scholarly journals Benznidazole Treatment: Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 729
Author(s):  
Kátia da Silva Fonseca ◽  
Luísa Perin ◽  
Nívia Carolina Nogueira de Paiva ◽  
Beatriz Cristiane da Silva ◽  
Thays Helena Chaves Duarte ◽  
...  
Keyword(s):  
Treatment Adherence ◽  
Treatment Efficacy ◽  
Treatment Time ◽  
Standard Dose ◽  
Acute Infection ◽  
Chronic Phase ◽  
Disease Status ◽  
Dose Dependence ◽  
New Drugs ◽  
Treatment Regimens

As the development of new drugs for Chagas disease is not a priority due to its neglected disease status, an option for increasing treatment adherence is to explore alternative treatment regimens, which may decrease the incidence of side effects. Therefore, we evaluated the efficacy of different therapeutic schemes with benznidazole (BNZ) on the acute and chronic phases of the disease, using mice infected with strains that have different BNZ susceptibilities. Our results show that the groups of animals infected by VL-10 strain, when treated in the chronic phase with a lower dose of BNZ for a longer period of time (40 mg/kg/day for 40 days) presented better treatment efficacy than with the standard protocol (100 mg/kg/day for 20 days) although the best result in the treatment of the animals infected by the VL-10 strain was with100 mg/kg/day for 40 days. In the acute infection by the Y and VL-10 strains of T. cruzi, the treatment with a standard dose, but with a longer time of treatment (100 mg/kg/day for 40 days) presented the best results. Given these data, our results indicate that for BNZ, the theory of dose and time proportionality does not apply to the phases of infection.

scholarly journals Azithromycin resistant gonococci: a literature review

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Awoke Derbie ◽  
Daniel Mekonnen ◽  
Yimtubezinash Woldeamanuel ◽  
Tamrat Abebe
Keyword(s):  
Treatment Time ◽  
Efflux Pump ◽  
Treatment Options ◽  
Ribosomal Subunit ◽  
Antimicrobial Treatment ◽  
New Drugs ◽  
Cochrane Library ◽  
Coding Region ◽  
Sexually Transmitted ◽  
Treatment Regimens

Abstract Objective Gonorrhea is the second most common sexually transmitted bacterial infection (STI) next to Chlamydia. Untreated cases could results in major complications like pelvic inflammatory disease (PID), ectopic pregnancy, infertility, miscarriage, fetal death and congenital infections. Gonorrhea has been treated with antibiotics for more than eight decades. However, the emergence and spread of antimicrobial resistance (AMR) in gonococcus seriously compromises the management of the disease. The aim of this review was to describe the current developments in the field of azithromycin resistant gonococci. Methods Literatures published in English in the last 10 years were retrieved from PubMed, SCOPUS, Google scholar, Cochrane library and the Google databases using relevant searching terms. Results Gonococcus is capable of using a number of strategies to confer resistance as the bacterium has an extraordinary capacity to alter its genome. So far the accumulated data on the field showed that the world is heading towards a pandemic of extensively drug-resistant (XDR) gonococcus which is now seems to be evolving into a true “superbug”. Hence, in the near future gonorrhea may become untreatable on the international basis unless new drugs become available. An antibiotic resistance in gonococcus has been noted beginning in 1940s against sulfonamides. Since then, resistance has rapidly emerged to penicillins, tetracyclines, macrolides, fluoroquinolones, and cephalosporins. Currently, in most nations, the injectable extended-spectrum cephalosporin (ESC), i.e. ceftriaxone based therapy is the only remaining option for gonorrhea. Based on the WHO and the US-CDC recommendations, countries are increasingly using a combination of cephalosporin and azithromycin for the treatment of gonorrhoea. Azithromycin revolutionized gonoccocal therapy as it shortened treatment time by more than half from 7 to 14 days and improved patient compliance due to high tissue levels and long half-life. However, constantly emerging reports from different parts of the globe showed that N. gonorrhoeae is developing significant level of resistance against azithromycin, and so far more than 33% level of resistance was reported. Two strategies have been commonly implicated in gonococcal resistance against azithromycin: over expression of an efflux pump (due to mutations at mtrR coding region) and decreased antimicrobial affinity (due to mutations in genes encoding the 23S ribosomal subunit). Conclusions With no alternative antimicrobial treatment options for gonorrhoea and only a few new drugs in the development pipeline, it is necessary to monitor drug resistance and optimize treatment regimens regularly. Moreover, investigations for novel drugs should be wired.

Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

2019 ◽  
Vol 26 (36) ◽  
pp. 6519-6543 ◽  
Author(s):  
Adriana Egui ◽  
Paola Lasso ◽  
Elena Pérez-Antón ◽  
M. Carmen Thomas ◽  
Manuel Carlos López
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Cardiac Tissue ◽  
Acute Infection ◽  
Clinical Status ◽  
Chronic Phase ◽  
Parasite Load ◽  
Chronic Patients ◽  
Cruzi Infection

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

4H-1,3-Benzothiazin-4-one a Promising Class Against MDR/XDR-TB

2019 ◽  
Vol 19 (8) ◽  
pp. 567-578 ◽  
Author(s):  
Marcus Vinicius Nora de Souza ◽  
Thais Cristina Mendonça Nogueira
Keyword(s):  
Treatment Time ◽  
Public Health Problem ◽  
New Drugs ◽  
Global Public Health ◽  
Synthesis Mechanism ◽  
Highly Active ◽  
Latent Disease ◽  
Resistant Strains ◽  
Chemical Class ◽  
Global Public Health Problem

Nowadays, tuberculosis (TB) is an important global public health problem, being responsible for millions of TB-related deaths worldwide. Due to the increased number of cases and resistance of Mycobacterium tuberculosis to all drugs used for the treatment of this disease, we desperately need new drugs and strategies that could reduce treatment time with fewer side effects, reduced cost and highly active drugs against resistant strains and latent disease. Considering that, 4H-1,3-benzothiazin-4-one is a promising class of antimycobacterial agents in special against TB-resistant strains being the aim of this review the discussion of different aspects of this chemical class such as synthesis, mechanism of action, medicinal chemistry and combination with other drugs.

New Drugs and Treatment Regimens

2013 ◽  
Vol 9 (3) ◽  
pp. 200-210 ◽  
Author(s):  
Derek Sloan ◽  
Geraint Davies ◽  
Saye Khoo
Keyword(s):  
New Drugs ◽  
Treatment Regimens

scholarly journals New Perspectives in Stroke Management: Old Issues and New Pathways

2021 ◽  
Vol 11 (6) ◽  
pp. 767
Author(s):  
Fabio Pilato ◽  
Rosalinda Calandrelli ◽  
Fioravante Capone ◽  
Michele Alessiani ◽  
Mario Ferrante ◽  
...  
Keyword(s):  
Time Window ◽  
Enhanced Recovery ◽  
Current Knowledge ◽  
Oral Anticoagulants ◽  
Chronic Phase ◽  
Stroke Care ◽  
New Drugs ◽  
Stroke Patients ◽  
Social Burden ◽  
Novel Approaches

Stroke is a leading cause of disability and death worldwide and social burden is huge in terms of disabilities, mortality and healthcare costs. Recently, in an acute stroke setting, renewed interest in disease-modifying therapies and novel approaches has led to enhanced recovery and the reduction of long-term disabilities of patients who suffered a stroke. In the last few years, the basic principle “time is brain” was overcome and better results came through the implementation of novel neuroimaging tools in acute clinical practice, allowing one to extend acute treatments to patients who were previously excluded on the basis of only a temporal selection. Recent studies about thrombectomy have allowed the time window to be extended up to 24 h after symptoms onset using advanced neuroradiological tools, such as computer tomography perfusion (CTP) and magnetic resonance imaging (MRI) to select stroke patients. Moreover, a more effective acute management of stroke patients in dedicated wards (stroke units) and the use of new drugs for stroke prevention, such as novel oral anticoagulants (NOACs) for atrial fibrillation, have allowed for significant clinical improvements. In this editorial paper, we summarize the current knowledge about the main stroke-related advances and perspectives and their relevance in stroke care, highlighting recent developments in the definition, management, treatment, and prevention of acute and chronic complications of stroke. Then, we present some papers published in the Special Issue “Clinical Research on Ischemic Stroke: Novel Approaches in Acute and Chronic Phase”.

scholarly journals Efficacy and Tolerability after Unusually Low Doses of Dasatinib in Chronic Myeloid Leukemia Patients Intolerant to Standard-Dose Dasatinib Therapy

2010 ◽  
Vol 4 ◽  
pp. CMO.S6413 ◽  
Author(s):  
Mariana Serpa ◽  
Sabri S. Sanabani ◽  
Israel Bendit ◽  
Fernanda Seguro ◽  
Flávia Xavier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Patient Treatment ◽  
Hematological Toxicity ◽  
Drug Discontinuation ◽  
Once Daily ◽  
Starting Dose

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase ( n 2) and accelerated phase ( n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.

scholarly journals Chronic myeloid leukemia: successful therapy with nilotinib in a young patient with high Sokal risk and in sub-optimal response with imatinib

2015 ◽  
Vol 4 (6S) ◽  
pp. 13-16
Author(s):  
Fausto Palmieri
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Young Patient ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Chronic Phase ◽  
Molecular Response ◽  
Optimal Response ◽  
Increased Risk

Here we describe a case of a young patient with chronic myeloid leukemia, at high-risk according to the Sokal index, who started imatinib at standard dose and obtained a sub-optimal response at 12 months. This condition was not automatically an indication to change therapy, but considering the patient as suboptimal, we decided to switch to a second-generation tyrosine kinase inhibitor (TKI), nilotinib 800 mg/die, obtaining soon a complete cytogenetic response (CCYR), thereafter a major molecular response (MMolR). Delayed achievement of cytogenetic and molecular is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving imatinib therapy. Therefore we can hypothesise that this kind of patient could be elegible for an early switch to second-generation TKI.

