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1.
Front Immunol ; 15: 1357731, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38784379

RESUMEN

Long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the identification of T-cell epitopes affecting host immunogenicity. In this computational study, we explored the CD8+ epitope diversity estimated in 27 of the most common HLA-A and HLA-B alleles, representing most of the United States population. Analysis of 16 SARS-CoV-2 variants [B.1, Alpha (B.1.1.7), five Delta (AY.100, AY.25, AY.3, AY.3.1, AY.44), and nine Omicron (BA.1, BA.1.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1, XBB.1, XBB.1.5)] in analyzed MHC class I alleles revealed that SARS-CoV-2 CD8+ epitope conservation was estimated at 87.6%-96.5% in spike (S), 92.5%-99.6% in membrane (M), and 94.6%-99% in nucleocapsid (N). As the virus mutated, an increasing proportion of S epitopes experienced reduced predicted binding affinity: 70% of Omicron BQ.1-XBB.1.5 S epitopes experienced decreased predicted binding, as compared with ~3% and ~15% in the earlier strains Delta AY.100-AY.44 and Omicron BA.1-BA.5, respectively. Additionally, we identified several novel candidate HLA alleles that may be more susceptible to severe disease, notably HLA-A*32:01, HLA-A*26:01, and HLA-B*53:01, and relatively protected from disease, such as HLA-A*31:01, HLA-B*40:01, HLA-B*44:03, and HLA-B*57:01. Our findings support the hypothesis that viral genetic variation affecting CD8 T-cell epitope immunogenicity contributes to determining the clinical severity of acute COVID-19. Achieving long-term COVID-19 immunity will require an understanding of the relationship between T cells, SARS-CoV-2 variants, and host MHC class I genetics. This project is one of the first to explore the SARS-CoV-2 CD8+ epitope diversity that putatively impacts much of the United States population.


Asunto(s)
COVID-19 , Biología Computacional , Epítopos de Linfocito T , SARS-CoV-2 , Humanos , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , SARS-CoV-2/inmunología , SARS-CoV-2/genética , COVID-19/inmunología , COVID-19/virología , Estados Unidos/epidemiología , Biología Computacional/métodos , Linfocitos T CD8-positivos/inmunología , Antígenos HLA-B/genética , Antígenos HLA-B/inmunología , Alelos , Antígenos HLA-A/genética , Antígenos HLA-A/inmunología , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética
2.
Microbiol Spectr ; 12(1): e0235123, 2024 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-38018984

RESUMEN

IMPORTANCE: The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline's efficacy in addressing the pressing global challenge of MDR bacterial infections.


Asunto(s)
Antibacterianos , Tetraciclinas , Humanos , Estudios Retrospectivos , Tetraciclinas/uso terapéutico , Tetraciclinas/farmacología , Antibacterianos/efectos adversos , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Evaluación de Resultado en la Atención de Salud , Bacterias Gramnegativas
3.
BMC Microbiol ; 23(1): 225, 2023 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-37596530

RESUMEN

INTRODUCTION: Whole genome sequencing (WGS) of bacterial isolates can be used to identify antimicrobial resistance (AMR) genes. Previous studies have shown that genotype-based AMR has variable accuracy for predicting carbapenem resistance in carbapenem-resistant Enterobacterales (CRE); however, the majority of these studies used short-read platforms (e.g. Illumina) to generate sequence data. In this study, our objective was to determine whether Oxford Nanopore Technologies (ONT) long-read WGS would improve detection of carbapenem AMR genes with respect to short-read only WGS for nine clinical CRE samples. We measured the minimum inhibitory breakpoint (MIC) using two phenotype assays (MicroScan and ETEST) for six antibiotics, including two carbapenems (meropenem and ertapenem) and four non-carbapenems (gentamicin, ciprofloxacin, cefepime, and trimethoprim/sulfamethoxazole). We generated short-read data using the Illumina NextSeq and long-read data using the ONT MinION. Four assembly methods were compared: ONT-only assembly; ONT-only assembly plus short-read polish; ONT + short-read hybrid assembly plus short-read polish; short-read only assembly. RESULTS: Consistent with previous studies, our results suggest that the hybrid assembly produced the highest quality results as measured by gene completeness and contig circularization. However, ONT-only methods had minimal impact on the detection of AMR genes and plasmids compared to short-read methods, although, notably, differences in gene copy number differed between methods. All four assembly methods showed identical presence/absence of the blaKPC-2 carbapenemase gene for all samples. The two phenotype assays showed 100% concordant results for the non-carbapenems, but only 65% concordance for the two carbapenems. The presence/absence of AMR genes was 100% concordant with AMR phenotypes for all four non-carbapenem drugs, although only 22%-50% sensitivity for the carbapenems. CONCLUSIONS: Overall, these findings suggest that the lack of complete correspondence between CRE AMR genotype and phenotype for carbapenems, while concerning, is independent of sequencing platform/assembly method.


