0.031), 3.41% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 56.92 vs. 58.93, P = 0.028), 19.48% and 22.28% lower mean annualized per-patient all-cause ED costs (vs. other LAMA + LABAs: $755 vs. $971, P < 0.001; vs. UMEC + VI: $749 vs. $930, P < 0.001), and 10.86% lower mean annualized per-patient outpatient setting costs (vs. UMEC + VI: $3,348 vs. $3,756, P = 0.050). There were no statistically significant differences for the other outcome measures. CONCLUSIONS: In a real-world setting, differences in HCRU and costs were observed between FDC LAMA + LABAs, with patients initiating TIO + OLO having lower ED visits/costs, COPD-related pharmacy fills/costs, and all-cause pharmacy use and outpatient visits/costs than those initiating other FDC LAMA + LABAs or UMEC + VI specifically. The remaining HCRU and cost measures were not significantly different. DISCLOSURES: This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI; Ridgefield, CT). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Palli is an employee of BIPI. Xie, Chastek, Elliott, and Bengtson are employees of Optum, which was contracted by BIPI to conduct this study. The authors received no direct compensation related to the development of the manuscript. Part of the results of this study were accepted and presented at the 30th European Respiratory Society (ERS) International Congress (September 7-9, 2020; virtual).
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/economía , Combinación de Medicamentos , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/economía , Aceptación de la Atención de Salud , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/economía , Administración por Inhalación , Anciano , Benzoxazinas/administración & dosificación , Alcoholes Bencílicos/administración & dosificación , Broncodilatadores , Clorobencenos/administración & dosificación , Preparaciones de Acción Retardada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinuclidinas/administración & dosificación , Estudios Retrospectivos , Bromuro de Tiotropio/administración & dosificación , Estados UnidosRESUMEN
BACKGROUND: Airway inflammation is a key feature of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroids (ICS) remain the main treatment for airway inflammation. Studies have noted the increased efficacy of ICS and long-acting beta 2 agonist (LABA) combination therapy in controlling exacerbations and improving airway inflammation than either monotherapy. Further studies have suggested that LABAs may have inherent anti-inflammatory potential, but this has not been well-studied. OBJECTIVE: We hypothesize that the LABA olodaterol can inhibit airway inflammation resulting from exposure to respiratory syncytial virus (RSV) via its binding receptor, the ß2-adrenergic receptor. METHODS: Human bronchial epithelial brushing from patients with and without COPD were cultured into air-liquid interface (ALI) cultures and treated with or without olodaterol and RSV infection to examine the effect on markers of inflammation including interleukin-8 (IL-8) and mucus secretion. The cell line NCI-H292 was utilized for gene silencing of the ß2-adrenergic receptor via siRNA as well as receptor blocking via ICI 118,551 and butaxamine. RESULTS: At baseline, COPD-ALIs produced greater amounts of IL-8 than control ALIs. Olodaterol reduced RSV-mediated IL-8 secretion in both COPD and control ALIs and also significantly reduced Muc5AC staining in COPD-ALIs infected with RSV. A non-significant reduction was seen in control ALIs. Gene silencing of the ß2-adrenergic receptor in NCI-H292 negated the ability of olodaterol to inhibit IL-8 secretion from both RSV infection and lipopolysaccharide stimulus, as did blocking of the receptor with ICI 118,551 and butaxamine. CONCLUSIONS: Olodaterol exhibits inherent anti-inflammatory properties on the airway epithelium, in addition to its bronchodilation properties, that is mediated through the ß2-adrenergic receptor and independent of ICS usage.