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Pharmaceuticals (Basel, Switzerland) Feb 2024Leishmaniasis, a neglected tropical disease, poses a significant global health challenge, necessitating the urgent development of innovative therapies. In this study, we...
Leishmaniasis, a neglected tropical disease, poses a significant global health challenge, necessitating the urgent development of innovative therapies. In this study, we aimed to identify compounds from the COVID Box with potential efficacy against two species, laying the foundation for future chemical development. Four promising molecules were discovered, demonstrating notable inhibitory effects against and . Our study revealed that bortezomib, almitrine, and terconazole induced a significant decrease in mitochondrial membrane potential, while the above compounds and ABT239 induced plasma permeability alterations, chromatin condensation, and reactive oxygen species accumulation, indicating early apoptosis in promastigotes, preventing inflammatory responses and tissue damage, thereby improving patient outcomes. Furthermore, ADME predictions revealed favorable pharmacokinetic profiles for all compounds, with bortezomib and ABT239 standing out as potential candidates. These compounds exhibited intestinal absorption, blood-brain barrier penetration (excluding bortezomib), and good drug-likeness for bortezomib and ABT239. Toxicity predictions for CYP-inhibition enzymes favored bortezomib as the safest candidate. In conclusion, our study identifies bortezomib as a promising aspirant for leishmaniasis treatment, demonstrating potent antiparasitic activity, favorable pharmacokinetics, and low toxicity. These findings emphasize the potential repurposing of existing drugs for neglected diseases and highlight the importance of the COVID Box in drug discovery against tropical diseases.
PubMed: 38543052
DOI: 10.3390/ph17030266 -
Frontiers in Pharmacology 2023During the coronavirus disease 2019 (COVID-19) pandemic, a large number of critically ill and severe COVID-19 patients meet the diagnostic criteria for sepsis and even...
During the coronavirus disease 2019 (COVID-19) pandemic, a large number of critically ill and severe COVID-19 patients meet the diagnostic criteria for sepsis and even septic shock. The treatments for COVID-19 patients with sepsis are still very limited. For sepsis, improving ventilation is one of the main treatments. Nitric oxide (NO) and almitrine have been reported to improve oxygenation in patients with "classical" sepsis. Here, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of NO, almitrine, and the combination of both for COVID-19 (at the edge of sepsis) patients. A systematic search was performed on Embase, PubMed, the Cochrane Library, the Web of Science, Wanfang Data, and China National Knowledge Infrastructure. Randomized clinical trials, cohort studies, cross-sectional studies, case-control studies, case series, and case reports in COVID-19 patients with suspected or confirmed sepsis were performed. Study characteristics, patient demographics, interventions, and outcomes were extracted from eligible articles. A total of 35 studies representing 1,701 patients met eligibility criteria. Inhaled NO did not affect the mortality (OR 0.96, 95% CI 0.33-2.8, I = 81%, very low certainty), hospital length of stay (SMD 0.62, 95% CI 0.04-1.17, I = 83%, very low certainty), and intubation needs (OR 0.82, 95% CI 0.34-1.93, I = 56%, very low certainty) of patients with COVID-19 (at the edge of sepsis). Meanwhile, almitrine did not affect the mortality (OR 0.44, 95% CI 0.17-1.13, low certainty), hospital length of stay (SMD 0.00, 95% CI -0.29-0.29, low certainty), intubation needs (OR 0.94, 95% CI 0.5-1.79, low certainty), and SAEs (OR 1.16, 95% CI 0.63-2.15, low certainty). Compared with pre-administration, the PaO/FiO of patients with NO (SMD-0.87, 95% CI -1.08-0.66, I = 0%, very low certainty), almitrine (SMD-0.73, 95% CI-1.06-0.4, I = 1%, very low certainty), and the combination of both (SMD-0.94, 95% CI-1.71-0.16, I = 47%, very low certainty) increased significantly. Inhaled NO, almitrine, and the combination of the two drugs improved oxygenation significantly, but did not affect the patients' mortality, hospitalization duration, and intubation needs. Almitrine did not significantly increase the patients' SAEs. Well-designed high-quality studies are needed for establishing a stronger quality of evidence. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=367667, identifier CRD42022367667.
PubMed: 38318311
DOI: 10.3389/fphar.2023.1172447 -
Alzheimer's Research & Therapy Jan 2024Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel...
BACKGROUND
Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.
METHODS
We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent.
RESULTS
We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment.
CONCLUSIONS
Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.
Topics: Humans; Alzheimer Disease; Proteomics; Risk Factors; Blood Proteins; Biomarkers; Genome-Wide Association Study
PubMed: 38212844
DOI: 10.1186/s13195-023-01378-4 -
PloS One 2023Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world's population and can cause severe congenital,...
