Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30.033
Filtrar
1.
Cell ; 183(1): 169-184.e13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931734

RESUMO

The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread.


Assuntos
Infecções por Coronavirus/imunologia , Imunogenicidade da Vacina , Pneumonia Viral/imunologia , Vacinas Virais/imunologia , Adenoviridae/genética , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Humanos , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , Pneumonia Viral/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero , Vacinas Virais/administração & dosagem
2.
Lancet ; 396(10255): 887-897, 2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-32896291

RESUMO

BACKGROUND: We developed a heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine. METHODS: We did two open, non-randomised phase 1/2 studies at two hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18-60 years to both studies. In phase 1 of each study, we administered intramuscularly on day 0 either one dose of rAd26-S or one dose of rAd5-S and assessed the safety of the two components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered intramuscularly a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (number of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a SARS-CoV-2 neutralisation assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875. FINDINGS: Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation. INTERPRETATION: The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19. FUNDING: Ministry of Health of the Russian Federation.


Assuntos
Infecções por Coronavirus/prevenção & controle , Imunização Secundária , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Adenoviridae , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus , Infecções por Coronavirus/imunologia , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulina G/sangue , Injeções Intramusculares , Masculino , Federação Russa , Vacinas Virais/efeitos adversos , Adulto Jovem
3.
Lancet ; 396(10255): 887-897, 2020 09 26.
Artigo em Inglês | MEDLINE | ID: covidwho-748093

RESUMO

BACKGROUND: We developed a heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine. METHODS: We did two open, non-randomised phase 1/2 studies at two hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18-60 years to both studies. In phase 1 of each study, we administered intramuscularly on day 0 either one dose of rAd26-S or one dose of rAd5-S and assessed the safety of the two components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered intramuscularly a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (number of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a SARS-CoV-2 neutralisation assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875. FINDINGS: Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation. INTERPRETATION: The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19. FUNDING: Ministry of Health of the Russian Federation.


Assuntos
Infecções por Coronavirus/prevenção & controle , Imunização Secundária , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Adenoviridae , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus , Infecções por Coronavirus/imunologia , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulina G/sangue , Injeções Intramusculares , Masculino , Federação Russa , Vacinas Virais/efeitos adversos , Adulto Jovem
4.
Cell ; 183(1): 169-184.e13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: covidwho-720448

RESUMO

The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread.


Assuntos
Infecções por Coronavirus/imunologia , Imunogenicidade da Vacina , Pneumonia Viral/imunologia , Vacinas Virais/imunologia , Adenoviridae/genética , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Humanos , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Pandemias , Pneumonia Viral/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero , Vacinas Virais/administração & dosagem
5.
Artigo em Russo | MEDLINE | ID: mdl-32790979

RESUMO

OBJECTIVE: A retrospective analysis of the experience of using Incobotulinum toxin A injections for the treatment of spasticity in children with cerebral palsy (CP). MATERIAL AND METHODS: One hundred and eighty-five children with spastic forms of CP, including 114 boys (61,6%), were studied. The average age of the patients was 3,8±2,5 years; the average weight was 14,2±6,9. The patients received injections of Incobotulinum toxin A according to registered indications or recommendations of a consultation of specialists and voluntary informed consent of the patient's representative. At least 1 point decrease of muscle tone according to the modified Ashworth scale was used as a criterion of the antispastic effect of Incobotulinum toxin A. RESULTS: The total dose of Incobotulinum toxin A for the whole group of patients with CP was 154,5±67,7 U and 11,6±4,7 U per kg/body weight. The gracilis muscle (65,4% of cases, 95%CI 58,1-72,2) and the gastrocnemius muscle (49,4% of cases, 95%CI 41,8-56,6) were the most frequently injected targets in the lower extremities, and the pronator teres muscle (58,9% of cases, 95%CI 51,5-66,1) - in the upper extremities. Adverse events were observed in 13 patients (7,0%). They were mild in 9 patients and moderate in 4 patients. CONCLUSION: Our data confirmed the effectiveness and safety of Incobotulinum toxin A injections in spastic CP. The calculated average doses of Incobotulinum toxin A for target muscles and the frequency of different spasticity patterns could serve as a reference for the botulinum therapy planning.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Paralisia Cerebral/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Criança , Pré-Escolar , Humanos , Injeções Intramusculares , Masculino , Espasticidade Muscular/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
6.
Medicine (Baltimore) ; 99(34): e21830, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846828

