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Annual Review of Microbiology Sep 2020Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. parasites resistant to... (Review)
Review
Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification. The structure of PfCRT, solved by cryogenic electron microscopy, shows mutations surrounding an electronegative central drug-binding cavity where they presumably interact with drugs and natural substrates to control transport. susceptibility to heme-binding antimalarials is also modulated by overexpression or mutations in the digestive vacuole membrane-bound ABC transporter PfMDR1 ( multidrug resistance 1 transporter). Artemisinin resistance is primarily mediated by mutations in Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and artemisinin activation. Combating drug-resistant malaria urgently requires the development of new antimalarial drugs with novel modes of action.
Topics: Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Membrane Transport Proteins; Mutation; Plasmodium falciparum; Protozoan Proteins; Quinolines
PubMed: 32905757
DOI: 10.1146/annurev-micro-020518-115546 -
Trends in Parasitology Aug 2022African children under 5 years of age bear the main burden of global malaria mortality. Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus... (Review)
Review
African children under 5 years of age bear the main burden of global malaria mortality. Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) given monthly during the rainy season is a highly effective malaria intervention for children aged between 3 months and 5 years living in the Sahel region, a region of intense but seasonal malaria transmission. This intervention is now being considered for other regions of Africa where malaria parasites are more drug resistant. Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy (ACT), has proved to be highly effective and well tolerated in intermittent preventive treatment in pregnant women and children. This combination may be a suitable alternative for SMC. Understanding the safety, pharmacokinetic and pharmacodynamic properties of antimalarial combination therapies is crucial in optimising dosing.
Topics: Amodiaquine; Antimalarials; Chemoprevention; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Malaria; Pregnancy; Pyrimethamine; Seasons; Sulfadoxine
PubMed: 35688778
DOI: 10.1016/j.pt.2022.05.003 -
Pharmacological Research May 2023Neuroinflammation is tightly associated with onset of depression. The nuclear receptor related 1 protein (Nurr1, also called Nr4a2), its roles in dopaminergic neurons is...
Neuroinflammation is tightly associated with onset of depression. The nuclear receptor related 1 protein (Nurr1, also called Nr4a2), its roles in dopaminergic neurons is well understood, which can alleviate inflammation. Nevertheless, potential effects of Nr4a2 on neuroinflammation associated with depression still remains unclear. Chronic lipopolysaccharides (LPS) stress induced depressive-behaviors were confirmed via behavioral tests. Differentially expressed genes were detected by using RNA-sequencing. The anterior cingulate cortex (ACC) tissues were collected for biochemical experiments. The Golgi-Cox staining and virus labeling were used to evaluate the dendritic spines. We applied fluoxetine (FLX) and amodiaquine dihydrochloride (AQ, a highly selective agonist of Nr4a2) in mice. Overexpression experiments were performed by injecting with AAV-Nr4a2-EGFP into ACC. Chemogenetic activation of CamkII neurons via injecting the hM3Dq virus. Mice treated with LPS displayed depressive- and anxiety-like behaviors. The reduction of Nr4a2 and FosB induced by LPS were rescued by pretreatment with FLX or AQ. More importantly, LPS-induced behavior deficits in mice were also alleviated via fluoxetine treatment and pharmacological activation the expression of Nr4a2. Meanwhile, enhancing the level of Nr4a2 could improve dendritic spines loss of neuron and morphological changes in microglia. Overexpression of Nr4a2 in ACC reversed the depressive- and anxiety-like behaviors caused by LPS administration. Activation of CamkII neurons in ACC could robustly increase the expression of Nr4a2 and improve LPS-induced behavior deficits. Our findings demonstrate that the Nr4a2 may regulate depressive-like behaviors via alleviating the impairment of morphology and function on microglia and CamkII neurons induced by chronic neuroinflammation.
Topics: Animals; Mice; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Depression; Fluoxetine; Gyrus Cinguli; Lipopolysaccharides; Microglia; Neuroinflammatory Diseases; Neurons; Nuclear Receptor Subfamily 4, Group A, Member 2
PubMed: 36948326
DOI: 10.1016/j.phrs.2023.106717 -
Briefings in Functional Genomics Sep 2019Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all... (Review)
Review
Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.
Topics: Aminoquinolines; Anti-Bacterial Agents; Antimalarials; Artemisinins; Atovaquone; Drug Resistance; Drug Resistance, Multiple; Folic Acid Antagonists; Humans; Malaria; Plasmodium falciparum; Plasmodium vivax; Quinine
PubMed: 31119263
DOI: 10.1093/bfgp/elz008 -
Nature Communications Jul 2023The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's...
The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1's transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD.
Topics: Mice; Animals; Male; Parkinson Disease; Dopaminergic Neurons; Mesencephalon; Brain; Neuroprotective Agents; Disease Models, Animal; Nuclear Receptor Subfamily 4, Group A, Member 2
PubMed: 37463889
DOI: 10.1038/s41467-023-39970-9 -
Infection and Drug Resistance 2022The use of poor quality drugs will have multiple consequences with an extended hazard of growing drug-resistant strains. (Review)
Review
BACKGROUND
The use of poor quality drugs will have multiple consequences with an extended hazard of growing drug-resistant strains.
PURPOSE
The review aimed to provide the quality status of antimalarial drugs in East Africa.
DATA SOURCE
PubMed, Scopus, Web of Science, and Google Scholar were searched from September 5 to September 12, 2021.