Repurposing the Medicines for Malaria Venture's COVID Box to discover potent inhibitors of Toxoplasma gondii, and in vivo efficacy evaluation of almitrine bismesylate (MMV1804175) in chronically infected mice.
Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world's population and can cause severe congenital, neurological and ocular issues. Current treatment options are limited, and there are no human vaccines available to prevent transmission. Drug repurposing has been effective in identifying anti-T. gondii drugs. In this study, the screening of the COVID Box, a compilation of 160 compounds provided by the "Medicines for Malaria Venture" organization, was conducted to explore its potential for repurposing drugs to combat toxoplasmosis. The objective of the present work was to evaluate the compounds' ability to inhibit T. gondii tachyzoite growth, assess their cytotoxicity against human cells, examine their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and investigate the potential of one candidate drug through an experimental chronic model of toxoplasmosis. Early screening identified 29 compounds that could inhibit T. gondii survival by over 80% while keeping human cell survival up to 50% at a concentration of 1 μM. The Half Effective Concentrations (EC50) of these compounds ranged from 0.04 to 0.92 μM, while the Half Cytotoxic Concentrations (CC50) ranged from 2.48 to over 50 μM. Almitrine was chosen for further evaluation due to its favorable characteristics, including anti-T. gondii activity at nanomolar concentrations, low cytotoxicity, and ADMET properties. Administering almitrine bismesylate (Vectarion®) orally at dose of 25 mg/kg/day for ten consecutive days resulted in a statistically significant (p < 0.001) reduction in parasite burden in the brains of mice chronically infected with T. gondii (ME49 strain). This was determined by quantifying the RNA of living parasites using real-time PCR. The presented results suggest that almitrine may be a promising drug candidate for additional experimental studies on toxoplasmosis and provide further evidence of the potential of the MMV collections as a valuable source of drugs to be repositioned for infectious diseases.
Topics: Animals; Mice; Toxoplasma; Almitrine; Drug Repositioning; COVID-19; Toxoplasmosis; Malaria
PubMed: 37418497
DOI: 10.1371/journal.pone.0288335 -
British Journal of Anaesthesia Jan 2023Intrapulmonary shunt is a major determinant of oxygenation in thoracic surgery under one-lung ventilation. We reviewed the effects of available treatments on shunt,... (Meta-Analysis)
Meta-Analysis
Impact of pharmacological interventions on intrapulmonary shunt during one-lung ventilation in adult thoracic surgery: a systematic review and component network meta-analysis.
BACKGROUND
Intrapulmonary shunt is a major determinant of oxygenation in thoracic surgery under one-lung ventilation. We reviewed the effects of available treatments on shunt, Pao/FiO and haemodynamics through systematic review and network meta-analysis.
METHODS
Online databases were searched for RCTs comparing pharmacological interventions and intrapulmonary shunt in thoracic surgery under one-lung ventilation up to March 30, 2022. Random-effects (component) network meta-analysis compared 24 treatments and 19 treatment components. The Confidence in Network Meta-Analysis (CINeMA) framework assessed evidence certainty. The primary outcome was intrapulmonary shunt fraction during one-lung ventilation.
RESULTS
A total of 55 RCTs were eligible for systematic review (2788 participants). The addition of NO (mean difference [MD]=-15%; 95% confidence interval [CI], -25 to -5; P=0.003) or almitrine (MD=-13%; 95% CI, -20 to -6; P<0.001) to propofol anaesthesia were efficient at decreasing shunt. Combined epidural anaesthesia (MD=3%; 95% CI, 1-5; P=0.005), sevoflurane (MD=5%; 95% CI, 2-8; P<0.001), isoflurane (MD=6%; 95% CI, 4-9; P<0.001), and desflurane (MD=9%; 95% CI, 4-14; P=0.001) increased shunt vs propofol. Almitrine (MD=147 mm Hg; 95% CI, 58-236; P=0.001), dopexamine (MD=88 mm Hg; 95% CI, 4-171; P=0.039), and iloprost (MD=81 mm Hg; 95% CI, 4-158; P=0.038) improved Pao/FiO. Certainty of evidence ranged from very low to moderate.
CONCLUSIONS
Adding NO or almitrine to propofol anaesthesia reduced intrapulmonary shunt during one-lung ventilation. Halogenated anaesthetics increased shunt in comparison with propofol. The effects of NO, iloprost, and dexmedetomidine should be investigated in future research. NO results constitute a research hypothesis currently not backed by any direct evidence. The clinical availability of almitrine is limited.
