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1.
Trials ; 22(1): 931, 2021 Dec 18.
Article in English | MEDLINE | ID: covidwho-1765462

ABSTRACT

BACKGROUND: Second-line treatment of HIV-2 in resource-limited settings (RLS) is complicated by a lack of controlled trial data, limited availability of HIV-2-active antiretroviral drugs, and inadequate access to drug resistance testing. We conducted an implementation trial of a dried blood spot- (DBS) based, drug resistance genotype-informed antiretroviral therapy (ART) switching algorithm for HIV-2-infected patients in Senegal. METHODS: HIV-2-infected adults initiating or receiving ART through the Senegalese national AIDS program were invited to participate in this single-arm trial. DBS from participants with virologic failure (defined as viral load (VL) > 250 copies/mL after > 6 months on the current ART regimen) were shipped to Seattle for genotypic drug resistance testing. Participants with evidence of drug resistance in protease or reverse transcriptase were switched to new regimens according to a pre-specified algorithm. Participant clinical and immuno-virologic outcomes were assessed, as were implementation challenges. RESULTS: We enrolled 152 participants. Ten were initiating ART. The remainder were ART-experienced, with 91.0% virologically suppressed (< 50 copies/mL). Problems with viral load testing capability resulted in obtaining VL results for only 227 of 613 (37.0%) participant-visits. Six of 115 participants (5.2%) with VL available after > 6 months on current ART regimen experienced virologic failure, with per-protocol genotypic testing attempted. One additional test was performed for a participant with a VL of 222 copies/mL. Genotypes from three participants showed no evidence of major drug resistance mutations, two showed nucleoside reverse transcriptase inhibitor (NRTI) resistance, one showed both NRTI and protease inhibitor resistance, and one test failed. No integrase inhibitor resistance was observed. Five of six successfully-tested participants switched to the correct regimen or received additional adherence counseling according to the algorithm; the sixth was lost to follow-up. Follow-up VL testing was available for two participants; both of these were virally suppressed (< 10 copies/mL). The trial was terminated early due to the COVID-19 pandemic (which prevented further VL and genotypic testing), planned rollout of dolutegravir-based 1st-line ART, and funding. CONCLUSIONS: The RESIST-2 trial demonstrated that a DBS-based genotypic test can be used to help inform second-line ART decisions as part of a programmatic algorithm in RLS, albeit with significant implementation challenges. TRIAL REGISTRATION: ClinicalTrials.gov NCT03394196 . Registered on January 9, 2018.


Subject(s)
COVID-19 , HIV Infections , Drug Resistance , Genotype , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV-2 , Humans , Pandemics , SARS-CoV-2 , Senegal
2.
EMBO Rep ; 23(4): e54199, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1732510

ABSTRACT

The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1,000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants.


Subject(s)
COVID-19 , Single-Domain Antibodies , Antibodies, Neutralizing , Antibodies, Viral/metabolism , COVID-19/drug therapy , Drug Resistance , Humans , Pandemics , Protein Binding , SARS-CoV-2/genetics , Single-Domain Antibodies/genetics , Single-Domain Antibodies/metabolism , Single-Domain Antibodies/pharmacology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
3.
Front Biosci (Landmark Ed) ; 27(2): 65, 2022 02 14.
Article in English | MEDLINE | ID: covidwho-1716428