scholarly journals Tuberculosis: Development of New Drugs and Treatment Regimens

2021 ◽  
Vol 7 (1) ◽  
pp. 36
Author(s):  
Soedarsono Soedarsono
Keyword(s):  
Treatment Guidelines ◽  
New Drugs ◽  
World Health ◽  
Health Crisis ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Repurposed Drugs ◽  
Latent Tb Infection ◽  
Health Organization ◽  
Who Guideline

Tuberculosis (TB) still becomes a public health crisis. Drug-resistant TB (DR-TB) becomes a concern as the increasing DR-TB cases in countries with high TB burden. The 2017 World Health Organization (WHO) guideline recommended a combination of TB treatment consisting of 2 months of intensive phase with isoniazid (H), rifampisin (R), pyrazinamid (Z), and ethambutol (E), followed by 4 months of continuation phase with HR daily. WHO has updated DR-TB treatment guidelines several times. In 2016, WHO recommended shorter regimen and individual regimen based on certain conditions. The most updated 2020 WHO guideline recommended the short regimen consisting of all oral drugs as well as changes in the grouping of medicines used in DR-TB regimens in longer/individual regimens. Bedaquiline, delamanid, pretomanid, and sutezolid are new drugs which have been studied for their uses as anti-TB drugs (ATD). Bedaquilin and delamanid, which have passed phase 3 trials, have been approved and recommended by WHO for DR-TB treatment. Repurposed drugs have been used for DR-TB treatment during the time of evaluation of drugs list and regimens for DR-TB treatment. Fluoroquinolones, clofazimine, linezolid, carbapenem, amoxicillin/clavulanic acid are repurposed drugs. TB and DR-TB management will be updated at any time, based on the latest findings in studies, to evaluate and improve the effectiveness of current treatments. Prevention of active TB disease by the treatment of latent TB infection (LTBI) is also a critical component of the end TB strategy by WHO. Therefore, the development of new drugs for the LTBI treatment is also needed.

Serologic, Virologic, and Histologic Characteristics of Chronic Phase Hepatitis C Virus Disease in Children Infected by Transfusion

PEDIATRICS ◽  
1994 ◽  
Vol 94 (6) ◽  
pp. 919-922
Author(s):  
Suguru Matsuoka ◽  
Katsuyoshi Tatara ◽  
Yasunobu Hayabuchi ◽  
Yoshiyuki Taguchi ◽  
Kazuhiro Mori ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Acute Infection ◽  
Chronic Phase ◽  
Hcv Infection ◽  
Core Antigen ◽  
Hcv Rna ◽  
Histologic Evidence ◽  
Group A ◽  
Group B

Objective. We studied the time course of hepatic dysfunction, seropositivity to hepatitis C virus (HCV) antibodies, viremia, and histologic evidence of hepatic injury to evaluate the course of HCV infection in children infected by blood transfusion. Patients and methods. Twenty-nine patients (ages 4 to 18 years) who underwent open-heart surgeries for congenital heart disease were grouped into three categories based on alterations in serum alanine aminotransferase (ALT) levels: Group A, acute infection; Group B, subacute infection; and Group C, chronic infection. Results. In Group C, all 13 patients had detectable HCV RNA in serum. In contrast, all patients in Group A had no detectable HCV RNA. In Group B, one of nine patients had detectable HCV RNA and two of four patients examined had persistent chronic hepatitis by histologic criteria. Antibodies directed against C100-3 antigen or core-antigen were more useful than second-generation HCV antibody assays in determining the relationship between viremia and immunologic response. Infection with HCV genotype II and the presence of higher HCV RNA copy numbers were associated with histologic evidence of hepatic damage. Conclusion. An abnormal ALT value is frequently associated with viremia, and biochemically resolved acute infection reflects clearance of HCV. However, a normal ALT does not always reflect an absence of hepatocyte damage and HCV replication in patients with subacute disease. The measures outlined in this study are useful indicators of disease activity during the chronic phase of post-transfusion HCV infection.

Ponatinib, Lestaurtinib and mTOR/PI3K inhibitors are promising repurposing candidates against Entamoeba histolytica

2021 ◽  
Author(s):  
Monica M. Kangussu-Marcolino ◽  
Upinder Singh
Keyword(s):  
Entamoeba Histolytica ◽  
Current Treatment ◽  
Clinical Development ◽  
New Drugs ◽  
Phase Iii ◽  
Significant Advance ◽  
Pi3k Inhibitors ◽  
Treatment Regimens ◽  
Clinical Resistance ◽  
Tk Inhibitors

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened the ReFRAME library (11,948 compounds assembled for Repurposing, Focused Rescue, and Accelerated Medchem) against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 μM and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation including 6 FDA approved, 5 orphan designation, and 15 which are currently in clinical trials (3 phase III, 7 phase II and 5 phase I). We found that all 26 compounds are active against metronidazole resistant E. histolytica and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: the Bcr-Abl TK inhibitors, with the ponatinib (EC 50 0.39) as most potent and mTOR or PI3K inhibitors with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for drug development against E. histolytica .

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