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1.
BMC Infect Dis ; 21(1): 112, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485301

RESUMO

BACKGROUND: The plasma concentration of patients treated with efavirenz (EFV) 600 mg was found to exceed the upper limit of the proposed therapeutic window in most Chinese HIV-infected individuals; thus, dosage reduction of EFV to 400 mg daily warranted consideration. This study aimed to assess the pharmacodynamics of EFV 400 mg for HIV-1-infected patients in China. METHOD: Twenty cART-naïve individuals were enrolled in this study. EFV 400 mg combined with tenofovir (TDF) and lamivudine (3TC) as an initial antiretroviral regimen was administered for 48 weeks. EFV concentration and T cell subsets as well as HIV RNA load were evaluated at baseline and at 4, 12, 24, and 48 weeks. Moreover, neuropsychiatric adverse effects were also assessed by the Hamilton depression (HAMD) scale and Pittsburgh sleep quality index (PSQI). RESULTS: Eighteen males and two females whose median age was 26 (interquartile range [IQR]: 23-32) years completed 48 weeks of follow-up. The median EFV concentrations were 1.88 (IQR: 1.54-2.42), 1.74 (IQR: 1.36-1.93), 1.93 (IQR: 1.66-2.22), and 1.85 (IQR: 1.54-2.14) mg/L at weeks 4, 12, 24, and 48, respectively. The viral load was 4.59 (IQR: 4.10-5.19) log10 copies/mL at baseline, and it decreased by 4.6 (IQR: 3.98-5.18) log10 copies/mL from baseline to week 48. Three of 20 (15%), 10 of 20 (50.0%), 17 of 20 (85%), and 18 of 19 (95%) participants had a plasma viral load less than 50 copies/mL at weeks 4, 12, 24, and 48, respectively. The median CD4 cell count was 330 (IQR: 237-410) cells/µL at baseline, and it increased to 473 (IQR: 344-574) cells/µL at 48 weeks. The HAMD score was 5 (IQR: 3-9.8) and 3 (IQR: 2.25-4) at baseline and 48 weeks, respectively. The PSQI score was 4 (IQR: 2-5.8) and 3 (IQR: 2-4) at baseline and 48 weeks, respectively. Dizziness was the most common event, occurring in 70% of patients within the first 2 weeks of treatment. CONCLUSION: Patients prescribed with EFV 400 mg-containing agents demonstrated favourable virological and immunological responses. And the plasma EFV concentration was within the recommended therapeutic range, with fewer adverse reactions than with EFV 600 mg. EFV 400 mg was effective and safe in Chinese HIV-infected patients. TRIAL REGISTRATION: NCT04596488 ; Registered 21 October, 2020; Retrospectively registered.


Assuntos
Alquinos/farmacocinética , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/farmacocinética , Ciclopropanos/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Alquinos/administração & dosagem , Alquinos/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Contagem de Linfócito CD4 , China , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Estudos Prospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
2.
PLoS One ; 15(12): e0242710, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362248

RESUMO

INTRODUCTION: The use of patient-reported outcomes (PROs) to systematically quantify adverse events (AE) will assist in the improvement of medical care and the QoL of patients living with HIV (PLWH). The aim of this study was to investigate the associations between self-reported side effects and other PROs, demographics and laboratory data, and further evaluate the Health Questionnaire (HQ) as a tool for following trends in patient-reported side effects over time in relation to trends in prescribed third agent in ART. MATERIALS AND METHODS: The Swedish National Registry InfCareHiv includes an annual self-reported nine-item HQwhich is used in patient-centered HIV care in all Swedish HIV units. In this study, the experience of side effects was addressed. We analyzed 9,476 HQs completed by 4,186 PLWH together with details about their prescribed ART and relevant biomarkers collected during 2011-2017. Data were analyzed using descriptive statistics, Pearson's correlation coefficient and mixed logistic regression. RESULTS: The cross-sectional analysis of the HQs showed that the frequency of reported side effects decreased from 32% (2011) to 15% (2017). During the same period, there was a shift in ART prescription from efavirenz (EFV) to dolutegravir (DTG) (positive correlation coefficient r = 0.94, p = 0.0016). Further, PLWH who reported being satisfied with their physical health (OR: 0.47, p = <0.001) or psychological health (OR: 0.70, p = 0.001) were less likely to report side effects than those less satisfied. CONCLUSIONS: Self-reported side effects were found to have a close relationship with the patient's ratings of their overall health situation and demonstrated a strong correlation with the sharp decline in use of EFV and rise in use of DTG, with reported side effects being halved. This study supports the feasibility of using the HQ as a tool for longitudinal follow up of trends in PROs.