ABSTRACT

Severe acute respiratory syndrom coronavirus-2 (SARS CoV-2) is the causative agent of coronavirus disease-19 (Covid-19) which has been designated a worldwide pandemic by the World Health Organization on March 11, 2020. Since that time, the virus has mutated and an assortment of variants have been successful at establishing themselves in the human population. This review article describes the SARS CoV-2 genome, hot spot mutations, variants, and then focuses on the Delta variant, finishing up with an update on the Omicron variant. The genome encompasses 11 open reading frames, one of which encodes the spike or S protein that has been the target for vaccines and some of the drugs because of its role in attachment to the human host cell, as well as antibodies. Mutations in the S protein that are common among several of the variants include D614G that increases transmissibility and viral load and is often associated with P323L on the RNA dependent RNA polymerase. N501Y is a mutation in the receptor binding domain of the S protein that increases binding to the ACE-2 receptor on the human host cells by 10 fold. The discussed variants carry combinations of these and other mutations and are classified by the World Health Organization as variants of concern, variants of interest, and variants under monitoring. All variants are characterized by increased transmissibility (relative to the original SARS CoV-2), which is the reason for their ability to establish themselves. Several but not all variants are more resistant to antiviral drugs and less susceptible to antibodies/vaccines. The Delta variant that dominated the world until November 2021 causes an increased risk for hospitalization and death, but is still very susceptible to the current vaccines. The most recent variant, Omicron, is characterized by increased transmissibility and decreased antibody susceptibility.


Subject(s)
COVID-19 , Vaccines , Antibodies, Neutralizing , Drug Resistance , Humans , Mutation , SARS-CoV-2/genetics , Virulence/genetics
4.
Microbiol Spectr ; 10(1): e0108021, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1673361

ABSTRACT

The spread of carbapenem-resistant Pseudomonas aeruginosa and carbapenemase-producing Enterobacterales (CPE) has dramatically impacted morbidity and mortality. COVID-19 pandemic has favored the selection of these microorganisms because of the excessive and prolonged use of broad-spectrum antibiotics and the outbreaks related to patient transfer between hospitals and inadequate personal protective equipment. Therefore, early CPE detection is considered essential for their control. We aimed to compare conventional phenotypic synergy tests and two lateral flow immunoassays for detecting carbapenemases in Enterobacterales and P. aeruginosa. We analyzed 100 carbapenem-resistant Gram-negative bacilli isolates, 80 Enterobacterales, and 20 P. aeruginosa (86 isolates producing KPC, NDM, OXA-48, IMP, and VIM carbapenemases and 14 non-carbapenemase-producing isolates). We performed a modified Hodge test, boronic acid and ethylenediaminetetraacetic acid (EDTA) synergy tests, and two lateral flow immunoassays: RESIST-4 O.K.N.V. (Coris Bioconcept) and NG Test Carba 5 (NG Biotech). In total, 76 KPC, seven VIM, one NDM, one OXA-48, and one isolate coproducing KPC + NDM enzymes were included. The concordance of different methods estimated by the Kappa index was 0.432 (standard error: 0.117), thus showing a high variability with the synergy tests with boronic acid and EDTA and reporting 16 false negatives that were detected by the two immunochromatographic methods. Co-production was only detected using immunoassays. Conventional phenotypic synergy tests with boronic acid and EDTA for detecting carbapenemases are suboptimal, and their routine use should be reconsidered. These tests depend on the degree of enzyme expression and the distance between disks. Lateral flow immunoassay tests are a rapid and cost-effective tool to detect and differentiate carbapenemases, improving clinical outcomes through targeted therapy and promoting infection prevention measures. IMPORTANCE Infections due to multidrug-resistant pathogens are a growing problem worldwide. The production of carbapenemases in Pseudomonas aeruginosa and Enterobacterales cause a high impact on the mortality of infected patients. Therefore, it is of great importance to have methods that allow the early detection of these multi-resistant microorganisms, achieving the confirmation of the type of carbapenemase present, with high sensitivity and specificity, with the aim of improving epidemiological control, dissemination, the clinical course to through targeted antibiotic therapy and promoting infection control in hospitals.