STUDY SELECTION
The review included articles available as original research targeted at evaluating the quality of antimalarial drugs. For inclusion, data on at least one of the following quality control parameters were required: packaging and labeling, hardness, friability, weight variation/uniformity of weight, disintegration, dissolution, and assay/percentage purity. Mendeley citation manager version 1.19.4 was used to avoid duplication and organize references, and titles and abstracts were primarily used for screening.
DATA EXTRACTION
The sample collection site, drug name, and the quality control parameters tested were retrieved from the selected studies.
DATA SYNTHESIS
Totally, 300 antimalarial drug samples from Ethiopia, Kenya and Tanzania were included in this review. No antimalarial drug tested failed the identification and disintegration test. However, 15.93% (36/226), 5.00% (15/300), and 1.90% (3/158) of antimalarial samples failed the dissolution, assay and mass uniformity test, respectively. Moreover, amodiaquine and sulfadoxine/pyrimethamine samples failed dissolution and assay tests. In addition, amodiaquine samples failed the mass uniformity test. However, artemether/lumefantrine and quinine passed all quality control parameters tested. Overall, 19.67% (59/300) of antimalarial drug samples did not meet at least one quality control parameter. And the higher faller rate was reported for sulfadoxine/pyrimethamine accounting for 52.86% (37/70).
CONCLUSIONS
An unneglected amount of antimalarial drug failed to meet at least one quality control parameter. Strengthening pharmaceutical management systems, including post-marketing surveillance, and providing the resources required for medication quality assurance, are recommended.
PubMed: 36277242
DOI: 10.2147/IDR.S373059 -
The New England Journal of Medicine Sep 2023Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin...
BACKGROUND
Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in on the continent is troubling, given the lack of alternative treatments.
METHODS
In this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in as predictive markers of partial resistance to artemisinin and screened for deletions in and that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.
RESULTS
We noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both and were identified in 16.9% of the parasites that carried the R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.
CONCLUSIONS
The emergence and spread of lineages with both -mediated partial resistance to artemisinin and deletions in and in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.).
Topics: Humans; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Eritrea; Malaria, Falciparum; Plasmodium falciparum; Prevalence
PubMed: 37754284
DOI: 10.1056/NEJMoa2210956 -
British Journal of Clinical Pharmacology Mar 2023Amodiaquine is a 4-aminoquinoline used extensively for the treatment and prevention of malaria. Orally administered amodiaquine is largely converted to the active...
AIMS
Amodiaquine is a 4-aminoquinoline used extensively for the treatment and prevention of malaria. Orally administered amodiaquine is largely converted to the active metabolite desethylamodiaquine. Amodiaquine can cause bradycardia, hypotension, and electrocardiograph QT interval prolongation, but the relationship of these changes to drug concentrations is not well characterized.
METHODS
We conducted a secondary analysis of a pharmacokinetic study of the cardiac safety of amodiaquine (10 mg base/kg/day over 3 days) in 54 Kenyan adults (≥18 years) with uncomplicated malaria. Nonlinear mixed effects modelling was used to assess amodiaquine and desethylamodiaquine concentration-effect relationships for vital sign (pulse rate, blood pressure) and electrocardiograph interval (QT, QRS, PR) outcomes. We also measured the spontaneous beating heart rate after cumulative dosing of amodiaquine and desethylamodiaquine in isolated mouse atrial preparations.
RESULTS
Amodiaquine and desethylamodiaquine caused concentration-dependent mean decreases in pulse rate (1.9 beats/min per 100 nmol/L; 95% confidence interval: 1.5-2.4), supine systolic blood pressure (1.7 mmHg per 100 nmol/L; 1.2-2.1), erect systolic blood pressure (1.5 mmHg per 100 nmol/L; 1.0-2.0) and erect diastolic blood pressure (1.4 mmHg per 100 nmol/L; 1.0-1.7). The mean QT interval prolongation was 1.4 ms per 100 nmol/L irrespective of correction factor after adjustment for residual heart rate dependency. There was no significant effect of drug concentration on postural change in blood pressure or PR and QRS intervals. In mouse atria, the spontaneous beating rate was significantly reduced by amodiaquine (n = 6) and desethylamodiaquine (n = 8) at 3 μmol/L (amodiaquine: 10 ± 2%; desethylamodiaquine: 12 ± 3%) and 10 μmol/L (amodiaquine: 50 ± 7%; desethylamodiaquine: 46 ± 6%) concentrations with no significant difference in potency between the 2 compounds.
CONCLUSION
Amodiaquine and desethylamodiaquine have concentration-dependent effects on heart rate, blood pressure, and ventricular repolarization.
Topics: Animals; Mice; Amodiaquine; Antimalarials; Kenya; Malaria
PubMed: 36256474
DOI: 10.1111/bcp.15569 -
International Journal of Molecular... Jun 2022Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation...
Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1-H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.
Topics: Drug Repositioning; Histamine; Histamine Agents; Humans; Multiple Sclerosis; Receptors, Histamine H4; Remyelination
PubMed: 35683024
DOI: 10.3390/ijms23116347 -
Viruses Jun 2020As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases...
As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.
Topics: Amodiaquine; Animals; Antiviral Agents; Betacoronavirus; COVID-19; Caco-2 Cells; Cell Line, Tumor; Chlorocebus aethiops; Coronavirus Infections; Drug Therapy, Combination; Emetine; HEK293 Cells; HT29 Cells; Homoharringtonine; Humans; Immune Sera; Immunization, Passive; Indoles; Nelfinavir; Neutralization Tests; Pandemics; Pneumonia, Viral; Pyrans; Pyrroles; SARS-CoV-2; Vero Cells; COVID-19 Serotherapy
PubMed: 32545799
DOI: 10.3390/v12060642