Assuntos
Alquinos/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/efeitos adversos , Ciclopropanos/efeitos adversos , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Qualidade de Vida/psicologia , Sistema de Registros , Adulto , Alquinos/administração & dosagem , Fármacos Anti-HIV/administração & dosagem , Artralgia/induzido quimicamente , Artralgia/diagnóstico , Artralgia/fisiopatologia , Benzoxazinas/administração & dosagem , Estudos Transversais , Ciclopropanos/administração & dosagem , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/diagnóstico , Disfunção Erétil/fisiopatologia , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/fisiopatologia , Infecções por HIV/psicologia , Infecções por HIV/virologia , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/diagnóstico , Náusea/fisiopatologia , Oxazinas/administração & dosagem , Medidas de Resultados Relatados pelo Paciente , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Suécia
3.
Lancet HIV ; 7(10): e666-e676, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010240

RESUMO

BACKGROUND: ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study. METHODS: This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262. FINDINGS: Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common. INTERPRETATION: Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study. FUNDING: USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adenina/administração & dosagem , Adenina/análogos & derivados , Adolescente , Adulto , Alquinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Composição Corporal , Peso Corporal , Ciclopropanos , Duração da Terapia , Emtricitabina/administração & dosagem , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Tenofovir/administração & dosagem , Resultado do Tratamento , Carga Viral , Adulto Jovem
4.
Lancet HIV ; 7(10): e677-e687, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010241

RESUMO

BACKGROUND: Updated WHO guidelines recommend a dolutegravir-based regimen as the preferred first-line treatment for HIV infection and low-dose efavirenz (400 mg) as an alternative. We aimed to report the non-inferior efficacy of dolutegravir compared with efavirenz 400 mg at week 96. METHODS: We did a multicentre, randomised, open label, phase 3 trial in in three hospitals in Yaoundé, Cameroon, in HIV-1 infected antiretroviral-naive adults with an HIV RNA viral load of greater than 1000 copies per mL to compare dolutegravir 50 mg with efavirenz 400 mg (reference treatment), both combined with lamivudine and tenofovir disoproxil fumarate. The primary endpoint was the proportion with a viral load of less than 50 copies per mL at week 48 (10% non-inferiority margin). The study is registered with ClinicalTrials.gov, NCT02777229 and is ongoing. FINDINGS: Between July, 2016, and August, 2019, of 820 patients assessed, 613 were randomly assigned to receive at least one dose of study medication, with 310 in the dolutegravir group and 303 in the efavirenz 400 mg group. At week 96 in the intention-to-treat analysis, 229 (74%) of 310 patients receiving dolutegravir and 219 (72%) of 303 patients receiving efavirenz, achieved plasma HIV-1 RNA less than 50 copies per mL (difference 1·6%, 95% CI -5·4 to 8·6; p=0.66). Viral load suppression was reached significantly more rapidly in the dolutegravir group (p<0·001). Virological failure (>1000 copies per mL) was observed in 27 patients (eight in the dolutegravir group, among which, three women switched to efavirenz 600 mg because of the dolutegravir teratogeneicity signal, and 19 in the efavirenz 400 mg group). No acquired resistance mutations to dolutegravir were observed against 17 mutations to efavirenz with or without mutations to lamivudine and tenofovir disoproxil fumarate among the 19 efavirenz 400 mg participants with virological failure. Weight gain was greater in the dolutegravir group (median weight gain, 5·0 kg in the dolutegravir group and 3·0 kg in the efavirenz 400 mg group, p<0·001, and incidence of obesity, 22% in the dolutegravir group and 16% in the efavirenz 400 mg group, p=0·043). The incidence of new WHO HIV-related stage 3 and 4 events was similar in each group (12 [4%] in each group). The two groups had similar rates of serious adverse events (28 [9%] of 310 in the dolutegravir group and 21 [7%] of 303 in the efavirenz 400 mg group). 18 deaths were observed during the 96-week follow-up (eight in the dolutegravir group and ten in the efavirenz 400 mg group). INTERPRETATION: The non-inferior efficacy of the dolutegravir-based regimen and non-emergence of dolutegravir resistance at 96 weeks supports its use as a first-line regimen for antiretroviral-naive adults with HIV-1 infection. Viral load suppression was reached more quickly in the dolutegravir group and weight gain was significantly higher. FUNDING: UNITAID and the French National Agency for AIDS Research.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adulto , Alquinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Benzoxazinas/administração & dosagem , Contagem de Linfócito CD4 , Ciclopropanos , Duração da Terapia , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Resultado do Tratamento , Carga Viral , Adulto Jovem
5.
J Pharmacol Sci ; 144(3): 95-101, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32921396

RESUMO

Patients living with HIV in malarial endemic regions may experience clinically significant drug interaction between antiretroviral and antimalarial drugs. Effects of nevirapine (NVP), efavirenz (EFV) and lopinavir/ritonavir (LPVr) on lumefantrine (LM) therapeutic concentrations and toxicity were evaluated. In a four-arm parallel study design, the blood samples of 40 participants, treated with artemether/lumefantrine (AL), were analysed. Lumefantrine Cmax was increased by 32% (p = 0.012) and 325% (p < 0.0001) in the NVP and LPVr arms respectively but decreased by 62% (p < 0.0001) in the EFV-arm. AUC of LM was, respectively, increased by 50% (p = 0.27) and 328% (p < 0.0001) in the NVP and LPVr arms but decreased in the EFV-arm by 30% (p = 0.019). Median day 7 LM concentration was less than 280 ng/mL in EFV-arm (239 ng/mL) but higher in control (290 ng/mL), NVP (369 ng/mL, p = 0.004) and LPVr (1331 ng/mL, p < 0.0001) arms. There were no clinically relevant toxicities nor adverse events in both control and test arms. Artemether/lumefantrine is safe and effective for treatment of malaria in PLWHA taking NVP and LPVr based ART regimen but not EFV-based regimen.


Assuntos
Antirretrovirais/efeitos adversos , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Benzoxazinas/efeitos adversos , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Malária/tratamento farmacológico , Nevirapina/efeitos adversos , Adulto , Alquinos , Antirretrovirais/administração & dosagem , Antirretrovirais/sangue , Antimaláricos/administração & dosagem , Antimaláricos/sangue , Combinação Arteméter e Lumefantrina/administração & dosagem , Combinação Arteméter e Lumefantrina/sangue , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Ciclopropanos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Humanos , Lopinavir , Malária/complicações , Masculino , Pessoa de Meia-Idade , Nevirapina/administração & dosagem , Nevirapina/sangue , Nigéria , Ritonavir , Resultado do Tratamento , Adulto Jovem
6.
Life Sci ; 258: 118252, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791149

RESUMO

AIMS: This study aimed to analyze the impact of four synthesized benzoxazinone derivatives as screening drugs on c-Myc-overexpressed cancer cells (H7402, HeLa, SK-RC-42, SGC7901, and A549) and to explore their interaction mechanisms in detail. MATERIALS AND METHODS: Using morphological analysis, real-time cytotoxicity analysis, wound healing assay, reverse transcription PCR, electrophoretic mobility shift assay, and circular dichroism spectroscopy techniques. KEY FINDINGS: Results revealed that these four compounds could inhibit proliferation of SK-RC-42, SGC7901, and A549 cells in five cancer cell lines to varying degrees and significantly hinder migration. More importantly, the RT-PCR assay showed that the compounds could surprisingly downregulate the expression of c-Myc mRNA in a dose-dependent manner in the five cancer cells, which may be one of the causes of cancer cell proliferation in vitro inhibition. Further EMSA assays demonstrated that at the molecular level of DNA, four compounds can induce the formation of G-quadruplexes (G4-DNAs) in the c-Myc gene promoter. In addition, the CD result of compound 1 clearly indicates that it specifically induces a c-Myc GC-rich 36mer double-stranded DNA in the c-Myc promoter to form a G-quadruplex hybrid configuration. In conclusion, the compounds studied could dose-dependently inhibit the growth and migration of the cancer cells being investigated. This is positively associated with the reduction of overexpression of the c-Myc gene, which may be significantly regulated by the association of compounds with the G-quadruplexes produced in the c-Myc gene promoter region. SIGNIFICANCE: We conclude that three compounds merit further study, particularly against non-small-cell lung cancer, as leading compounds of anticancer drugs.


Assuntos
Antineoplásicos/administração & dosagem , Benzoxazinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Quadruplex G/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Células A549 , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7
7.
AIDS Res Ther ; 17(1): 46, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703286

RESUMO

BACKGROUND: The COVID-19 has been a severe pandemic all around the world. Nowadays the patient with co-infection of HIV and SARS-CoV-2 was rarely reported. Here we reported a special case with HIV and SARS-CoV-2 co-infection, which showed a prolonged viral shedding duration. CASE PRESENTATION: The patient was infected with HIV 8 years ago through sexual transmission and had the normal CD4+T cell count. She was found SARS-CoV-2 positive using real-time Polymerase Chain Reaction (RT-PCR) during the epidemic. Most importantly, the patient had a prolonged viral shedding duration of SARS-CoV-2 about 28 days. CONCLUSION: The viral shedding duration may be prolonged in people living with HIV. The 14 days isolation strategy might not be long enough for them. The isolation or discharge of these patients needs further confirmation for preventing epidemics.


Assuntos
Antirretrovirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por HIV/complicações , Pneumonia Viral/diagnóstico , Eliminação de Partículas Virais , Alquinos , Benzoxazinas/administração & dosagem , Betacoronavirus/genética , Betacoronavirus/imunologia , Proteína C-Reativa/análise , Contagem de Linfócito CD4 , Calafrios , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Ciclopropanos , Fadiga , Feminino , Febre , HIV/crescimento & desenvolvimento , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Hospedeiro Imunocomprometido , Imunoglobulina M/sangue , Lamivudina/administração & dosagem , Pessoa de Meia-Idade , Pandemias , Faringite , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/tratamento farmacológico , Reação em Cadeia da Polimerase em Tempo Real , Escarro/virologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Eliminação de Partículas Virais/imunologia , Zidovudina/administração & dosagem
8.
Pharm Res ; 37(6): 92, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32394200

RESUMO

PURPOSE: The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. METHODS: Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. RESULTS: 250-300 nm spherical particles with a final concentration of 4.75 mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. CONCLUSION: Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane.


Assuntos
Benzoxazinas/química , Portadores de Fármacos/química , Géis/química , Nanocápsulas/química , Álcool de Polivinil/química , Ácidos Esteáricos/química , Óleo de Girassol/química , Alquinos , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclopropanos , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Humanos , Absorção Intestinal , Masculino , Solubilidade , Suspensões/química , Distribuição Tecidual
9.
PLoS One ; 15(5): e0233693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469985

RESUMO

Efavirenz-based first-line regimens have been widely used for children ≥3 years of age starting antiretroviral therapy, despite possible resistance with prior exposure to non-nucleoside reverse transcriptase inhibitors for prevention of mother-to-child transmission (PMTCT). We used logistic regression to examine the association between PMTCT exposure and viral failure (VF) defined as two consecutive viral loads (VL)>1000 copies/ml between 6-18 months on ART. Children with previous nevirapine exposure for PMTCT were not at higher risk of VF compared to unexposed children (adjusted Odds Ratio (aOR): 0.79; 95% CI:0.56, 1.11).


Assuntos
Antirretrovirais/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV , HIV-1 , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Adolescente , Adulto , Alquinos , Criança , Pré-Escolar , Ciclopropanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Humanos , Masculino , Fatores de Risco
10.
Emerg Microbes Infect ; 9(1): 843-850, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32267205

RESUMO

Reduced doses of antiretroviral (ARV) drugs may lower toxicity while preserving efficacy. We aimed to evaluate the efficacy of reduced doses of both tenofovir disoproxil fumarate (TDF) and efavirenz for the treatment of HIV-1 infection. In this open-label, non-inferiority trial, HIV-1-infected antiretroviral-naive adults were randomly assigned to receive either a lower dose anti-retroviral regimen comprised of TDF (200 mg), efavirenz (400 mg), and standard dose lamivudine (300 mg) or the standard dose regimen. The primary endpoint was the proportion of participants with HIV-1 RNA≤ 50 copies/mL at week 48 using a non-inferiority margin of -10%. At week 48, 79 of 92 (85.9%) participants in the lower dose regimen group and 78 of 92 (84.8%) in the standard dose regimen group achieved HIV-1 RNA≤ 50 copies/mL (treatment difference 1.1%, 95% CI -9.1 to 11.3) in the intention-to-treat analysis. Drug-related adverse events occurred more frequently in the participants receiving the standard dose regimen compared with the lower dose one (63.0% vs 80.4%). Changes in estimated glomerular filtration rate and bone mineral density were comparable between the two groups. The non-inferior efficacy and better safety profile of the lower dose ARV regimen support its use as alternative initial therapy for HIV-1 infected patients.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Tenofovir/administração & dosagem , Carga Viral/efeitos dos fármacos , Adulto , Alquinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Densidade Óssea/efeitos dos fármacos , China , Ciclopropanos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Masculino , RNA Viral/sangue , Tenofovir/efeitos adversos , Resultado do Tratamento
11.
Psychopharmacology (Berl) ; 237(6): 1643-1655, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32095916

RESUMO

RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.


Assuntos
Antagonistas de Receptores de Canabinoides/administração & dosagem , Inibição Pré-Pulso/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Canabinoides/fisiologia , Esquizofrenia/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Benzoxazinas/administração & dosagem , Moduladores de Receptores de Canabinoides/administração & dosagem , Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Fluorbenzenos/administração & dosagem , Masculino , Camundongos , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Piperidinas/administração & dosagem , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Resultado do Tratamento
12.
Lancet HIV ; 7(3): e193-e200, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035041

RESUMO

BACKGROUND: The integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens. METHODS: We updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking dolutegravir at time of conception, as well as the effects of dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a dolutegravir-based regimen in others, and a dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted. FINDINGS: Considering updated information on risks and benefits, a policy of ART initiation with a dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2·9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain. INTERPRETATION: In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for dolutegravir as a preferred drug for ART initiators. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Adolescente , Adulto , África ao Sul do Saara , Alquinos , Fármacos Anti-HIV/economia , Benzoxazinas/economia , Análise Custo-Benefício , Ciclopropanos , Feminino , Infecções por HIV/economia , Infecções por HIV/transmissão , Compostos Heterocíclicos com 3 Anéis/economia , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Guias de Prática Clínica como Assunto , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/virologia , Piridonas , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
13.
J Int AIDS Soc ; 23(1): e25444, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953919

RESUMO

INTRODUCTION: Liver disease is a common cause of non-AIDS morbidity and mortality in people living with HIV (PLHIV), but the prevalence and significance of liver function test (LFT) abnormalities in early HIV infection is unknown. This study aimed to characterize LFTs in a large cohort of participants with acute HIV infection initiating immediate antiretroviral therapy (ART) and examine the association between LFTs and biomarkers of HIV infection and inflammation. METHODS: We measured LFTs at the time of HIV diagnosis and at 4, 12, 24 and 48 weeks after ART initiation in 426 Thai individuals with acute HIV infection from 2009 to 2018. A subset of individuals had data available at 96 and 144 weeks. We excluded individuals with concomitant viral hepatitis. Alanine aminotransferase (ALT) was the primary outcome of interest; values greater than 1.25 times the upper limit of normal were considered elevated. Analyses utilized descriptive statistics, non-parametric tests and multivariate logistic regression. RESULTS: Sixty-six of the 426 individuals (15.5%) had abnormal baseline ALT levels; the majority (43/66, 65.5%) had Grade 1 elevations. Elevated baseline ALT correlated with Fiebig stages III to V (p = 0.001) and baseline HIV RNA >6 log10 copies/mL (p = 0.012). Baseline elevations resolved by 48 weeks on ART in 59 of the 66 individuals (89%). ALT elevations at 24 and 48 weeks correlated with Fiebig stages I to II at diagnosis (p < 0.001), baseline plasma HIV RNA levels <6 log10 copies/mL (p < 0.001), abnormal baseline ALT (p < 0.001), baseline CD4 >350 cells/µL (p = 0.03) and older age (p = 0.03). Individuals initiating efavirenz-based regimens were more likely to have elevated ALT levels at 48 weeks compared with those on non-efavirenz-based regimens (p = 0.003). CONCLUSIONS: One in six people with acute HIV infection have elevated LFTs. Clinical outcomes with ART started in acute HIV are generally good, with resolution of ALT elevations within 48 weeks on ART in most cases. These results suggest a multifactorial model for hepatic injury involving a combination of HIV-associated and ART-associated processes, which may change over time.