RESUMO

Brachial plexus birth palsy (BPBP) is a neurologic injury that can result in mild to full paralysis of the affected upper extremity. In severe cases, nerve surgery is often performed before age 1 year. Several studies report gains in elbow flexion with onabotulinum toxin type A (OBTT-A) injections to the triceps; however, its use in infants is not widely reported. The purpose of this study is to present our experience using these injections before 6 months of age to therapeutically unmask elbow flexion and diagnostically guide surgical decision making.This is a retrospective observational cohort study. The cohort included infants with BPBP who received OBTT-A injection to the triceps before age 6 months. Indications for the injections include trace elbow flexion and palpable co-contraction of the biceps and triceps. Elbow flexion was evaluated using the Toronto Test score. Therapeutic success was defined as an increase in post-injection scores. These scores were then used diagnostically as an indication for surgery if the infant did not achieve full elbow flexion by 8 months. A treatment algorithm for OBTT-A triceps injection was developed based on all treatment options offered to infants with elbow flexion deficits seen in the clinic.Of the 12 infants that received OBTT-A triceps injections, 10 (83%) had improved Toronto test elbow flexion scores post-injection. Gains in elbow flexion once attained were maintained. Of the 9 OBTT-A infants with at least 2 years follow-up, 4 achieved full elbow flexion without surgery; the remainder after surgery. No complications with OBTT-A injections were noted and patients were followed on average 6 years. The average age at time of injection was 4 months (range: 2-5 months). Compared to other treatments given, OBTT-A infants tended to present with more elbow flexion than the 4 infants requiring immediate surgical intervention and less elbow flexion than the 16 infants treated conservatively.OBTT-A injection to the triceps in infants with BPBP before 6 months of age therapeutically improved elbow flexion and diagnostically guided surgical decisions when full elbow flexion was not achieved by 8 months of age with no known complications.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Articulação do Cotovelo/fisiopatologia , Músculo Esquelético/fisiopatologia , Paralisia do Plexo Braquial Neonatal/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Amplitude de Movimento Articular/efeitos dos fármacos , Braço , Toxinas Botulínicas Tipo A/administração & dosagem , Criança , Pré-Escolar , Tomada de Decisão Clínica , Seguimentos , Humanos , Lactente , Injeções Intramusculares , Paralisia do Plexo Braquial Neonatal/fisiopatologia , Paralisia do Plexo Braquial Neonatal/cirurgia , Fármacos Neuromusculares/administração & dosagem , Estudos Retrospectivos
7.
Medicine (Baltimore) ; 99(34): e21846, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846833

RESUMO

INTRODUCTION: Stroke often causes residual hemiparesis, and upper extremity motor impairment is usually more disabling than lower extremity in those who are suffering from post-stroke hemiparesis. Cell therapy is one of the promising therapies to reduce post-stroke disability. PATIENT CONCERNS: Three male participants were included in the study to investigate the feasibility and tolerability of autologous adipose tissue derived stromal vascular fraction. DIAGNOSIS: All participants had hemiparesis after 1st-ever stroke longer than 6 months previously. INTERVENTIONS: Under general anesthesia, liposuction of abdominal subcutaneous fat was performed. Stromal vascular fraction freshly isolated from the adipose tissue extract was injected into the muscles of paretic upper extremity. All participants received inpatient stroke rehabilitation consisted of physical and occupational therapy more than 3 hours a day for 2 months or more. OUTCOMES: The whole procedure did not produce any significant adverse event in all participants. Adipose tissue extracts yielded sufficient stromal cells. One participant showed clinically important change in upper extremity Fugl-Meyer assessment after the injection and it lasted up to 6 months. Functional magnetic resonance imaging showed concomitant increase in ipsilesional cortical activity. The other 2 participants did not show remarkable changes. LESSONS: Intramuscular injection of autologous adipose tissue derived stromal vascular fraction seems to be a safe and tolerable procedure in subjects with chronic stroke, and its utility in rehabilitation needs further investigation.


