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International Journal For Parasitology.... Apr 2024Target-based approaches have traditionally been used in the search for new anti-infective molecules. Target selection process, a critical step in Drug Discovery,...
Target-based approaches have traditionally been used in the search for new anti-infective molecules. Target selection process, a critical step in Drug Discovery, identifies targets that are essential to establish or maintain the infection, tractable to be susceptible for inhibition, selective towards their human ortholog and amenable for large scale purification and high throughput screening. The work presented herein validates the Plasmodium falciparum mRNA 5' triphosphatase (PfPRT1), the first enzymatic step to cap parasite nuclear mRNAs, as a candidate target for the development of new antimalarial compounds. mRNA capping is essential to maintain the integrity and stability of the messengers, allowing their translation. PfPRT1 has been identified as a member of the tunnel, metal dependent mRNA 5' triphosphatase family which differs structurally and mechanistically from human metal independent mRNA 5' triphosphatase. In the present study the essentiality of PfPRT1 was confirmed and molecular biology tools and methods for target purification, enzymatic assessment and target engagement were developed, with the goal of running a future high throughput screening to discover PfPRT1 inhibitors.
PubMed: 38810336
DOI: 10.1016/j.ijpddr.2024.100537 -
PloS One 2024The dispensation of medicines in some low- and middle-income countries is often carried out by private vendors operating under constrained conditions. The aim of this...
INTRODUCTION
The dispensation of medicines in some low- and middle-income countries is often carried out by private vendors operating under constrained conditions. The aim of this study was to understand the challenges reported by employees of dispensaries, specifically, chemical and herbal shops and pharmacies in Accra, Ghana. Our objectives were twofold: (1) to assess challenges faced by medicine vendors related to dispensing antimicrobials (antibiotic and antimalarial medications), and (2) to identify opportunities for improving their stewardship of antimicrobials.
METHODS
Data were collected in 79 dispensaries throughout Accra, in 2021, using a survey questionnaire. We used open-ended questions, grounded on an adapted socioecological model of public health, to analyze these data and determine challenges faced by respondents.
RESULTS
We identified multiple, interlocking challenges faced by medicine vendors. Many of these relate to challenges of antimicrobial stewardship (following evidence-based practices when dispensing medicines). Overall, medicine vendors frequently reported challenges at the Customer and Community levels. These included strained interactions with customers and the prohibitive costs of medications. The consequences of these challenges reverberated and manifested through all levels of the socioecological model of public health (Entity, Customer, Community, Global).
DISCUSSION
The safe and effective distribution of medications was truncated by strained interactions, often related to the cost of medicines and gaps in knowledge. While addressing these challenges requires multifaceted approaches, we identified several areas that, if intervened upon, could unlock the great potential of antimicrobal stewardship. The effective and efficient implementation of key interventions could facilitate efforts spearheaded by medicine vendors and leverage the benefits of their role as health educators and service providers.
CONCLUSION
Addressing barriers faced by medicine vendors would provide an opportunity to significantly improve the provision of medications, and ultimately population health. Such efforts will likely expand access to populations who may otherwise be unable to access medications and treatment in formal institutions of care such as hospitals. Our findings also highlight the broad range of care provided by shopkeepers and vendors at dispensaries. These findings suggest that the meaningful engagement of dispensaries as valued conduits of community health is a promising pathway for interventions aiming to improve antimicrobial stewardship.
Topics: Ghana; Humans; Pharmacies; Surveys and Questionnaires; Antimicrobial Stewardship; Anti-Infective Agents; Commerce; Anti-Bacterial Agents; Antimalarials; Public Health
PubMed: 38809832
DOI: 10.1371/journal.pone.0281699 -
Oncology Letters Jul 2024Artesunate (ART), an antimalarial drug, has a broad spectrum of antitumour effects in cancer types such as esophageal and gastric cancer. However, evidence demonstrating...
