Neutrexin (trimetrexate) / Pfizer - LARVOL DELTA

Cerebral Spinal Fluid Attenuates the Efficacy of Methotrexate Against Acute Lymphoblastic Leukemia Cells (ASH 2023) - "While this was confirmed for several ALL drugs including cytarabine and anthracyclines, we strikingly found that methotrexate was significantly less efficacious and potent against ALL cells in CSF relative to standard tissue culture media or the more physiologically relevant human plasma-like media (HPLM). CSF also attenuated the sensitivity of ALL cells to other anti-folates including raltitrexed, trimetrexate, and pralatrexate...Activation of the UPR with thapsigargin, a sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor that triggers ER stress, increased methotrexate resistance in leukemia cells...Moreover, we anticipate that our current work defining the mechanisms driving this resistance may identify novel approaches for maximizing methotrexate efficacy and more completely eradicating leukemia cells in CSF and the CNS. Finally, this work highlights the importance of critically evaluating even long-established standards of care."

Clinical • Acute Lymphocytic Leukemia • Central Nervous System Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia

Antimicrobial potential of compounds from the MMV pandemic response box and COVID box against carbapenem-resistant Acinetobacter baumannii. (PubMed, Braz J Microbiol) - "Additionally, their effects on biofilm inhibition, protein leakage, and synergy with meropenem were assessed. Among the tested compounds, 10 demonstrated notable antimicrobial activity, including doxycycline, atazanavir, alexidine, eravacycline, erythromycin, gepotidacin, trimetrexate, MMV1634402 (brilacidin), MMV1580854 and MMV1578564...The present study highlights the antimicrobial activity of MMV1634402 (brilacidin) and gepotidacin, providing preliminary evidence of their potential as therapeutic candidates against CRAB. However, further studies involving a broader range of isolates and clinical validation are essential to confirm their efficacy and safety."

Journal • Infectious Disease • Malaria • Novel Coronavirus Disease

Diverse Inhibitors of De Novo Purine Synthesis Promote AICAR-Induced AMPK Activation and Glucose Uptake in L6 Myotubes. (PubMed, Biofactors) - "Methotrexate, an immunosuppressant and anticancer drug, promotes glucose uptake and lipid oxidation in skeletal muscle via activation of AMP-activated protein kinase (AMPK)...Using L6 myotubes, we found that AICAR-induced AMPK activation and glucose uptake were enhanced by inhibitors of the conversion of IMP to GMP (mycophenolate mofetil) or of IMP to AMP (alanosine) as well as by indirect inhibitors of human (trimetrexate) and bacterial ATIC (sulfamethoxazole). 6-Mercaptopurine, which inhibits the conversion of IMP to GMP and AMP, activated AMPK, increased glucose uptake, and suppressed insulin signaling, but did not enhance the effect of AICAR. As determined by measuring oxygen consumption rate, none of these agents suppressed mitochondrial function. Overall, our results indicate that IMP metabolism is a gateway for the modulation of AMPK and its metabolic effects in skeletal muscle cells."

Journal • Oncology

Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV - A systematic review and network meta-analysis of randomized controlled trials. (PubMed, Clin Microbiol Infect) - "We conclude that TMP-SMX should be reassessed as the stand-alone first-line therapy for PCP in PWH, given the better tolerability and comparable efficacy of other treatments. In places with access to alternative drugs for PCP treatment, our analysis suggests that alternative regimens may offer comparable effectiveness, providing flexibility to use alternative treatments when comorbidities necessitate it."

Journal • Retrospective data • Review • Human Immunodeficiency Virus • Infectious Disease • Pneumonia • Respiratory Diseases • CD4

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability. (PubMed, Drug Resist Updat) - "MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • FPGS

DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. (PubMed, Viruses) - "Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines...Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • DHFR

A Mobile Social Networking App for Weight Management and Physical Activity Promotion: Results From an Experimental Mixed Methods Study. (PubMed, J Med Internet Res) - "This study shows the effects of different interventions on participants from higher and lower BMI groups and different perspectives regarding the intervention, particularly with respect to its social features. Participants in the overweight-obese group did not sustain a short-term decrease in their BMI and mentioned negative emotions from app use, while participants in the underweight-normal BMI group used the app more frequently and significantly increased their daily step count. These differences highlight the importance of intervention personalization. Future research should explore the role of personalized features to help overcome personal barriers and better match individual preferences and needs."

Journal • Obesity

Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection. (PubMed, Bioorg Med Chem Lett) - "Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors...Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling. (PubMed, Int J Mol Sci) - "Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease."

Journal • DHFR • TYMS

Molecular characterization and haplotypes of sheep and goat isolates of Cysticercus tenuicollis in Turkey. (PubMed, Parasitology) - "After the isolation of total genomic DNA from C. tenuicollis isolates, genetic characterization of the mitochondrial NADH dehydrogenase subunit 1 gene region was amplified using specific JB11-JB12 primers in PCR and the PCR products were sequenced and haplotype and genetic diversity analyses were utilized. As a result, multiple nucleotide changes were determined in the sequence analyses of the isolates leading to detection of 16 and 15 different haplotypes in sheep and goat samples, respectively. These findings are important in terms of showing the diversity of nucleotide variation in C. tenuicollis in Turkey."

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