Assuntos
Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/transplante , Transplante de Células-Tronco Mesenquimais/métodos , Reabilitação do Acidente Vascular Cerebral/métodos , Células Estromais/transplante , Tecido Adiposo/citologia , Adulto , Hemorragia Cerebral/complicações , Humanos , Injeções Intramusculares , Lipectomia/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Células-Tronco Mesenquimais , Terapia Ocupacional/métodos , Paresia/fisiopatologia , Paresia/reabilitação , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Células Estromais/citologia , Extremidade Superior/fisiopatologia
8.
Cell ; 182(5): 1271-1283.e16, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32795413

RESUMO

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.


Assuntos
RNA Mensageiro/genética , RNA Viral/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , Chlorocebus aethiops , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Células HeLa , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Th1/imunologia , Potência de Vacina , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Células Vero , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
9.
Cochrane Database Syst Rev ; 8: CD004834, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853410

RESUMO

BACKGROUND: On the American continent, cutaneous and mucocutaneous leishmaniasis (CL and MCL) are diseases associated with infection by several species of Leishmania parasites. Pentavalent antimonials remain the first-choice treatment. There are alternative interventions, but reviewing their effectiveness and safety is important as availability is limited. This is an update of a Cochrane Review first published in 2009. OBJECTIVES: To assess the effects of interventions for all immuno-competent people who have American cutaneous and mucocutaneous leishmaniasis (ACML). SEARCH METHODS: We updated our database searches of the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and CINAHL to August 2019. We searched five trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing either single or combination treatments for ACML in immuno-competent people, diagnosed by clinical presentation and Leishmania infection confirmed by smear, culture, histology, or polymerase chain reaction on a biopsy specimen. The comparators were either no treatment, placebo only, or another active compound. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our key outcomes were the percentage of participants 'cured' at least three months after the end of treatment, adverse effects, and recurrence. We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 75 studies (37 were new), totalling 6533 randomised participants with ATL. The studies were mainly conducted in Central and South America at regional hospitals, local healthcare clinics, and research centres. More male participants were included (mean age: roughly 28.9 years (SD: 7.0)). The most common confirmed species were L. braziliensis, L. panamensis, and L. mexicana. The most assessed interventions and comparators were non-antimonial systemics (particularly oral miltefosine) and antimonials (particularly meglumine antimoniate (MA), which was also a common intervention), respectively. Three studies included moderate-to-severe cases of mucosal leishmaniasis but none included cases with diffuse cutaneous or disseminated CL, considered the severe cutaneous form. Lesions were mainly ulcerative and located in the extremities and limbs. The follow-up (FU) period ranged from 28 days to 7 years. All studies had high or unclear risk of bias in at least one domain (especially performance bias). None of the studies reported the degree of functional or aesthetic impairment, scarring, or quality of life. Compared to placebo, at one-year FU, intramuscular (IM) MA given for 20 days to treat L. braziliensis and L. panamensis infections in ACML may increase the likelihood of complete cure (risk ratio (RR) 4.23, 95% confidence interval (CI) 0.84 to 21.38; 2 RCTs, 157 participants; moderate-certainty evidence), but may also make little to no difference, since the 95% CI includes the