SYSTEMATIC REVIEW PROTOCOL
PROSPERO CRD42022310313.
Topics: Adult; Humans; Almitrine; Iloprost; Network Meta-Analysis; One-Lung Ventilation; Propofol; Thoracic Surgery
PubMed: 36939497
DOI: 10.1016/j.bja.2022.08.039 -
Respiratory Research Jan 2023Almitrine, a selective pulmonary vasoconstrictor in hypoxic area, improves oxygenation in mechanically ventilated patients with COVID-19 but its effects in spontaneously...
BACKGROUND
Almitrine, a selective pulmonary vasoconstrictor in hypoxic area, improves oxygenation in mechanically ventilated patients with COVID-19 but its effects in spontaneously breathing patients with COVID-19 remain to be determined.
METHODS
We prospectively studied the effects of almitrine (16 µg/kg/min over 30 min followed by continuous administration in responders only) in 62 patients (66% of male, 63 [53-69] years old) with COVID-19 treated with high-flow nasal cannula oxygen therapy (HFNO) and with persistent hypoxemia, defined as a PaO/FiO ratio < 100 with FiO > 80% after a single awake prone positioning session. Patients with an increase in PaO/FiO ratio > 20% were considered as responders.
RESULTS
Overall, almitrine increased the PaO/FiO ratio by 50% (p < 0.01), decreased the partial arterial pressure of carbon dioxide by 7% (p = 0.01) whereas the respiratory rate remained unchanged and 46 (74%) patients were responders. No patient experienced right ventricular dysfunction or acute cor pulmonale. The proportion of responders was similar regardless of the CT-Scan radiological pattern: 71% for the pattern with predominant ground-glass opacities and 76% for the pattern with predominant consolidations (p = 0.65). Responders had lower intubation rate (33 vs. 88%, p < 0.01), higher ventilator-free days at 28-day (28 [20-28 ] vs. 19 [2-24] days, p < 0.01) and shorter ICU length of stay (5 [3-10] vs.12 [7-30] days, p < 0.01) than non-responders.
CONCLUSIONS
Almitrine could be an interesting therapy in spontaneously breathing patients with COVID-19 treated with HFNO and with persistent hypoxemia, given its effects on oxygenation without serious adverse effects regardless of the CT-Scan pattern, and potentially on intubation rate. These preliminary results need to be confirmed by further randomized studies.
Topics: Humans; Male; Middle Aged; Aged; Almitrine; COVID-19; Cannula; Respiratory Distress Syndrome; Hypoxia; Oxygen
PubMed: 36600234
DOI: 10.1186/s12931-022-02308-y -
EClinicalMedicine Oct 2022Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because...
Effect of intravenous almitrine on intubation or mortality in patients with COVID-19 acute hypoxemic respiratory failure: A multicentre, randomised, double-blind, placebo-controlled trial.
BACKGROUND
Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because almitrine improves V/Q, it might reduce the risk for mechanical ventilation (MV) in such patients. Our primary objective was to determine the effect of almitrine on the need for MV at day 7.
METHODS
In a randomised double-blind placebo-controlled trial involving 15 ICUs, patients hospitalized for COVID-19 pneumonia and experiencing acute hypoxemic respiratory failure were randomly assigned to receive 5 days of intravenous low-dose (2 µg.kg.min) almitrine or placebo. The primary outcome was endotracheal intubation for MV or death within 7 days after randomisation. Secondary outcomes included in-hospital mortality, 28-day mortality, number of ventilator-free days, number of days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects. This trial was registered with ClinicalTrials.gov, NCT04357457.
FINDINGS
Between September 3, 2020 and September 25, 2021 181 patients were enrolled and randomly assigned to almitrine (n=89) or placebo (n=92). 179 patients (excluding two who withdrew from the study) were included in the intention-to-treat analysis (mean age: 60·1 years; 34% women) and analyzed. On day 7, the primary endpoint occurred in 32 patients assigned to almitrine (36%) and in 37 patients assigned to placebo (41%), for a difference of -4·3% (95% confidence interval: -18·7% to 10·2%). Secondary outcomes (28-day mortality, in-hospital mortality, ventilator-free days at day 28, days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects) did not differ between the two groups.
INTERPRETATION
In patients with COVID-19 acute hypoxemic respiratory failure, low-dose almitrine failed in reducing the need for MV or death at day 7.
FUNDING
Programme Hospitalier de Recherche Clinique (PHRC COVID 2020) funded by the French Ministry of Health, Les Laboratoires Servier (Suresnes, France) providing the study drug free of charge.