Asunto(s)
Antibacterianos , Carbapenémicos , Fenotipo , Genotipo , Carbapenémicos/farmacología , Antibacterianos/farmacología , Ertapenem
4.
Health Promot Pract ; : 15248399221142633, 2023 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-36600627

RESUMEN

Alcohol consumption is known to increase risk for chronic diseases and other negative health outcomes. Abstinence, even temporary, from alcohol consumption can have positive health impacts. In this article, we describe implementation and process evaluation of Ochsner Eat Fit's Alcohol Free for 40 (AFF40), an annual, 40-day voluntary alcohol abstinence challenge that takes place in six regions of Louisiana. Participants are challenged to abstain from alcohol consumption for 40 days to promote behavior change. To support participants' success, staff conduct pre and post metrics (physical and laboratory) and host community-based events to encourage replacement behaviors. Process evaluation included measures of reach, recruitment, dose, and fidelity through tracking of participant registrations, an exit survey, media analytics, and program activity logs. In 2021, 493 participants enrolled in AFF40, with 347 completing laboratory metrics and 298 completing physical metrics. Majority of exit survey respondents (74.5%) reported no alcohol consumption during the 40-day challenge and that they planned to participate in AFF40 2022 (90.9%). The Eat Fit team documented moderate engagement (48.7% of enrolled participants) in program events. Social and digital impressions and page views recorded 23,591 hits while print media resulted in over 750,000 impressions. AFF40 has shown to be highly engaging for participants and effective in supporting temporary abstinence from alcohol. Incorporating stronger methods and evaluation will enhance future program implementation and community impact. Lessons learned and implications for practice are transferable to other community-based efforts to reduce alcohol consumption.

5.
Research (Wash D C) ; 2022: 9769803, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35928300

RESUMEN

Identification of epitopes targeted following virus infection or vaccination can guide vaccine design and development of therapeutic interventions targeting functional sites, but can be laborious. Herein, we employed peptide microarrays to map linear peptide epitopes (LPEs) recognized following SARS-CoV-2 infection and vaccination. LPEs detected by nonhuman primate (NHP) and patient IgMs after SARS-CoV-2 infection extensively overlapped, localized to functionally important virus regions, and aligned with reported neutralizing antibody binding sites. Similar LPE overlap occurred after infection and vaccination, with LPE clusters specific to each stimulus, where strong and conserved LPEs mapping to sites known or likely to inhibit spike protein function. Vaccine-specific LPEs tended to map to sites known or likely to be affected by structural changes induced by the proline substitutions in the mRNA vaccine's S protein. Mapping LPEs to regions of known functional importance in this manner may accelerate vaccine evaluation and discovery of targets for site-specific therapeutic interventions.