Assuntos
Infecções por HIV/complicações , Hepatopatias/etiologia , Hepatopatias/fisiopatologia , Adulto , Alanina Transaminase/sangue , Alquinos , Benzoxazinas/administração & dosagem , Estudos de Coortes , Ciclopropanos , Feminino , Humanos , Hepatopatias/tratamento farmacológico , Testes de Função Hepática , Masculino , Tailândia , Adulto Jovem
14.
J Acquir Immune Defic Syndr ; 83(2): 140-147, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929402

RESUMO

BACKGROUND: The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women. METHODS: A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz. RESULTS: Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy. CONCLUSIONS: Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.


Assuntos
Antirretrovirais/farmacocinética , Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina/farmacocinética , Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Malária/tratamento farmacológico , Adolescente , Adulto , Alquinos , Fármacos Anti-HIV/farmacocinética , Antirretrovirais/administração & dosagem , Artemeter , Combinação Arteméter e Lumefantrina/administração & dosagem , Artemisininas , Benzoxazinas/administração & dosagem , Ciclopropanos , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Infecções por HIV/complicações , Humanos , Lumefantrina , Malária/complicações , Malária Falciparum/tratamento farmacológico , Gravidez , Estudos Prospectivos , Uganda , Adulto Jovem
15.
Sci Rep ; 10(1): 590, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953431

RESUMO

Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.


Assuntos
Benzoxazinas/administração & dosagem , Cuprizona/efeitos adversos , Doenças Desmielinizantes/tratamento farmacológico , Morfolinas/administração & dosagem , Bainha de Mielina/metabolismo , Naftalenos/administração & dosagem , Animais , Benzoxazinas/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Corpo Caloso/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Relação Dose-Resposta a Droga , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Morfolinas/farmacologia , Bainha de Mielina/genética , Naftalenos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo
16.
J Microbiol Immunol Infect ; 53(1): 60-68, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29884449

RESUMO

BACKGROUND: Optimal efavirenz (EFV) dose that minimizes adverse effects while maintaining efficacy has yet to be elucidated. With a therapeutic drug monitoring (TDM)-guided strategy, we assessed the effectiveness of half-a-tablet EFV plus 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) in HIV-infected Taiwanese who had achieved viral suppression with full-dose (600 mg) EFV. METHODS: HIV-infected adults receiving EFV-containing regimens who had plasma mid-dose EFV concentration (C12) ≥2.0 mg/L and had plasma HIV RNA load (PVL) <200 copies/mL were enrolled in this single-arm, open-label study by reducing EFV to half-a-tablet daily. The primary endpoint was PVL <50 copies/ml in an intention-to-treat (ITT) population at week 48. The secondary endpoints were the plasma EFV C12, the proportion of patients with plasma EFV C12 <1.0 mg/L, PVL <50 copies/ml at week 96 and week 144. RESULTS: Between April 2013 and September 2016, 203 patients (93.6% male; median age, 39.0 years) were enrolled. The median EFV C12 before switch was 2.80 mg/L (interquartile range (IQR), 2.41-3.73), which decreased to 1.59 mg/L (IQR, 1.23-2.03) after switch with a reduction of 47.4% (IQR, 38.3-55.5%). In ITT analysis, 93.6%, 92.3% and 87.3% of the patients achieved PVL <50 copies/ml at weeks 48, 96 and 144, respectively. More than 70% of the patients reported alleviation of EFV-associated adverse effects following the switch. CONCLUSION: Under the guidance of TDM, switch to half-a-tablet EFV plus 2 NRTIs is effective in maintaining viral suppression in HIV-infected Taiwanese with EFV C12 ≥ 2.0 mg/L.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/administração & dosagem , Monitoramento de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Resposta Viral Sustentada , Adulto , Alquinos , Ciclopropanos , Quimioterapia Combinada , Feminino , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Comprimidos/administração & dosagem , Carga Viral
17.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 838-844, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694094

RESUMO

Objective: To compare the efficacy and safety profiles of tiotropium/olodaterol with the mono-components in Chinese and total study population from TONADO trial. Methods: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase Ⅲ TONADO studies (TONADO 1+2), patients received tiotropium/olodaterol, tiotropium, or olodaterol via the Respimat(®) Inhaler (Boehringer Ingelheim, Germany). Primary end points were forced expiratory volume in 1 second (FEV(1)) area under the curve from 0 to 3 hours (AUC(0-3h)) response and trough FEV(1) response, and St George's respiratory questionnaire (SGRQ) total score at 24 weeks. Adverse events were also collected. This subgroup analysis only focused on the efficacy and safety of the drug at the approved dose in China. Results: 548 Chinese patients were randomized, aged 41 to 82 years [mean age, (63±8) years] and most were male (526, 96%), 111 received tiotropium/olodaterol 5/5 µg, and 127 received tiotropium 5 µg and 95 received olodaterol 5 µg. The baseline characteristics of these groups were similar. After 24 weeks, treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg and olodaterol 5 µg resulted in an adjusted mean FEV(1) AUC(0-3h) response of 0.240, 0.157 and 0.079 L, and trough FEV(1) response of 0.117, 0.068 and-0.001 L, respectively. Tiotropium/olodaterol 5/5 µg significantly improved SGRQ scores in Chinese patients compared with olodaterol 5 µg (32.729 and 37.202, respectively). Generally, the safety profile of tiotropium/olodaterol was comparable with mono-components in 52 weeks. Conclusion: Compared with tiotropium or olodaterol, tiotropium/olodaterol in Chinese patients provided significant improvement in lung function and quality of life, and the safety profiles were similar.


Assuntos
Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoxazinas/uso terapêutico , Broncodilatadores/uso terapêutico , China/epidemiologia , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Brometo de Tiotrópio/uso terapêutico , Resultado do Tratamento
18.
Int J Chron Obstruct Pulmon Dis ; 14: 2047-2060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564852

RESUMO

Background: This was the first real-world head-to-head study comparing inhaled long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination treatments as maintenance therapy. Methods: Retrospective observational study including commercial, Medicare Advantage with Part D or Part D-only enrollees aged ≥40 years from the Optum Research Database. Patients initiated umeclidinium/vilanterol (UMEC/VI) or tiotropium bromide/olodaterol (TIO/OLO) between June 1, 2015 and November 30, 2016 (index date) with 12 months of pre- and post-index continuous enrollment. Outcomes were modeled following the inverse probability of treatment weighting. The primary endpoint, rescue medication use, was modeled using weighted ordinary least squares regression with bootstrapped variance estimation. Intent-to-treat analysis evaluated non-inferiority and superiority of UMEC/VI to TIO/OLO with thresholds of 0.30 and 0 units, respectively. On-treatment sensitivity analysis evaluated the superiority of UMEC/VI to TIO/OLO for rescue medication use. The secondary endpoint, medication adherence (proportion of days covered [PDC]≥80%), was evaluated using weighted logistic regression. Post hoc weighted Cox proportional hazards regression analysis evaluated escalation to multiple inhaler triple therapy (MITT). Results: The study population included 14,324 patients; 9549 initiated UMEC/VI and 4775 initiated TIO/OLO. During the 12-month post-index period, UMEC/VI initiators used 0.16 fewer adjusted mean units of rescue medication than TIO/OLO initiators (95% CI: -0.28, -0.04), meeting pre-specified non-inferiority (P<0.001) and superiority (P=0.005) criteria; the on-treatment sensitivity analysis for superiority was not statistically significant. Significantly more UMEC/VI than TIO/OLO initiators (28.6% vs 22.7%; P<0.001) achieved a clinically meaningful level (PDC≥80%) of medication adherence. The adjusted risk of escalation to MITT was similar between treatment groups (HR=0.93; 95% CI: 0.81, 1.06; P=0.268). Conclusion: UMEC/VI was superior to TIO/OLO for rescue medication use and UMEC/VI initiators had better medication adherence than TIO/OLO initiators. This study supports findings from a head-to-head trial that demonstrated significant, clinically meaningful improvements in lung function with UMEC/VI versus TIO/OLO.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Benzoxazinas/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Pulmão/efeitos dos fármacos , Adesão à Medicação , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Benzoxazinas/efeitos adversos , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Progressão da Doença , Combinação de Medicamentos , Feminino , Humanos , Pulmão/fisiopatologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento , Estados Unidos
19.
SEMERGEN, Soc. Esp. Med. Rural Gen. (Ed. Impr.) ; 45(7): 479-488, oct. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-189281