Subject(s)
Gammaproteobacteria/enzymology , Immunoassay/methods , Pseudomonas aeruginosa/enzymology , Carbapenems/metabolism , Carbapenems/pharmacology , Carbon-Nitrogen Ligases/metabolism , Drug Resistance , Immunoassay/standards , Phenotype , Pseudomonas aeruginosa/drug effects
5.
Euro Surveill ; 26(27)2021 07.
Article in English | MEDLINE | ID: covidwho-1577032

ABSTRACT

BackgroundInfluenza virus presents a considerable challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid infection diagnosis, rationalising antimicrobial therapy, and supporting infection-control interventions.AimTo evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings.MethodsWe conducted Oxford Nanopore Technologies (Oxford, United Kingdom (UK)) metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic standards (Xpert Xpress Flu/RSV assay; BioFire FilmArray Respiratory Panel 2 assay). We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data.ResultsCompared to standard testing, Nanopore metagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses. Of 59 samples with haemagglutinin subtype determined, 40 were H1 and 19 H3. We identified an influenza A(H3N2) genome encoding the oseltamivir resistance S331R mutation in neuraminidase, potentially associated with an emerging distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in a ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant community-circulating strain. We also detected other potentially pathogenic viruses and bacteria from the metagenome.ConclusionNanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Full genome generation can help investigate and manage nosocomial outbreaks.


Subject(s)
Cross Infection , Influenza, Human , Nanopores , Antiviral Agents/therapeutic use , Cross Infection/diagnosis , Cross Infection/drug therapy , Drug Resistance , Drug Resistance, Viral/genetics , Humans , Influenza A Virus, H3N2 Subtype/genetics , Influenza, Human/diagnosis , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Metagenome , Neuraminidase/genetics , Seasons , United Kingdom
6.
J Antimicrob Chemother ; 76(11): 2854-2862, 2021 10 11.
Article in English | MEDLINE | ID: covidwho-1537567

ABSTRACT

BACKGROUND: The first potential focus for artemisinin resistance in South America was recently confirmed with the presence of the C580Y mutation in the Plasmodium falciparum kelch 13 gene (pfk13) in Guyana. OBJECTIVES: This study aimed to strengthen pfk13 monitoring in the Amazon basin countries, to compile the available data and to evaluate the risk of spreading of mutations. METHODS: Sanger sequencing was done on 862 samples collected between 1998 and 2019, and a global map of pfk13 genotypes available for this region was constructed. Then, the risk of spreading of mutations based on P. falciparum case importation between 2015 and 2018 within countries of the Amazon basin was evaluated. RESULTS: No additional pfk13 C580Y foci were identified. Few mutations (0.5%, 95% CI = 0.3%-0.8%) in the propeller domain were observed in the general parasite population of this region despite a high proportion of K189T mutations (49.1%, 95% CI = 46.2%-52.0%) in the non-propeller domain. Case information revealed two patterns of intense human migration: Venezuela, Guyana and the Roraima State in Brazil; and French Guiana, Suriname and the Amapá State in Brazil. CONCLUSIONS: There are few pfk13 mutant foci, but a high risk of dispersion in the Amazon basin, mainly from the Guiana Shield, proportionate to mining activities. Therefore, access to prompt diagnosis and treatment, and continuous molecular monitoring is essential in these geographical areas.


Subject(s)
Malaria, Falciparum , Mutation , Plasmodium falciparum , Antimalarials/pharmacology , Antimalarials/therapeutic use , Brazil , Drug Resistance , Humans , Kelch Repeat , Plasmodium falciparum/genetics , Protozoan Proteins/genetics
7.
Elife ; 102021 07 19.
Article in English | MEDLINE | ID: covidwho-1513059

ABSTRACT

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.


Subject(s)
Artemisinins/pharmacology , Drug Resistance/drug effects , Drug Resistance/genetics , Mutation , Plasmodium falciparum/drug effects , Plasmodium falciparum/genetics , Protozoan Proteins/genetics , Africa , Antimalarials/pharmacology , Asia , Cambodia , Humans , Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Molecular Epidemiology
8.
J Infect Public Health ; 14(12): 1848-1853, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1500076