6.
Ochsner J ; 22(2): 129-133, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35756598

RESUMEN

Background: In the state of Louisiana, the prevalence of Alzheimer disease (AD) is projected to increase 26.4% by 2025 because of the rapidly increasing geriatric population. While significant research is available on risk factors for developing AD, less data are available regarding AD progression and the rate of change among patients with the disease. To date, no research has established the baseline cognitive decline of patients with AD residing in New Orleans, Louisiana. Methods: We evaluated 100 patients in the Ochsner Health system from September 2013 to December 2019 who had a diagnosis of AD and repeated Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) scores to determine annual rates of decline. Associated variables that were analyzed included race, age at diagnosis, social factors, and comorbidities. Results: The average annual rates of decline for MMSE and MoCA scores were 2.43 (SD 2.82) points and 2.39 (SD 1.88) points, respectively. Our results were significant for a faster rate of decline in MMSE scores among smokers (3.50 points, SD 3.20) vs nonsmokers (1.54 points, SD 2.07). We found no significant difference in MoCA scores for smokers vs nonsmokers, in addition to other demographic and lifestyle variables. Conclusion: The rate of decline seen in an urban population of patients with AD is lower than the average rate of decline reported in the literature, a finding that can help inform future interventional studies that use rate of decline as a primary outcome.

7.
Am J Infect Control ; 50(9): 1013-1019, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35598812

RESUMEN

BACKGROUND: Industrial hygienists (IH) in the oil and gas business instituted an extraordinary number of safety protocols to limit spread of SARS-CoV-2 onto offshore platforms in the Gulf of Mexico. We used genomic surveillance to provide actionable information concerning the efficacy of their efforts. METHODS: Over 6 months, employees at a single company were serology and PCR tested during a 1-5 day predeployment quarantine and when postdeployment symptoms were reported. From each positive test (n = 49), SARS-CoV-2 genomes were sequenced. Phylogenetic analysis was used to investigate the epidemiology of transmissions. RESULTS: Genomic surveillance confirmed 2 viral strains were infecting 18 offshore workers. Genomic data combined with epidemiological data suggested that a change in quarantine protocols contributed to these outbreaks. A pre-deployment outbreak involved a WHO variant of interest (Theta) that had infected 4 international workers. Two additional predeployment clusters of infections were identified. CONCLUSIONS: Our findings support that IH quarantine/testing protocols limited viral transmissions, halted offshore outbreaks, and stopped the spread of a variant of interest. The study demonstrates how genomic data can be used to understand viral transmission dynamics in employee populations and evaluate safety protocols in the offshore oil and gas industry.


Asunto(s)
COVID-19 , Petróleo , COVID-19/epidemiología , COVID-19/prevención & control , Genómica , Humanos , Control de Infecciones , Filogenia , SARS-CoV-2/genética
8.
MMWR Morb Mortal Wkly Rep ; 71(3): 96-102, 2022 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-35051133

RESUMEN

The COVID-19 pandemic has magnified longstanding health care and social inequities, resulting in disproportionately high COVID-19-associated illness and death among members of racial and ethnic minority groups (1). Equitable use of effective medications (2) could reduce disparities in these severe outcomes (3). Monoclonal antibody (mAb) therapies against SARS-CoV-2, the virus that causes COVID-19, initially received Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA) in November 2020. mAbs are typically administered in an outpatient setting via intravenous infusion or subcutaneous injection and can prevent progression of COVID-19 if given after a positive SARS-CoV-2 test result or for postexposure prophylaxis in patients at high risk for severe illness.† Dexamethasone, a commonly used steroid, and remdesivir, an antiviral drug that received EUA from FDA in May 2020, are used in inpatient settings and help prevent COVID-19 progression§ (2). No large-scale studies have yet examined the use of mAb by race and ethnicity. Using COVID-19 patient electronic health record data from 41 U.S. health care systems that participated in the PCORnet, the National Patient-Centered Clinical Research Network,¶ this study assessed receipt of medications for COVID-19 treatment by race (White, Black, Asian, and Other races [including American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and multiple or Other races]) and ethnicity (Hispanic or non-Hispanic). Relative disparities in mAb** treatment among all patients†† (805,276) with a positive SARS-CoV-2 test result and in dexamethasone and remdesivir treatment among inpatients§§ (120,204) with a positive SARS-CoV-2 test result were calculated. Among all patients with positive SARS-CoV-2 test results, the overall use of mAb was infrequent, with mean monthly use at 4% or less for all racial and ethnic groups. Hispanic patients received mAb 58% less often than did non-Hispanic patients, and Black, Asian, or Other race patients received mAb 22%, 48%, and 47% less often, respectively, than did White patients during November 2020-August 2021. Among inpatients, disparities were different and of lesser magnitude: Hispanic inpatients received dexamethasone 6% less often than did non-Hispanic inpatients, and Black inpatients received remdesivir 9% more often than did White inpatients. Vaccines and preventive measures are the best defense against infection; use of COVID-19 medications postexposure or postinfection can reduce morbidity and mortality and relieve strain on hospitals but are not a substitute for COVID-19 vaccination. Public health policies and programs centered around the specific needs of communities can promote health equity (4). Equitable receipt of outpatient treatments, such as mAb and antiviral medications, and implementation of prevention practices are essential to reducing existing racial and ethnic inequities in severe COVID-19-associated illness and death.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Minorías Étnicas y Raciales/estadística & datos numéricos , Etnicidad/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Disparidades en Atención de Salud/etnología , Determinantes Sociales de la Salud , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Dexametasona/uso terapéutico , Humanos , Estados Unidos
9.
PLoS One ; 16(11): e0260164, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34847149

RESUMEN

OBJECTIVE: Determine whether an individual is at greater risk of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection because of their community or their individual risk factors. STUDY DESIGN AND SETTING: 4,752 records from two large prevalence studies in New Orleans and Baton Rouge, Louisiana were used to assess whether zip code tabulation areas (ZCTA)-level area deprivation index (ADI) or individual factors accounted for risk of infection. Logistic regression models assessed associations of individual-level demographic and socioeconomic factors and the zip code-level ADI with SARS-CoV-2 infection. RESULTS: In the unadjusted model, there were increased odds of infection among participants residing in high versus low ADI (both cities) and high versus mid-level ADI (Baton Rouge only) zip codes. When individual-level covariates were included, the odds of infection remained higher only among Baton Rouge participants who resided in high versus mid-level ADI ZCTAs. Several individual factors contributed to infection risk. After adjustment for ADI, race and age (Baton Rouge) and race, marital status, household size, and comorbidities (New Orleans) were significant. CONCLUSIONS: While higher ADI was associated with higher risk of SARS-CoV-2 infection, individual-level participant characteristics accounted for a significant proportion of this association. Additionally, stage of the pandemic may affect individual risk factors for infection.


Asunto(s)
COVID-19/epidemiología , COVID-19/virología , Características de la Residencia , SARS-CoV-2/fisiología , Privación Social , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ciudades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nueva Orleans , Probabilidad , Factores de Riesgo , Estudios Seroepidemiológicos , Factores de Tiempo , Adulto Joven
10.
Cell ; 184(19): 4939-4952.e15, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-34508652

RESUMEN

The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana had limited diversity compared to other U.S. states and that one introduction of SARS-CoV-2 led to almost all of the early transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras, and the festival dramatically accelerated transmission. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate epidemics.


Asunto(s)
COVID-19/epidemiología , Epidemias , SARS-CoV-2/fisiología , COVID-19/transmisión , Bases de Datos como Asunto , Brotes de Enfermedades , Humanos , Louisiana/epidemiología , Filogenia , Factores de Riesgo , SARS-CoV-2/clasificación , Texas , Viaje , Estados Unidos/epidemiología
11.
medRxiv ; 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33564781

RESUMEN

The emergence of the early COVID-19 epidemic in the United States (U.S.) went largely undetected, due to a lack of adequate testing and mitigation efforts. The city of New Orleans, Louisiana experienced one of the earliest and fastest accelerating outbreaks, coinciding with the annual Mardi Gras festival, which went ahead without precautions. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large, crowded events may have accelerated early transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana initially had limited sequence diversity compared to other U.S. states, and that one successful introduction of SARS-CoV-2 led to almost all of the early SARS-CoV-2 transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras and that the festival dramatically accelerated transmission, eventually leading to secondary localized COVID-19 epidemics throughout the Southern U.S.. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate COVID-19 epidemics on a local and regional scale.