RESUMO

El curso natural de la enfermedad pulmonar obstructiva crónica incluye habitualmente exacerbaciones. Los pacientes con enfermedad pulmonar obstructiva crónica sufren de 1-4 exacerbaciones al año de media. Estas se asocian a un empeoramiento de la calidad de vida y a un aumento de la mortalidad. Disminuir y controlar el número de exacerbaciones es uno de los objetivos principales del tratamiento de la enfermedad pulmonar obstructiva crónica. Entre los tratamientos actuales, tiotropio es el principio activo que dispone de la evidencia más sólida en la reducción de exacerbaciones moderadas/graves, acompañado de un buen perfil de seguridad y tolerabilidad. La suma de olodaterol a tiotropio ofrece una doble broncodilatación bien tolerada y eficaz en la mejora de la función pulmonar, calidad de vida y disminución de la disnea en comparación con sus monocomponentes, y reduce un 7% la tasa anual de exacerbaciones moderadas/graves vs. tiotropio, no alcanzando el nivel de significación estadística preespecificado de p < 0,01


The natural course of chronic obstructive pulmonary disease usually includes exacerbations. chronic obstructive pulmonary disease patients suffer from 1-4 exacerbations per year on average. These are associated with worsening quality of life and increased mortality. Reducing and controlling the number of exacerbations is one of the main goals of chronic obstructive pulmonary disease treatment. Among current treatments, tiotropium is the active substance with the strongest evidence in the reduction of moderate/severe exacerbations, together with a good safety and tolerability profile. The addition of olodaterol to tiotropium offers well-tolerated and effective double bronchodilation for improving lung function, quality of life, and decreased dyspnoea compared to its single components. This also reduces the annual rate of moderate/severe exacerbations vs. tiotropium by 7%, although not reaching the pre-specified statistical significance level of P<.01


Assuntos
Humanos , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Broncodilatadores/efeitos adversos , Tratamento Farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/efeitos adversos
20.
Respir Med ; 157: 59-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31522031

RESUMO

BACKGROUND: Hyperinflation has been associated with negative cardiocirculatory consequences in patients with chronic obstructive pulmonary disease (COPD). These abnormalities are likely to worsen when the demands for O2 increase, e.g., under the stress of exercise. Thus, pharmacologically-induced lung deflation may improve cardiopulmonary interactions and exertional cardiac output leading to higher limb muscle blood flow and oxygenation in hyperinflated patients with COPD. METHODS: 20 patients (residual volume = 201.6 ±â€¯63.6% predicted) performed endurance cardiopulmonary exercise tests (75% peak) 1 h after placebo or tiotropium/olodaterol 5/5 µg via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Cardiac output was assessed by signal-morphology impedance cardiography. Near-infrared spectroscopy determined quadriceps blood flow (indocyanine green dye) and intra-muscular oxygenation. RESULTS: Tiotropium/olodaterol was associated with marked lung deflation (p < 0.01): residual volume decreased by at least 0.4 L in 14/20 patients (70%). The downward shift in the resting static lung volumes was associated with less exertional inspiratory constraints and dyspnoea thereby increasing exercise endurance by ~50%. Contrary to our premises, however, neither central and peripheral hemodynamics nor muscle oxygenation improved after active intervention compared to placebo. These results were consistent with those found in a subgroup of patients showing the largest decrements in residual volume (p < 0.05). CONCLUSIONS: The beneficial effects of tiotropium/olodaterol on resting and operating lung volumes are not translated into enhanced cardiocirculatory responses to exertion in hyperinflated patients with COPD. Improvement in exercise tolerance after dual bronchodilation is unlikely to be mechanistically linked to higher muscle blood flow and/or O2 delivery.


Assuntos
Benzoxazinas/efeitos adversos , Broncodilatadores/efeitos adversos , Débito Cardíaco/efeitos dos fármacos , Atelectasia Pulmonar/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Brometo de Tiotrópio/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Benzoxazinas/administração & dosagem , Benzoxazinas/uso terapêutico , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , Estudos de Casos e Controles , Estudos Cross-Over , Estudos Transversais , Combinação de Medicamentos , Dispneia/fisiopatologia , Teste de Esforço/métodos , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Oxigênio/metabolismo , Esforço Físico/efeitos dos fármacos , Placebos/administração & dosagem , Músculo Quadríceps/irrigação sanguínea , Músculo Quadríceps/diagnóstico por imagem , Músculo Quadríceps/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Volume Residual/efeitos dos fármacos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/uso terapêutico
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