possibility of both increased and reduced healing (cure rates), and IMMA probably increases severe adverse effects such as myalgias and arthralgias (RR 1.51, 95% CI 1.17 to 1.96; 1 RCT, 134 participants; moderate-certainty evidence). IMMA may make little to no difference to the recurrence risk, but the 95% CI includes the possibility of both increased and reduced risk (RR 1.79, 95% CI 0.17 to 19.26; 1 RCT, 127 participants; low-certainty evidence). Compared to placebo, at six-month FU, oral miltefosine given for 28 days to treat L. mexicana, L. panamensis and L. braziliensis infections in American cutaneous leishmaniasis (ACL) probably improves the likelihood of complete cure (RR 2.25, 95% CI 1.42 to 3.38), and probably increases nausea rates (RR 3.96, 95% CI 1.49 to 10.48) and vomiting (RR 6.92, 95% CI 2.68 to 17.86) (moderate-certainty evidence). Oral miltefosine may make little to no difference to the recurrence risk (RR 2.97, 95% CI 0.37 to 23.89; low-certainty evidence), but the 95% CI includes the possibility of both increased and reduced risk (all based on 1 RCT, 133 participants). Compared to IMMA, at 6 to 12 months FU, oral miltefosine given for 28 days to treat L. braziliensis, L. panamensis, L. guyanensis and L. amazonensis infections in ACML may make little to no difference to the likelihood of complete cure (RR 1.05, 95% CI 0.90 to 1.23; 7 RCTs, 676 participants; low-certainty evidence). Based on moderate-certainty evidence (3 RCTs, 464 participants), miltefosine probably increases nausea rates (RR 2.45, 95% CI 1.72 to 3.49) and vomiting (RR 4.76, 95% CI 1.82 to 12.46) compared to IMMA. Recurrence risk was not reported. For the rest of the key comparisons, recurrence risk was not reported, and risk of adverse events could not be estimated. Compared to IMMA, at 6 to 12 months FU, oral azithromycin given for 20 to 28 days to treat L. braziliensis infections in ACML probably reduces the likelihood of complete cure (RR 0.51, 95% CI 0.34 to 0.76; 2 RCTs, 93 participants; moderate-certainty evidence). Compared to intravenous MA (IVMA) and placebo, at 12 month FU, adding topical imiquimod to IVMA, given for 20 days to treat L. braziliensis, L. guyanensis and L. peruviana infections in ACL probably makes little to no difference to the likelihood of complete cure (RR 1.30, 95% CI 0.95 to 1.80; 1 RCT, 80 participants; moderate-certainty evidence). Compared to MA, at 6 months FU, one session of local thermotherapy to treat L. panamensis and L. braziliensis infections in ACL reduces the likelihood of complete cure (RR 0.80, 95% CI 0.68 to 0.95; 1 RCT, 292 participants; high-certainty evidence). Compared to IMMA and placebo, at 26 weeks FU, adding oral pentoxifylline to IMMA to treat CL (species not stated) probably makes little to no difference to the likelihood of complete cure (RR 0.86, 95% CI 0.63 to 1.18; 1 RCT, 70 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Evidence certainty was mostly moderate or low, due to methodological shortcomings, which precluded conclusive results. Overall, both IMMA and oral miltefosine probably result in an increase in cure rates, and nausea and vomiting are probably more common with miltefosine than with IMMA. Future trials should investigate interventions for mucosal leishmaniasis and evaluate recurrence rates of cutaneous leishmaniasis and its progression to mucosal disease.


Assuntos
Leishmaniose Cutânea/terapia , Administração Oral , Adulto , Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Vacina BCG/uso terapêutico , Feminino , Humanos , Hipertermia Induzida , Imunocompetência , Injeções Intramusculares , Injeções Intravenosas , Interferon gama/uso terapêutico , Vacinas contra Leishmaniose/uso terapêutico , Leishmaniose Mucocutânea/terapia , Masculino , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/efeitos adversos , Pentoxifilina/administração & dosagem , Pentoxifilina/efeitos adversos , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Cell ; 182(5): 1271-1283.e16, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: covidwho-666099

RESUMO

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.