12.
Clin Microbiol Infect ; 27(4): 633.e9-633.e16, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33421576

RESUMEN

OBJECTIVE: While many seroprevalence studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been performed, few are demographically representative. This investigation focused on defining the nature and frequency of symptomatic and asymptomatic SARS-CoV-2 infection in a representative, cross-sectional sample of communities in Louisiana, USA. METHODS: A sample of 4778 adults from New Orleans and Baton Rouge, Louisiana were given a survey of symptoms and co-morbidities, nasopharyngeal swab to test for active infection (PCR), and blood draw to test for past infection (IgG). Odds ratios, cluster analysis, quantification of virus and antibody, and linear modelling were used to understand whether certain symptoms were associated with a positive test, how symptoms grouped together, whether virus or antibody varied by symptom status, and whether being symptomatic was different across the age span. RESULTS: Reported anosmia/ageusia was strongly associated with a positive test; 40.6% (93/229) tested positive versus 4.8% (218/4549) positivity in those who did not report anosmia/ageusia (OR 13.6, 95% CI 10.1-18.3). Of the people who tested positive, 47.3% (147/311) were completely asymptomatic. Symptom presentation clustered into three groups; low/no symptoms (0.4 ± 0.9, mean ± SD), highly symptomatic (7.5 ± 1.9) or moderately symptomatic (4.0 ± 1.5). Quantity of virus was lower in the asymptomatic versus symptomatic group (cycle number 23.3 ± 8.3 versus 17.3 ± 9.0; p < 0.001). Modelling the probability of symptoms showed changes with age; the highest probability of reporting symptoms was 64.6% (95% CI 50.4-76.5) at age 29 years, which decreased to a probability of 49.3% (95% CI 36.6-62.0) at age 60 years and only 25.1% (95% CI 5.0-68.1) at age 80 years. CONCLUSION: Anosmia/ageusia can be used to differentiate SARS-CoV-2 infection from other illnesses, and, given the high ratio of asymptomatic individuals, contact tracing should include those without symptoms. Regular testing in congregant settings of those over age 60 years may help mitigate asymptomatic spread.


Asunto(s)
Ageusia/diagnóstico , Anosmia/diagnóstico , Infecciones Asintomáticas/epidemiología , COVID-19/diagnóstico , COVID-19/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Prueba de Ácido Nucleico para COVID-19 , Prueba Serológica para COVID-19 , Comorbilidad , Estudios Transversales , Femenino , Humanos , Inmunoglobulina G/sangre , Louisiana/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , SARS-CoV-2/inmunología
13.
Emerg Infect Dis ; 27(1)2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33171096

RESUMEN

By using paired molecular and antibody testing for severe acute respiratory syndrome coronavirus 2 infection, we determined point prevalence and seroprevalence in Louisiana, USA, during the second phase of reopening. Infections were highly variable by race and ethnicity, work environment, and ZIP code. Census-weighted seroprevalence was 3.6%, and point prevalence was 3.0%.


Asunto(s)
COVID-19/sangre , COVID-19/epidemiología , Grupos Raciales , SARS-CoV-2 , Factores Socioeconómicos , Lugar de Trabajo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Louisiana/epidemiología , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Adulto Joven
14.
Emerg Infect Dis ; 26(11): 2766-2769, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32731911

RESUMEN

Using a novel recruitment method and paired molecular and antibody testing for severe acute respiratory syndrome coronavirus 2 infection, we determined seroprevalence in a racially diverse municipality in Louisiana, USA. Infections were highly variable by ZIP code and differed by race/ethnicity. Overall census-weighted seroprevalence was 6.9%, and the calculated infection fatality ratio was 1.63%.


Asunto(s)
Anticuerpos Antivirales/sangre , Betacoronavirus , Técnicas de Laboratorio Clínico/estadística & datos numéricos , Infecciones por Coronavirus/mortalidad , Neumonía Viral/mortalidad , ARN Viral/sangre , Adulto , Anciano , Betacoronavirus/genética , Betacoronavirus/inmunología , COVID-19 , Prueba de COVID-19 , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Femenino , Humanos , Louisiana/epidemiología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , SARS-CoV-2 , Estudios Seroepidemiológicos
15.
Ochsner J ; 20(1): 44-49, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32284682

