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IUBMB Life Mar 2022Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice... (Review)
Review
Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice possess a broad range of severe adverse effects towards vital organs which emphasizes the importance of the discovery of new therapeutic agents or repurposing of existing drugs for the treatment of human cancers. Pyrimethamine is an antiparasitic drug used for the treatment of malaria and toxoplasmosis with a well-documented excellent safety profile. In the last 5 years, numerous efforts have been made to explore the anticancer potential of pyrimethamine in in vitro and in vivo preclinical models and to repurpose it as an anticancer agent. The studies have demonstrated that pyrimethamine inhibits oncogenic proteins such as STAT3, NF-κB, DX2, MAPK, DHFR, thymidine phosphorylase, telomerase, and many more in a different types of cancer models. Moreover, pyrimethamine has been reported to work in synergy with other anticancer agents, such as temozolomide, to induce apoptosis of tumor cells. Recently, the results of phase-1/2 clinical trials demonstrated that pyrimethamine administration reduces the expression of STAT3 signature genes in tumor tissues of chronic lymphocytic leukemia patients with a good therapeutic response. In the present article, we have reviewed most of the published articles related to the antitumor effects of pyrimethamine in malignancies of breast, liver, lung, skin, ovary, prostate, pituitary, and leukemia in in vitro and in vivo settings. We have also discussed the pharmacokinetic profile and results of clinical trials obtained after pyrimethamine treatment. From these studies, we believe that pyrimethamine has the potential to be repurposed as an anticancer drug.
Topics: Antineoplastic Agents; Apoptosis; Female; Humans; Neoplasms; Pyrimethamine; Temozolomide
PubMed: 34921584
DOI: 10.1002/iub.2590 -
Drugs in R&D Dec 2017Approximately a third of the population worldwide is chronically infected with Toxoplasma gondii. Pyrimethamine-based regimens are recommended for the treatment of... (Review)
Review
INTRODUCTION
Approximately a third of the population worldwide is chronically infected with Toxoplasma gondii. Pyrimethamine-based regimens are recommended for the treatment of toxoplasmosis.
OBJECTIVE
The aim was to evaluate the safety profile of pyrimethamine-based treatment for the three main Toxoplasma manifestations: toxoplasmic encephalitis (TE), ocular toxoplasmosis, and congenital toxoplasmosis.
METHODS
PubMed, Cochrane Library, and Google Scholar databases were searched through August 1, 2016. Randomized, observational, prospective/retrospective, and cohort studies were eligible. Thirty-one studies were included with a total of 2975 patients. Of these, 13 were in congenital toxoplasmosis (n = 929), 11 in ocular toxoplasmosis (n = 1284), and seven in TE (n = 687). Across manifestations, adverse event (AE)-related treatment discontinuation and/or change in therapy involved ≤37% of patients and occurred in >55% of studies: 100% for ocular toxoplasmosis, 57.1% for TE, and 61.5% for congenital toxoplasmosis. The most commonly observed AEs were bone marrow suppression, dermatologic, and gastrointestinal (GI). The prevalence of bone marrow suppression-related AEs was ≤50% in congenital toxoplasmosis, ≤42.7% in TE, and ≤9.0% in ocular toxoplasmosis. The frequency of GI and dermatologic AEs were ≤100 and ≤11.1%, respectively, for ocular toxoplasmosis, ≤10.7 and ≤17.9% for TE, and ≤10.8 and ≤2.1% for congenital toxoplasmosis. Steven-Johnson syndrome was reported in two patients with ocular toxoplasmosis and one with TE.
CONCLUSION
The AE profile associated with pyrimethamine-based treatments differed by each manifestation of toxoplasmosis and within a given manifestation. Hematologic AEs occurred across all manifestations indicating the importance of monitoring the blood of patients administered pyrimethamine-based regimens.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Infectious Encephalitis; Pyrimethamine; Toxoplasmosis, Cerebral; Toxoplasmosis, Congenital; Toxoplasmosis, Ocular
PubMed: 28879584
DOI: 10.1007/s40268-017-0206-8 -
Expert Opinion on Drug Delivery Feb 2023The focus of the present research is to develop printlet formulations of pyrimethamine (PMT).
OBJECTIVES
The focus of the present research is to develop printlet formulations of pyrimethamine (PMT).
METHODS
Printlets formulation of PMT were developed by screening design by varying laser scanning speed, Kollidon® VA 64, polyvinylpyrrolidone, and disintegrant.
RESULTS
Laser scanning speed, Kollidon® VA, and disintegrant had statistically significant effect on hardness, disintegration time, and/or dissolution (p < 0.05). Dissolution was almost 100% in 30 min. X-ray powder diffraction indicated partial amorphous transformation of the crystalline drug. Pharmacokinetic and anti-toxoplasma activity profiles of the printlets and compressed tablets were superimposable with no statistical difference (p > 0.05).
CONCLUSION
Clinical performance of the printlets would be similar to the compressed tablets.
Topics: Humans; Child; Pyrimethamine; Povidone; Toxoplasma; Excipients; Tablets; Toxoplasmosis; Solubility
PubMed: 36639201
DOI: 10.1080/17425247.2023.2169272 -
Molecular Biology Reports Jun 2022The emergence of nonresponse or resistance to traditional chemotherapeutic agents is one of the main challenges of colorectal cancer (CRC) therapies. Thus, novel...
BACKGROUND
The emergence of nonresponse or resistance to traditional chemotherapeutic agents is one of the main challenges of colorectal cancer (CRC) therapies. Thus, novel therapeutic drugs that can improve the clinical outcomes of CRC patients are urgently needed. The purpose of this study was to investigate the effects and mechanisms of pyrimethamine in CRC.
METHODS AND RESULTS
In this study, we assessed the role of pyrimethamine on CRC cell growth by cell counting kit-8 and colony formation assays. Cell cycle distribution and cellular senescence were determined by flow cytometry and senescence-associated β-galactosidase staining respectively. RNA-seq analysis and western blotting were used to investigate the potential pathways of pyrimethamine in CRC development. Moreover, animal experiments were performed to evaluate the effect of pyrimethamine in vivo. Our results demonstrated that pyrimethamine could inhibit cell growth by inducing S phase arrest followed by cellular senescence in CRC cells, and the p38MAPK-p53 axis was probably involved in that effect. In addition, pyrimethamine could also boost CD8 T-cell mediated cytotoxicity and exert antitumor activity in vivo.
CONCLUSION
These results indicated that pyrimethamine may be a promising candidate agent for CRC treatment.
Topics: Animals; Apoptosis; CD8-Positive T-Lymphocytes; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Colorectal Neoplasms; Pyrimethamine; T-Lymphocytes
PubMed: 35262820
DOI: 10.1007/s11033-022-07262-y -
Science Advances Mar 2023Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine... (Randomized Controlled Trial)
Randomized Controlled Trial
Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.
Topics: Humans; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Pyrimethamine; RNA; Valproic Acid; Virus Activation; Virus Latency
PubMed: 36921041
DOI: 10.1126/sciadv.ade6675 -
British Medical Journal Oct 1973
Topics: Anemia, Macrocytic; Ataxia; Blindness; Central Nervous System; Child, Preschool; Deafness; Female; Fever; Folic Acid; Folic Acid Antagonists; Humans; Infant; Intellectual Disability; Leucovorin; Male; Pyrimethamine
PubMed: 4543103
DOI: 10.1136/bmj.4.5885.147 -
Journal of Global Antimicrobial... Mar 2020The aim of this study was to evaluate the efficacy of pyrimethamine-loaded poloxamer 407 nanomicelles on Plasmodium berghei strain NICD in vivo.
OBJECTIVES
The aim of this study was to evaluate the efficacy of pyrimethamine-loaded poloxamer 407 nanomicelles on Plasmodium berghei strain NICD in vivo.
METHODS
Pyrimethamine-loaded nanomicelles were prepared and their zeta potential, particle size and polydispersity index were measured. For antiplasmodial assessment, 54 mice were randomly divided into six groups. Four groups were infected intraperitoneally with P. berghei, whereas the two remaining groups did not receive the parasite (negative controls). Three of the P. berghei-infected groups received treatment with either pyrimethamine-loaded nanomicelles (2 mg/kg), pyrimethamine (2 mg/kg) or empty nanomicelles (2 mg/kg); the fourth group remained untreated (positive control). The parasitaemia rate, survival rate and histopathological changes in the liver, spleen and kidneys were examined and were compared with the negative and positive control groups.
RESULTS
The mean parasitaemia rate differed significantly between the nanoformulated pyrimethamine group and each of the other groups (P<0.05). Moreover, the survival rate of mice in the nanoformulated pyrimethamine group (7/9; 78%) was significantly higher compared with each of the other groups (P<0.01). The main histopathological changes, including hepatic necrosis in the liver, lymphoid hypoplasia in the spleen, and tubular nephrosis and perivascular and interstitial lymphocytic infiltration in the kidneys, were considerably lower in the nanoformulated pyrimethamine group than in the pyrimethamine and positive control groups.
CONCLUSION
Pyrimethamine-loaded nanomicelles showed potent antimalarial activity and can be considered as a potential candidate for further examination of their suitability as an antimalarial drug.
Topics: Animals; Antimalarials; Disease Models, Animal; Drug Compounding; Liver; Malaria; Male; Mice; Micelles; Nanoparticles; Parasitemia; Particle Size; Plasmodium berghei; Poloxamer; Pyrimethamine; Random Allocation; Spleen; Survival Analysis; Treatment Outcome
PubMed: 31404680
DOI: 10.1016/j.jgar.2019.08.002 -
Molecules (Basel, Switzerland) Jun 2020While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is...
While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this study, pyrimethamine inhibited the level of DX2 (IC = 0.73 µM) in A549 cells expressing nanoluciferase-tagged DX2. In a panel of 5 lung cancer cell lines with various DX2 levels, pyrimethamine most potently suppressed the growth of H460 cells, which express high levels of DX2 (GI = 0.01 µM). An immunoblot assay in H460 cells showed that pyrimethamine decreased the DX2 level dose-dependently but did not affect the AIMP2 level. Further experiments confirmed that pyrimethamine resulted in ubiquitination-mediated DX2 degradation. In an in vivo mouse xenograft assay using H460 cells, intraperitoneal administration of pyrimethamine significantly reduced the tumor size and weight, comparable with the effects of taxol, without affecting body weight. Analysis of tumor tissue showed a considerably high concentration of pyrimethamine with a decreased levels of DX2. These results suggest that pyrimethamine, currently used as anti-parasite drug, could be repurposed to treat lung cancer patients expressing high level of DX2.
Topics: A549 Cells; Amino Acyl-tRNA Synthetases; Animals; Cell Line, Tumor; Exons; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Nuclear Proteins; Pyrimethamine; Ubiquitin; Xenograft Model Antitumor Assays
PubMed: 32549310
DOI: 10.3390/molecules25122763 -
Lancet (London, England) Nov 1983
Topics: Abnormalities, Drug-Induced; Female; Humans; Malaria; Pregnancy; Pregnancy Complications, Infectious; Pyrimethamine
PubMed: 6139544
DOI: 10.1016/s0140-6736(83)91237-0 -
Lancet (London, England) Jun 1973
Topics: Central Nervous System Diseases; Child; Humans; Leukemia; Pyrimethamine
PubMed: 4126098
DOI: 10.1016/s0140-6736(73)91325-1