Assuntos
RNA Mensageiro/genética , RNA Viral/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , Chlorocebus aethiops , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Células HeLa , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Th1/imunologia , Potência de Vacina , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Células Vero , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
11.
N Engl J Med ; 383(5): 415-425, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32726528

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose. METHODS: In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose. RESULTS: From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P<0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions. CONCLUSIONS: A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antivirais/administração & dosagem , Recém-Nascido Prematuro , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano , Infecções Respiratórias/prevenção & controle , Proteínas Virais de Fusão/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Antivirais/efeitos adversos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Lactente , Recém-Nascido , Injeções Intramusculares , Estimativa de Kaplan-Meier , Masculino , Distribuição de Poisson , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia
12.
N Engl J Med ; 383(5): 426-439, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32726529

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).


Assuntos
Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano , Infecções Respiratórias/prevenção & controle , Adolescente , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hipóxia/etiologia , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Doenças do Recém-Nascido/prevenção & controle , Injeções Intramusculares , Nanopartículas , Distribuição de Poisson , Gravidez , Terceiro Trimestre da Gravidez , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sincicial Respiratório Humano/imunologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Vacinação , Proteínas Virais de Fusão/imunologia , Adulto Jovem
13.
J Clin Psychiatry ; 81(4)2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32609958

RESUMO

The goals of schizophrenia treatment are to control symptoms, prevent relapse, and improve functioning and quality of life. For many patients, these goals are not being met. This report highlights information provided by experts on the reasons for, impact of, and means to reduce relapse in patients with schizophrenia; on patient-centered and patient-reported assessment; on the benefits and risks of medication options, including long-acting injectable (LAI) antipsychotics; and on psychosocial interventions that may improve adherence and help prevent relapse in individuals living with schizophrenia. Modifiable risk factors for poor outcomes in patients with schizophrenia include longer duration of untreated illness, comorbid substance abuse, early nonresponse to an antipsychotic, and the number of relapses that are related to nonadherence. Recommendations include 1) adopting a patient-centered approach that incorporates the use of patient-reported outcome measures; 2) selecting medications based on a balanced risk-benefit assessment, including a focus on addressing symptoms for which the agents were superior to placebo and/or active controls; 3) considering LAIs as an alternative to oral medications, as they offer benefits such as reliable drug delivery, uncovering nonadherence and pseudo-resistance, and reduced relapse risk and mortality; and 4) implementing psychosocial interventions that have been proven to be effective in improving adherence and overall outcomes.


Assuntos
Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Terapia Combinada/métodos , Preparações de Ação Retardada/uso terapêutico , Humanos , Injeções Intramusculares , Adesão à Medicação , Psicoterapia , Esquizofrenia/terapia , Prevenção Secundária
14.
J Clin Psychiatry ; 81(4)2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32609960

RESUMO

OBJECTIVE: INP105 is a drug-device combination of olanzapine and technology that delivers a powder formulation of olanzapine to the vascular-rich upper nasal space. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single ascending doses of INP105, olanzapine intramuscular (OLZ IM), and olanzapine oral disintegrating tablet (OLZ ODT). METHODS: This was a phase 1, active and double-blind placebo comparator-controlled, ascending-dose, 2-period, incomplete-block, 1-way crossover study in 40 healthy subjects, randomized to single doses of OLZ IM (5 or 10 mg) or OLZ ODT (10 mg) in Period 1 and then 1 of 3 doses (5 mg, 10 mg, or 15 mg) of INP105 or placebo in Period 2 between July and October 2018. Sedation and attention were evaluated by visual analog scale (VAS), the Agitation/Calmness Evaluation Scale (ACES), and the Digit Symbol Substitution Test (DSST). RESULTS: At equivalent doses, INP105 provided similar area under the drug concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity, and maximum observed concentration (Cmax) as OLZ IM and greater Cmax than but similar AUCs to OLZ ODT. Median time to maximum concentration was less for INP105 (15, 10, and 9.5 min for 5 mg, 10 mg, and 15 mg, respectively) than for OLZ IM (20 and 15 min for 5 mg and 10 mg, respectively) or OLZ ODT (120 min). Effects as measured with the VAS, ACES, and DSST with INP105 5 mg were comparable to those with OLZ IM 5 mg, with earlier onset for INP105 10 mg and 15 mg and greater effects than placebo and OLZ ODT. The incidence of treatment-emergent adverse events with INP105 5 mg, 10 mg, and 15 mg was 80%, 66.7%, and 75%, respectively, compared to 90% and 100% for OLZ IM 5 mg and 10 mg, respectively, and 83.3% for OLZ ODT; most common were dizziness, hypotension, and orthostatic symptoms. CONCLUSIONS: INP105 has rapid absorption and pharmacodynamic effects and may represent an effective, convenient, noninvasive, and well-tolerated alternative for treating acutely agitated patients by self- or caregiver administration in the home, community, or hospital environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03624322.