RESUMEN

Background: Clinical trials are an integral part of translating new basic science research into therapeutics. It is crucial for those who run clinical trials to realize the gravity of their responsibilities as principal investigators. Methods: This review focuses on the relevant investigator responsibilities under the Code of Federal Regulations Title 21, the contents of Form 1572, FDA inspections, and methods to improve compliance. Results: While responsibility for day-to-day study activities can be delegated to outside entities and to study staff, a clinical principal investigator who has signed US Food and Drug Administration (FDA) Form 1572 is held responsible for noncompliance and misconduct by anyone working on the study. Depending on the infraction, consequences can range from a publicly posted warning letter by the FDA to criminal prosecution and fines or imprisonment. Conclusion: Investigators are not only responsible for producing high-quality, meaningful, scientific research, but they are also responsible for maintaining public trust. If the principal investigator acts with integrity and provides training and oversight of employees, FDA inquiries should go smoothly. Following good clinical practice standards for clinical research will result in quality data collection and facilitate the analysis and publication process.

16.
J Neuroinflammation ; 16(1): 100, 2019 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-31109346

RESUMEN

BACKGROUND: Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain. METHODS: Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund's adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 µl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. RESULTS: As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. CONCLUSIONS: ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain.


Asunto(s)
Analgésicos Opioides/uso terapéutico , Analgésicos/uso terapéutico , Inmunomodulación/efectos de los fármacos , Morfina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Péptidos Cíclicos/uso terapéutico , Analgésicos/farmacología , Analgésicos Opioides/farmacología , Animales , Inmunomodulación/fisiología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Masculino , Morfina/farmacología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Dolor Postoperatorio/inmunología , Péptidos Cíclicos/farmacología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología
17.
J Pain ; 18(12): 1526-1541, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28939014

RESUMEN

Activation of the mu-opioid receptor provides the gold standard for pain relief, but most opioids used clinically have adverse effects that have contributed to an epidemic of overdose deaths. We recently characterized mu-opioid receptor selective endomorphin (EM) analogs that provide potent antinociception with reduction or absence of a number of side effects of traditionally prescribed opioids including abuse liability, respiratory depression, motor impairment, tolerance, and inflammation. The current study explores the effectiveness of these EM analogs relative to morphine in four major pain models by intrathecal as well as intravenous administration in male Sprague Dawley rats and subcutaneous administration in male CD-1 mice. In the spared nerve injury model of neuropathic pain, mechanical allodynia and mechanical hyperalgesia were assessed with von Frey and Randall-Selitto tests, respectively. In the paw incision model of postoperative pain, von Frey testing was used to assess mechanical allodynia and thermal hyperalgesia was evaluated with Hargreaves testing. In the Complete Freund's Adjuvant model of inflammatory pain, thermal hyperalgesia was assessed using Hargreaves testing. In CD-1 mice, visceral pain was assessed with the acetic acid writhing test. In all cases, EM analogs had equal or greater potency and longer duration of action relative to morphine. The data suggest that EM analogs, particularly analog 4 (ZH853), could provide effective therapy for a diverse spectrum of pain conditions with low risk of adverse side effects compared with currently used opioids such as morphine. PERSPECTIVE: Novel EM analogs show equal or greater potency and effectiveness relative to morphine in multiple pain models. Together with substantially reduced side effects, including abuse liability, the compounds show promise for addressing the critical need for effective pain relief as well as reducing the opioid overdose epidemic.


Asunto(s)
Analgésicos Opioides/farmacología , Hiperalgesia/tratamiento farmacológico , Morfina/farmacología , Neuralgia/tratamiento farmacológico , Dolor Nociceptivo/tratamiento farmacológico , Oligopéptidos/análisis , Dolor Postoperatorio/tratamiento farmacológico , Péptidos Cíclicos/farmacología , Dolor Visceral/tratamiento farmacológico , Analgésicos Opioides/administración & dosificación , Animales , Modelos Animales de Enfermedad , Inflamación/complicaciones , Inyecciones Intravenosas , Inyecciones Espinales , Masculino , Ratones , Dolor Nociceptivo/etiología , Péptidos Cíclicos/administración & dosificación , Ratas , Ratas Sprague-Dawley
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