Artesunate (ART), an antimalarial drug, has a broad spectrum of antitumour effects in cancer types such as esophageal and gastric cancer. However, evidence demonstrating the role of ART in cervical cancer cells is limited. In the present study, the inhibitory effect of ART on the growth of cervical cancer cells through the modulation of the cell cycle and apoptosis was investigated. The growth-inhibitory effect of ART on a cervical cancer cell line (SiHa) was detected using a Cell Counting Kit-8 assay after treatment with ART for 24 h, after which the half-maximal inhibitory concentration (IC) was calculated. Using flow cytometry assays, apoptosis, the cell cycle, the levels of reactive oxygen species (ROS) and calcium (Ca) ions, as well as the mitochondrial membrane potential were evaluated in SiHa cells following treatment with ART for 24 and 48 h. The mRNA expression levels of Bcl2, Bcl-xl, (myeloid cell leukaemia 1) Mcl-1, Bcl2-like protein 11 (BIM), (Bcl2-related ovarian killer protein) Bok, Bax and (Bcl2 homologous antagonist/killer) Bak in SiHa cells were detected using reverse transcription-quantitative PCR. ART inhibited the growth of SiHa cells in a dose-dependent manner. The IC of ART in SiHa cells was 26.32 µg/ml. According to the IC value, 15, 30 and 100 µg/ml ART were selected for further experiments, and normal saline (0 µg/ml ART) was used as the control group. The results indicated that treatment with 15, 30 and 100 µg/ml ART for 24 and 48 h induced apoptosis, increased the levels of ROS, the levels of Ca and the mRNA expression levels of BIM, Bok, Bax and Bak, but decreased the cell proliferation indices, the mitochondrial membrane potential and the mRNA expression levels of Bcl2, Bcl-xl and Mcl-1 in a dose- and time-dependent manner. In conclusion, ART inhibited the growth of SiHa cells and induced apoptosis via a mechanism associated with the regulation of Bcl2 family member expression, which was associated with the increase of the levels of ROS and Ca and the reduction of the mitochondrial membrane potential.
PubMed: 38807670
DOI: 10.3892/ol.2024.14447 -
World Journal of Urology May 2024To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center... (Comparative Study)
Comparative Study
BACKGROUND
To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center experience switching from ciprofloxacin to fosfomycin trometamol (FMT) alone and to an augmented prophylaxis combining fosfomycin and trimethoprim/sulfamethoxazole (TMP/SMX).
METHODS
Between 01/2019 and 12/2020 we compared three different regimes. The primary endpoint was the clinical diagnosis of an infection within 4 weeks after biopsy. We enrolled 822 men, 398 (48%) of whom received ciprofloxacin (group-C), 136 (16.5%) received FMT (group-F) and 288 (35%) received the combination of TMP/SMX and FMT (group-BF).
RESULTS
Baseline characteristics were similar between groups. In total 37/398 (5%) postinterventional infections were detected, of which 13/398 (3%) vs 18/136 (13.2%) vs 6/288 (2.1%) were detected in group-C, group-F and group-BF respectively. The relative risk of infectious complication was 1.3 (CI 0.7-2.6) for group-C vs. group-BF and 2.8 (CI 1.4-5.7) for group-F vs. group-BF respectively.
CONCLUSION
The replacement of ciprofloxacin by fosfomycin alone resulted in a significant increase of postinterventional infections, while the combination of FMT and TMP/SMX had a comparable infection rate to FQ without apparent adverse events. Therefore, this combined regimen of FMT and TMP/SMX is recommended.
Topics: Humans; Male; Fosfomycin; Ciprofloxacin; Trimethoprim, Sulfamethoxazole Drug Combination; Antibiotic Prophylaxis; Aged; Middle Aged; Prostate; Anti-Bacterial Agents; Drug Therapy, Combination; Biopsy; Retrospective Studies; Rectum; Postoperative Complications
PubMed: 38806739
DOI: 10.1007/s00345-024-05048-4 -
International Journal For Parasitology.... May 2024Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage...
Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage of the parasite's life cycle. So far, some of these proteins have been singly targeted yielding inhibitor compounds that have been limited by incidences of resistance which can be overcome via pan-inhibition strategies. Hence, herein, for the first time, we report the identification and in vitro antiplasmodial validation of Mitomycin (MMC) as a probable pan-inhibitor of class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis. We combined multiple in silico structure-based discovery strategies that first helped identify functional and druggable sites that were preferentially targeted by the compound in each of the plasmodial proteins: Ins1-Ins2 domain in Pf-ARS; anticodon binding domain in Pf-CRS; CP1-editing domain in Pf-IRS and Pf-MRS; C-terminal domain in Pf-LRS; and CP-core region in Pf-VRS. Molecular dynamics studies further revealed that MMC allosterically induced changes in the global structures of each protein. Likewise, prominent structural perturbations were caused by the compound across the functional domains of the proteins. More so, MMC induced systematic alterations in the binding of the catalytic nucleotide and amino acid substrates which culminated in the loss of key interactions with key active site residues and ultimate reduction in the nucleotide-binding affinities across all proteins, as deduced from the binding energy calculations. These altogether confirmed that MMC uniformly disrupted the structure of the target proteins and essential substrates. Further, MMC demonstrated IC < 5 μM against the Dd2 and 3D7 strains of parasite making it a good starting point for malarial drug development. We believe that findings from our study will be important in the current search for highly effective multi-stage antimalarial drugs.
PubMed: 38805932
DOI: 10.1016/j.ijpddr.2024.100548 -
Medical Sciences (Basel, Switzerland) May 2024Phospholipidosis is a rare disorder which consists of an excessive intracellular accumulation of phospholipids and the appearance of zebra bodies or lamellar bodies when... (Review)
Review
Double Hit of Hydroxichloroquine and Amiodarone Induced Renal Phospholipidosis in a Patient with Monoclonal Gammopathy and Sclerodermiform Syndrome: A Case Report and Review of the Literature.
Phospholipidosis is a rare disorder which consists of an excessive intracellular accumulation of phospholipids and the appearance of zebra bodies or lamellar bodies when looking at them using electron microscopy. This disease is associated with certain genetic diseases or is secondary to drugs or toxins. Drug-induced phospholipidosis encompasses many types of pharmaceuticals, most notably chloroquine, amiodarone or ciprofloxacin. Clinically and histologically, renal involvement can be highly variable, with the diagnosis not being made until the zebra bodies are seen under an electron microscope. These findings may require genetic testing to discount Fabry disease, as its histological findings are indistinguishable. Most of the chemicals responsible are cationic amphiphilic drugs, and several mechanisms have been hypothesized for the formation of zebra bodies and their pathogenic significance. However, the relationship between drug toxicity and phospholipid accumulation, zebra bodies and organ dysfunction remains enigmatic, as do the renal consequences of drug withdrawal. We present, to our knowledge, the first case report of acute renal injury with a monoclonal gammopathy of renal significance, lesions, and sclerodermiform syndrome, with zebra bodies that were associated with the initiation of a hydroxychloroquine and amiodarone treatment, as an example of drug-induced-phospholipidosis.
Topics: Humans; Acute Kidney Injury; Amiodarone; Hydroxychloroquine; Lipidoses; Paraproteinemias; Phospholipids; Female; Aged
PubMed: 38804381
DOI: 10.3390/medsci12020025 -
Cureus Apr 2024In Nigeria, 97% of the population is at risk of contracting malaria. It is transmitted by female mosquitoes carrying the parasite and can be lethal. An estimated 55...
Malaria Parasitemia and Severe Health Complications in Children Under Five Years of Age in Nigeria: A Study Using the Demographic and Health Survey (DHS) Malaria Indicator Survey (MIS) 2021.
BACKGROUND
In Nigeria, 97% of the population is at risk of contracting malaria. It is transmitted by female mosquitoes carrying the parasite and can be lethal. An estimated 55 million illnesses and 80,000 deaths per year result from it. Children under five are more likely to contract malaria. Efforts to control malaria in Nigeria include indoor residual spraying, insecticide-treated bed nets, and quick detection and treatment of confirmed cases with effective antimalarial medications. These attempts have been impeded by limited healthcare access, poor financing, and drug-resistant parasites. Thus, the study of the relationship between malaria complications and housing for children under five is essential.
METHODS
The Demographic and Health Survey (DHS) Malaria Indicator Survey (MIS) 2021, a nationally representative data set from developing countries on population and health, was used for this study. A sample size of 13,727 was employed (n=13,727). Logistic regression analyses were conducted to test the association between the type of place of residence and malaria complications (outcome).
RESULTS
Overall, 4.2% (n=570, weight HV005) of participants in the sample reported malaria complications. The results of the logistic regression revealed that children residing in urban settlements (aOR 0.37, 95% CI 0.37-0.37, p-value <0.001), children from the poorest class families (aOR 11.63, 95% CI 1.62-1.63, p-value 0.004), children from poorer class families (aOR 7.56, 95% CI 7.55-7.57, p-value <0.001), children from middle-class families (aOR 4.05, 95% CI 4.03-9.06, p-value <0.001), children from richer class families (aOR 1.22, 95% CI 2.21-2.23, p-value <0.001), children of mothers with primary education (aOR 0.42, 95% CI 2.32-4.112, p-value 0.001), children of mothers with secondary education (aOR 0.24, 95% CI 3.21-3.22, p-value <0.001), children of mothers with higher education (aOR 0.08, 95% CI 0.72-0.80, p-value <0.001), and children of the female gender (aOR 0.65, 95% CI 0.65-0.66, p-value <0.001) are all associated with severe malaria complications.
CONCLUSIONS
In conclusion, the study examined malaria complications in Nigerian children under five by residency. The findings imply that rural children are more likely to have serious malaria complications than urban children. This emphasizes the necessity for targeted malaria therapies in rural areas with limited healthcare access.
PubMed: 38800144
DOI: 10.7759/cureus.58907 -
Narra J Apr 2024In Indonesia, malaria remains a problem, with 94,610 active cases in 2021 and its current therapy includes chloroquine and artemisinin; however, resistance has been...