PubMed: 36157895
DOI: 10.1016/j.eclinm.2022.101663 -
Pharmaceutics Aug 2022is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when...
is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient's eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti- activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti- activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against tachyzoites) that was higher than 47, whilst being considered a lead compound against . Almitrine showed interactions with the Na/K ATPase transporter for and , indicating a possible mechanism of action of this compound.
PubMed: 36015260
DOI: 10.3390/pharmaceutics14081634 -
Journal of Infection and Public Health Feb 2022To clarify the work done by using AI for identifying the genomic sequences, development of drugs and vaccines for COVID-19 and to recognize the advantages and challenges... (Review)
Review
OBJECTIVES
To clarify the work done by using AI for identifying the genomic sequences, development of drugs and vaccines for COVID-19 and to recognize the advantages and challenges of using such technology.
METHODS
A non-systematic review was done. All articles published on Pub-Med, Medline, Google, and Google Scholar on AI or digital health regarding genomic sequencing, drug development, and vaccines of COVID-19 were scrutinized and summarized.
RESULTS
The sequence of SARS- CoV-2 was identified with the help of AI. It can help also in the prompt identification of variants of concern (VOC) as delta strains and Omicron. Furthermore, there are many drugs applied with the help of AI. These drugs included Atazanavir, Remdesivir, Efavirenz, Ritonavir, and Dolutegravir, PARP1 inhibitors (Olaparib and CVL218 which is Mefuparib hydrochloride), Abacavir, Roflumilast, Almitrine, and Mesylate. Many vaccines were developed utilizing the new technology of bioinformatics, databases, immune-informatics, machine learning, and reverse vaccinology to the whole SARS-CoV-2 proteomes or the structural proteins. Examples of these vaccines are the messenger RNA and viral vector vaccines. AI provides cost-saving and agility. However, the challenges of its usage are the difficulty of collecting data, the internal and external validation, ethical consideration, therapeutic effect, and the time needed for clinical trials after drug approval. Moreover, there is a common problem in the deep learning (DL) model which is the shortage of interpretability.
CONCLUSION
The growth of AI techniques in health care opened a broad gate for discovering the genomic sequences of the COVID-19 virus and the VOC. AI helps also in the development of vaccines and drugs (including drug repurposing) to obtain potential preventive and therapeutic agents for controlling the COVID-19 pandemic.
Topics: Artificial Intelligence; COVID-19; COVID-19 Vaccines; Drug Development; Humans; Pandemics; SARS-CoV-2; Viral Vaccines
PubMed: 35078755
DOI: 10.1016/j.jiph.2022.01.011 -
Frontiers in Medicine 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is manifested by an acute respiratory distress syndrome (ARDS) with intense inflammation and endothelial...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is manifested by an acute respiratory distress syndrome (ARDS) with intense inflammation and endothelial dysfunction leading to particularly severe hypoxemia. We hypothesized that an impaired hypoxic pulmonary vasoconstriction aggravates hypoxemia. The objective of the study was to test the effect of two pulmonary vasoactive drugs on patient oxygenation. Observational, single-center, open-label study in one intensive care unit (ICU) of the Paris area, realized in April 2020. Eligible patients had coronavirus disease 2019 (COVID-19) and moderate to severe ARDS [arterial partial pressure of oxygen/fraction of inspired oxygen (PaO/FiO) <200 mmHg] despite conventional protective ventilation. Exclusion criteria included pulmonary artery hypertension defined by a pulmonary artery systolic pressure (PAPs) >45 mmHg. The assessment of oxygenation was based on PaO/FiO at (1) baseline, then after (2) 30 min of inhaled nitric oxide (iNO) 10 ppm alone, then (3) 30 min combination of iNO + almitrine infusion 8 μg/kg/min, then (4) 30 min of almitrine infusion alone. Among 20 patients requiring mechanical ventilation during the study period, 12 met the inclusion criteria. Baseline PaO/FiO was 146 ± 48 mmHg. When iNO was combined with almitrine, PaO/FiO rose to 255 ± 90 mmHg (+80 ± 49%, = 0.005), also after almitrine alone: 238 ± 98 mmHg (+67 ± 75%, = 0.02), but not after iNO alone: 185 ± 73 mmHg (+30 ± 5%, = 0.49). No adverse events related to almitrine infusion or iNO was observed. Combining iNO and infused almitrine improved the short-term oxygenation in patients with COVID-19-related ARDS. This combination may be of interest when first-line therapies fail to restore adequate oxygenation. These findings argue for an impaired pulmonary hypoxic vasoconstriction in these patients.
PubMed: 34277653
DOI: 10.3389/fmed.2021.655763