Assuntos
Olanzapina/efeitos adversos , Olanzapina/farmacocinética , Administração Intranasal , Administração Oral , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Atenção/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Olanzapina/administração & dosagem , Olanzapina/farmacologia , Adulto Jovem
15.
Aust Vet J ; 98(10): 511-516, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32643182

RESUMO

OBJECTIVE: To characterise intramuscular ketamine-medetomidine-tramadol anaesthesia in hatchling green sea turtles (Chelonia mydas). STUDY DESIGN: Prospective clinical trial. ANIMALS: Ten hatchling green sea turtles. MATERIALS AND METHODS: Prior to anaesthesia, cardiopulmonary parameters, cloacal temperature, and venous blood gas and biochemistry were obtained from hatchling green sea turtles while they were being gently restrained. Animals were then anaesthetised with ketamine (5 mg kg-1 ), medetomidine (0.05 mg kg-1 ) and tramadol (5 mg kg-1 ) via intramuscular injection. Turtles were checked for the depth of anaesthesia at five-min intervals by recording reflexes (righting, palpebral, pinch, cloacal) and measuring heart rate, respiratory rate and cloacal temperature. After 20 min, a second venous blood sample was obtained for further blood gas and biochemical analysis and the medetomidine was antagonised using atipamezole (5:1 medetomidine, 0.25 mg kg-1 ). RESULTS: All turtles were successfully anaesthetised with a mean time to induction of 3.4 min (±1). In all animals, a loss of reflexes (except for palpebral reflex) and voluntary movement was observed for the entire 20 min. Anaesthesia resulted in marked apnoea for the duration of the procedure. Venous blood gas and biochemistry analysis indicated that a 20 min period of apnoea had no measurable effects on venous blood gas results. All turtles recovered uneventfully after atipamazole antagonisation, with a mean time to first breath 4.5 min (±3.7), and mean recovery time 15.5 min (±15.4). CONCLUSIONS AND CLINICAL RELEVANCE: Intramuscular ketamine-medetomidine-tramadol, antagonised with atipamazole appears to be an effective anaesthetic protocol in hatchling green sea turtles for short procedures with no deleterious effects on venous blood gases or biochemistry.


Assuntos
Anestesia/veterinária , Ketamina , Tramadol , Tartarugas , Anestésicos Combinados , Animais , Injeções Intramusculares/veterinária , Medetomidina , Estudos Prospectivos
18.
Front Immunol ; 11: 1091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574263