ABSTRACT

BACKGROUND: The increasing azole drug resistance in fungal pathogens poses a pressing threat to global health care. The coexistence of drug-resistant Candida albicans with tuberculosis patients and the failure of several drugs to treat C. albicans infection extend hospital stay, economic burden, and death. The misuse or abuse of azole-derived antifungals, chronic use of TB drugs, different immune-suppressive drugs, and diseases like HIV, COVID-19, etc., have aggravated the situation. So it is vital to understand the molecular changes in drug-resistant genes to modify the treatment to design an alternative mechanism. METHOD: C. albicans isolated from chronic tuberculosis patients were screened for antifungal sensitivity studies using disk diffusion assay. The multidrug-resistant C. albicans were further screened for molecular-level changes in drug resistance using MDR1 gene sequencing and compared with Gen bank data of similar species using the BLAST tool. RESULTS: The investigation proved that the isolated C. albicans from TB patients are significantly resistant to the action of six drugs. The molecular changes in MDR1 genes showed differences in seven nucleotide base pairs that interfered with the efflux pump.


Subject(s)
COVID-19 , Candida albicans , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Antifungal Agents/pharmacology , Candida albicans/genetics , Drug Resistance , Humans , Microbial Sensitivity Tests , SARS-CoV-2
10.
Mol Biol Rep ; 49(1): 605-615, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1469744

ABSTRACT

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) was first detected in Wuhan, China in December, 2019. The emerging virus causes a respiratory illness, that can trigger a cytokine storm in the body. METHOD: Cytokine storm in patient's body is associated with severe forms of disease. It is one of the main complications of coronavirus disease-2019 (COVID-19), in which immune cells play a major role. Studies have shown immune cells in the tumor environment can be effective to induce resistance to chemotherapy in cancer patients. RESULT: Therefore, considering the role of immune cells to induce cytokine storm in COVID-19 patients, and their role to cause resistance to chemotherapy, they are effective on disease progression and creation of severe form of disease. CONCLUSION: By examining the signaling pathways and inducing resistance to chemotherapy in tumor cells and the cells affect them, it is possible to prevent the occurrence of severe forms of the disease in cancer patients with COVID-19; it is applicable using target therapy and other subsequent treatment strategies.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , COVID-19/complications , COVID-19/immunology , Drug Resistance , Humans , SARS-CoV-2/immunology
11.
J Eur Acad Dermatol Venereol ; 35(10): 2007-2021, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1455573

ABSTRACT

In the late 90s, a sharp increase of treatment failures of Trichomonas vaginalis (TV) infections with metronidazole (MTZ) was reported, representing a problem due to limited treatment options. We proposed to review the available evidence on the frequency of MTZ resistance by TV isolates and the relationship between treatment failure and in vitro resistance to MTZ. A systematic review based on the PRISMA guidelines was conducted by searching published studies in three different databases (PubMed, Scopus and Web of Science) up to December 2020. The extracted studies were uploaded to Covidence software; screening was guided based on inclusion and exclusion criteria. Additionally, different articles were included through other sources. For each article, study design, objectives, study population and key outcomes were summarized. We found 403 references from the databases and four extra studies. After duplicate removal and screening of title, abstract and full text, 27 studies were included. The selected studies were published between 1983 and 2019; all except one addressed only vaginal TV infection. We identified four major populations in vitro MTZ resistance: two studies evaluated female adolescents; other two assessed HIV-positive women. Fifteen studies considered MTZ resistance in newly diagnosed vaginal TV infection. Finally, eight articles studied in vitro susceptibility of isolates from women with clinical resistant trichomoniasis. High level of in vitro MTZ resistance was rare; low-moderate level was described in most of the cases. Although clinical resistance to MTZ of trichomoniasis was widely reported, there was a paucity of prospective controlled studies. Our review unveiled the need to standardize susceptibility testing, to define breakpoints for detection of MTZ-resistant isolates and to correlate with clinical outcome. It is important to establish criteria to define clinical resistance to MTZ. Such a consensus would foster the development of surveillance studies about clinical and microbiological response to MTZ treatment.


Subject(s)
Trichomonas Infections , Trichomonas Vaginitis , Trichomonas vaginalis , Adolescent , Drug Resistance , Female , Humans , Metronidazole/pharmacology , Prospective Studies , Trichomonas Infections/drug therapy , Trichomonas Vaginitis/drug therapy
12.
Int Immunopharmacol ; 101(Pt A): 108200, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1440133

ABSTRACT

The world is facing up the most considerable vaccination effort in history to end the Coronavirus disease 2019 (COVID-19) pandemic. Several monoclonal antibodies (mAbs) direct against the Receptor binding domain of the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received an Emergency Use Authorization for outpatient management of mild to moderate manifestation from COVID-19. MAbs could prevent the transmission SARS-CoV-2 infection and protect individuals from progression to severe disease. Under the pressure of different treatment strategies, SARS-CoV-2 has been demonstrated to select for different sets of mutations named "variants" that could impair the effectiveness of mAbs by modifying target epitopes. We provide an overview of both completed and unpublished, or ongoing clinical trials of mAbs used and review state of art in order to describe clinical options, possible indications, and the place in therapy for these agents in the treatment of COVID-19 with a particular focus on anti-spike agents. Then, we reassume the current evidence on mutations of the SARS-CoV-2 that might confer resistance to neutralization by multiple mAbs.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , Animals , Clinical Trials as Topic , Drug Resistance/immunology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
13.
J Clin Psychiatry ; 82(5)2021 09 07.
Article in English | MEDLINE | ID: covidwho-1399456

ABSTRACT

Treatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.


Subject(s)
Antipsychotic Agents/administration & dosage , Clozapine/administration & dosage , Schizophrenia/drug therapy , Antipsychotic Agents/adverse effects , Clozapine/adverse effects , Drug Resistance/drug effects , Drug Tolerance , Female , Humans , Male
16.
BMC Pregnancy Childbirth ; 21(1): 567, 2021 Aug 18.
Article in English | MEDLINE | ID: covidwho-1365335

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) still is a global emergency. According to the studies, pregnant women are of the at risk populations and any underlying disease(s) might even worsen their condition. The aim of this study is reporting a complex case of immune thrombocytopenic purpura (ITP) during pregnancy who has been diagnosed with COVID-19 as well as suspicion of HELLP syndrome. CASE PRESENTATION: A 24-year-old woman with a platelet count of 6000/mL and resistance to conventional therapies was referred. A day after starting 0.5 g/day of methylprednisolone for her, fever and a decrease in SpO2 presented. According to the paraclinical investigations, COVID-19 was diagnosed and the conventional COVID-19 treatments started for her (the methylprednisolone pulse stopped). Due to the increased liver enzymes and low platelet count, with suspicion of HELLP syndrome, cesarean section surgery was performed which resulted in a healthy neonate. Then, the methylprednisolone pulse was restarted for and she developed an increase in the platelet count. CONCLUSION: It is not clear how COVID-19 and pregnancy affected the patient's condition and the underlying disease; however, it seems the delivery and/or restarting the methylprednisolone pulses caused improvement in her condition.


Subject(s)
COVID-19/diagnosis , Methylprednisolone/administration & dosage , Pregnancy Complications, Hematologic/drug therapy , Pregnancy Complications, Infectious/diagnosis , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Cesarean Section , Drug Resistance , Female , HELLP Syndrome/diagnosis , Humans , Infant, Newborn , Male , Platelet Count , Pregnancy , Pregnancy Complications, Hematologic/blood , Pregnancy Complications, Hematologic/diagnosis , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/virology , Pulse Therapy, Drug , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/complications , Purpura, Thrombocytopenic, Idiopathic/diagnosis , SARS-CoV-2/isolation & purification , Treatment Outcome , Young Adult
17.
Eur J Pharmacol ; 908: 174374, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1322083

ABSTRACT

The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.


Subject(s)
COVID-19/drug therapy , Chloroquine/pharmacology , Dual Specificity Phosphatase 1/genetics , Glucocorticoids/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cells, Cultured , Chloroquine/therapeutic use , Datasets as Topic , Down-Regulation/drug effects , Drug Resistance/drug effects , Drug Resistance/genetics , Drug Synergism , Dual Specificity Phosphatase 1/metabolism , Fibroblasts , Glucocorticoids/therapeutic use , Healthy Volunteers , Humans , Lung/cytology , Lung/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Middle Aged , Nasopharynx/virology , Off-Label Use , Primary Cell Culture , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
18.
Braz J Infect Dis ; 25(3): 101596, 2021.
Article in English | MEDLINE | ID: covidwho-1309170

ABSTRACT

Brazil is a huge continental country with striking geographic differences which are well illustrated in the HIV/AIDS epidemic. Contrasting with the significant decline in the national AIDS detection rate in the last decade, a linear growth has been reported in the Northern region. Despite its public health and epidemiologic importance, there is scarce HIV-1 molecular data from Northern Brazil. This scoping review summarizes recent epidemiologic data with special emphasis on HIV-1 genetic diversity and antiretroviral drug resistance mutations in patients from the seven Northern states of Brazil. Studies from the Northern Brazil on different HIV-1 genomic regions, mostly pol (protease/reverse transcriptase) sequences of naïve/antiretroviral treated adults/children were retrieved from PubMed/MEDLINE electronic database. These studies indicate a consistent molecular profile largely dominated by HIV-1 subtype B with minor contribution of subtypes F1 and C and infrequent detection of other subtypes (A1, D, K), recombinants (BF1, BC), circulating recombinant forms (CRF) as the new CRF90_BF1 and CRF02_AG-like, CRF28-29_BF-like, CRF31_BC-like, and a potential new CRF_BF1. This pattern indicates a founder effect of subtype B and the introduction of non-B-subtypes and recombinants probably generated in the Southern/Southeastern regions. In naïve populations transmitted drug resistance (TDR) can impact the outcome of first-line antiretroviral treatment and prophylactic/preventive regimens. In the Northern region TDR rates are moderate while patients failing highly active antiretroviral therapy (HAART) showed high prevalence of acquired drug resistance mutations. The limited HIV-1 molecular data from Northern Brazil reflects the great challenges to generate comprehensive scientific data in isolated, underprivileged areas. It also highlights the need to invest in local capacity building which supported by adequate infrastructure and funding can promote robust research activities to help reduce the scientific asymmetries in the Northern region. Currently the impacts of the overwhelming COVID-19 pandemic on the expanding HIV/AIDS epidemic in Northern Brazil deserves to be closely monitored.


Subject(s)
COVID-19 , HIV Infections , HIV-1 , Brazil , Drug Resistance , Drug Resistance, Viral/genetics , Genotype , HIV Infections/drug therapy , HIV Infections/epidemiology , HIV-1/genetics , Humans , Mutation , Pandemics , Phylogeny , SARS-CoV-2 , Sequence Analysis, DNA
19.
Molecules ; 25(21)2020 Nov 07.
Article in English | MEDLINE | ID: covidwho-1305742

ABSTRACT

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite's life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.


Subject(s)
Antimalarials/pharmacology , Drug Discovery/trends , Malaria/drug therapy , Plasmodium/drug effects , Protein Kinase Inhibitors/pharmacology , Animals , Calcium/metabolism , Casein Kinase I/metabolism , Culicidae , Drug Design , Drug Resistance , Glycogen Synthase Kinase 3/metabolism , Humans , Imidazoles/pharmacology , Inhibitory Concentration 50 , Life Cycle Stages/drug effects , MAP Kinase Signaling System , Phosphotransferases/chemistry , Plasmodium/enzymology , Pyridines/pharmacology
20.
Molecules ; 26(8)2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1302425

ABSTRACT

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.


Subject(s)
Antimalarials/therapeutic use , Drug Repositioning/methods , Animals , Anti-Bacterial Agents/therapeutic use , Drug Resistance/genetics , Humans , Malaria/physiopathology , Plasmodium falciparum/genetics , Plasmodium falciparum/pathogenicity
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