In Indonesia, malaria remains a problem, with 94,610 active cases in 2021 and its current therapy includes chloroquine and artemisinin; however, resistance has been commonly reported. To overcome this problem, studies about potential medicinal plants that can be used as antimalaria, such as moringa () started to receive more attention. The aim of this study was to investigate the effects of moringa in parasitemia, monocyte activation, and organomegaly on animal model malaria. This experimental study used male , infected by ANKA, as an animal malaria model. The extract was made by maceration of dry moringa leaves, which were then divided into three concentrations: 25%, 50%, and 75%. Dihydroartemisinin-piperazine was used as a positive control treatment, and distilled water as a negative control treatment. The animals were observed for six days to assess the parasitemia count and the number of monocyte activation. On day 7, the animals were terminated, and the liver, spleen, and kidney were weighed. The results showed that the effective concentrations in reducing parasitemia and inducing monocyte activation were 50% and 25% of moringa leaf extract, respectively. The smallest liver and spleen enlargement was observed among animals within the group treated with a 50% concentration of extract. In contrast, the smallest kidney enlargement was observed in the group treated with 25% of extract. Further analysis is recommended to isolate compounds with antimalarial properties in moringa leaves.
Topics: Animals; Mice; Plasmodium berghei; Plant Extracts; Male; Malaria; Monocytes; Parasitemia; Disease Models, Animal; Antimalarials; Moringa; Moringa oleifera; Plant Leaves; Spleen; Organ Size
PubMed: 38798832
DOI: 10.52225/narra.v4i1.653 -
BioRxiv : the Preprint Server For... May 2024malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, requires nutritional iron to support...
malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, requires nutritional iron to support essential metabolic pathways, but the critical mechanisms of iron acquisition and trafficking during RBC infection have remained obscure. Parasites internalize and liberate massive amounts of heme during large-scale digestion of RBC hemoglobin within an acidic food vacuole (FV) but lack a heme oxygenase to release porphyrin-bound iron. Although most FV heme is sequestered into inert hemozoin crystals, prior studies indicate that trace heme escapes biomineralization and is susceptible to non-enzymatic degradation within the oxidizing FV environment to release labile iron. Parasites retain a homolog of divalent metal transporter 1 (DMT1), a known mammalian iron transporter. This protein localizes to the FV membrane, but its role in iron acquisition has not been tested. Our phylogenetic and microscopy studies indicate that DMT1 (PfDMT1) retains conserved molecular features critical for metal transport and is oriented on the FV membrane in an export-competent topology. Conditional knockdown of PfDMT1 expression is lethal to parasites, which display broad cellular defects in iron-dependent functions, including impaired apicoplast biogenesis and mitochondrial polarization. Parasites are selectively rescued from partial PfDMT1 knockdown by supplementation with exogenous iron, but not other metals. These results support a cellular paradigm whereby PfDMT1 is the molecular gatekeeper to essential iron acquisition by blood-stage malaria parasites and suggest that therapeutic targeting of PfDMT1 may be a potent antimalarial strategy.
PubMed: 38798484
DOI: 10.1101/2024.05.10.587216 -
Microorganisms Apr 2024Three patients with relapsing and remitting borreliosis, babesiosis, and bartonellosis, despite extended anti-infective therapy, were prescribed double-dose dapsone...
Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review.
Three patients with relapsing and remitting borreliosis, babesiosis, and bartonellosis, despite extended anti-infective therapy, were prescribed double-dose dapsone combination therapy (DDDCT) for 8 weeks, followed by one or several two-week courses of pulsed high-dose dapsone combination therapy (HDDCT). We discuss these patients' cases to illustrate three important variables required for long-term remission. First, diagnosing and treating active co-infections, including and were important. required rotations of multiple anti-malarial drug combinations and herbal therapies, and required one or several 6-day HDDCT pulses to achieve clinical remission. Second, all prior oral, intramuscular (IM), and/or intravenous (IV) antibiotics used for chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDS), irrespective of the length of administration, were inferior in efficacy to short-term pulsed biofilm/persister drug combination therapy i.e., dapsone, rifampin, methylene blue, and pyrazinamide, which improved resistant fatigue, pain, headaches, insomnia, and neuropsychiatric symptoms. Lastly, addressing multiple factors on the 16-point multiple systemic infectious disease syndrome (MSIDS) model was important in achieving remission. In conclusion, DDDCT with one or several 6-7-day pulses of HDDCT, while addressing abnormalities on the 16-point MSIDS map, could represent a novel effective clinical and anti-infective strategy in CLD/PTLDS and associated co-infections including .
PubMed: 38792737
DOI: 10.3390/microorganisms12050909