RESUMO

Numerous clinical trials of mesenchymal stromal/stem cells (MSCs) as a new treatment for coronavirus-induced disease (COVID-19) have been registered recently, most of them based on intravenous (IV) infusion. There is no approved effective therapy for COVID-19, but MSC therapies have shown first promise in the treatment of acute respiratory distress syndrome (ARDS) pneumonia, inflammation, and sepsis, which are among the leading causes of mortality in COVID-19 patients. Many of the critically ill COVID-19 patients are in a hypercoagulable procoagulant state and at high risk for disseminated intravascular coagulation, thromboembolism, and thrombotic multi-organ failure, another cause of high fatality. It is not yet clear whether IV infusion is a safe and effective route of MSC delivery in COVID-19, since MSC-based products express variable levels of highly procoagulant tissue factor (TF/CD142), compromising the cells' hemocompatibility and safety profile. Of concern, IV infusions of poorly characterized MSC products with unchecked (high) TF/CD142 expression could trigger blood clotting in COVID-19 and other vulnerable patient populations and further promote the risk for thromboembolism. In contrast, well-characterized products with robust manufacturing procedures and optimized modes of clinical delivery hold great promise for ameliorating COVID-19 by exerting their beneficial immunomodulatory effects, inducing tissue repair and organ protection. While the need for MSC therapy in COVID-19 is apparent, integrating both innate and adaptive immune compatibility testing into the current guidelines for cell, tissue, and organ transplantation is critical for safe and effective therapies. It is paramount to only use well-characterized, safe MSCs even in the most urgent and experimental treatments. We here propose three steps to mitigate the risk for these vulnerable patients: (1) updated clinical guidelines for cell and tissue transplantation, (2) updated minimal criteria for characterization of cellular therapeutics, and (3) updated cell therapy routines reflecting specific patient needs.


Assuntos
Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Pneumonia Viral/terapia , Imunologia de Transplantes , Administração Intravenosa , Transtornos da Coagulação Sanguínea/etiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Guias como Assunto , Humanos , Injeções Intramusculares , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia
19.
Sci Adv ; 6(24): eaba8399, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32577525

RESUMO

Developing a vaccine to protect against the lethal effects of the many strains of coronavirus is critical given the current global pandemic. For Middle East respiratory syndrome coronavirus (MERS-CoV), we show that rhesus macaques seroconverted rapidly after a single intramuscular vaccination with ChAdOx1 MERS. The vaccine protected against respiratory injury and pneumonia and reduced viral load in lung tissue by several orders of magnitude. MERS-CoV replication in type I and II pneumocytes of ChAdOx1 MERS-vaccinated animals was absent. A prime-boost regimen of ChAdOx1 MERS boosted antibody titers, and viral replication was completely absent from the respiratory tract tissue of these rhesus macaques. We also found that antibodies elicited by ChAdOx1 MERS in rhesus macaques neutralized six different MERS-CoV strains. Transgenic human dipeptidyl peptidase 4 mice vaccinated with ChAdOx1 MERS were completely protected against disease and lethality for all different MERS-CoV strains. The data support further clinical development of ChAdOx1 MERS.


Assuntos
Imunogenicidade da Vacina/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Vacinação , Vacinas Virais/administração & dosagem , Vacinas Virais/uso terapêutico , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Dipeptidil Peptidase 4/genética , Feminino , Humanos , Injeções Intramusculares , Macaca mulatta , Masculino , Camundongos , Camundongos Transgênicos , Pneumonia Viral/prevenção & controle , Índice de Gravidade de Doença , Resultado do Tratamento , Vacinas Virais/imunologia , Replicação Viral/imunologia
20.
J Clin Psychiatry ; 81(4)2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32558403

RESUMO

People with bipolar I disorder experience an illness course marked by potentially disastrous manic episodes, disabling depressive episodes, and functional impairment. A frequent obstacle to wellness in these individuals is nonadherence to treatment. Long-acting injectable (LAI) antipsychotics have the potential to address nonadherence and thereby increase patients' chances at sustained recovery and normal psychosocial functioning. LAI formulations of 2 second-generation antipsychotics-aripiprazole monohydrate and risperidone-have received approval from the US Food and Drug Administration as monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adult patients. In a recent roundtable meeting, a panel of 4 experts discussed the use of these medications in bipolar I disorder. This Academic Highlights summarizes their discussion, which included the impact of functional impairment, the potential benefits of employing an LAI antipsychotic at earlier stages of bipolar illness, and the characteristics of patients who may be good candidates for treatment with an LAI antipsychotic.


Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Seleção de Pacientes , Risperidona/uso terapêutico , Aripiprazol/administração & dosagem , Análise Custo-Benefício , Preparações de Ação Retardada/uso terapêutico , Humanos , Injeções , Injeções Intramusculares , Adesão à Medicação , Guias de Prática Clínica como Assunto , Risperidona/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA