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Clinical Pharmacodynamics of Anticancer Drugs
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Howard L. McLeod, William E. Evans
This correlation between drug exposure and hematologic toxicity was also observed in 29 patients receiving trimetrexate 50 to 130 mg/m2 IV weekly for 3 weeks.62 Pharmacokinetic parameters were estimated using nonlinear least squares regression and plasma samples were collected for 96 h postinfusion. The percentage change in WBC and platelets was determined by (pretreatment count – nadir/pretreatment count)* 100. Sevenfold variability in trimetrexate systemic clearance was observed. Percent change in WBC and platelets was correlated with trimetrexate 24-h plasma concentration and AUC. The correlation between trimetrexate AUC and WBC and platelet reduction has been further observed in patients receiving both weekly IV bolus doses and 5-d IV bolus doses.63,64
Trimetrexate
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Sabine De Silva, M. Lindsay Grayson
Trimetrexate has been investigated for use in a variety of solid tumors, including colorectal, non–small cell lung, and head and neck cancers, demonstrating some benefit in advanced disease in some multicenter trials (Haller, 1997; Holen and Saltz, 2001; Punt et al., 2002; Micromedex Health Care Series, 2015).
Perspective on current and emerging drugs in the treatment of acute and chronic toxoplasmosis
Published in Postgraduate Medicine, 2019
Paula J. Lapinskas, Ruben R. Ben-Harari
The first program is based on optimization of chemical scaffolds related to marketed lipophilic DHFR inhibitors (trimethoprim, trimetrexate, and piritrexim), and initially reported drug candidate JPC-2056 to be advancing into clinical development for malaria, but also reported JPC-2067-B (and prodrug JPC-2056) as having potent activity against TgDHFR enzyme and selectivity versus rat liver DHFR enzyme (rlDHFR) and hDHFR [33]. JPC-2067-B demonstrated low nanomolar activity against TgDHFR but 3.4 to 5.9-fold selectivity for mammalian DHFR: Parasiticidal activity against T. gondii tachyzoites in infected human foreskin fibroblasts, and was highly effective in reducing parasite burden in acute mouse models of toxoplasmosis using the highly virulent RH strain of T. gondii, and treated mice remained in good physical condition, while control mice appeared ill. In a similar experiment in mice, JPC-2056 reduced parasite burden, and in toxicology studies JPC-2056 orally administered for up to 42 days in mice and monkeys showed only minimal adverse findings, including reduction in weight gain (mice) and sporadic episodes of loose stool and diarrhea (monkeys) with no gross or histopathologic findings. Both JPC-2056 and JPC-2067 were not mutagenic in a bacterial (Ames) assay.
Dihydrofolate reductase inhibitors: patent landscape and phases of clinical development (2001–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Kavita Bhagat, Nitish Kumar, Harmandeep Kaur Gulati, Aanchal Sharma, Amandeep Kaur, Jatinder Vir Singh, Harbinder Singh, Preet Mohinder Singh Bedi
In 2010, Gant et al. claimed deuterated diaminoquinazoline derivatives endowed with excellent DHFR inhibitory activity. These designed compounds would be subjected to several biological activity assays that have been predicted to possess altered metabolic properties. Deuterated compound 7 (Table 2) would be subjected to in vitro liver microsomal stability assay, in vitro metabolism using CYP 450, MAO A and B inhibition and oxidative turnover, determination of Trimetrexate in urine and human plasma by HPLC and GC-MS, relative DHFR binding affinity assay, DHFR binding Inhibition assay, mammalian cell growth inhibition assay, and antimalarial activity [65].
Bortezomib-loaded solid lipid nanoparticles: preparation, characterization, and intestinal permeability investigation
Published in Drug Development and Industrial Pharmacy, 2018
Mohammad Mahmoudian, Hadi Valizadeh, Parvin Zakeri-Milani
Oral delivery of anticancer drugs is a noninvasive way and can eliminate the risk of infection or extravasation related to injection. Oral chemotherapy can provide a long-term exposure for cancerous cells to the cytotoxic drugs. Moreover, the patient’s quality of life will be improved because of no need for medical or hospital visit. Most of approved or in development oral chemotherapy drugs like topotecan, trimetrexate, paclitaxel/valspodar, 5-flourouracil, are new formulations of existing drugs routinely administered i.v. [1–4].