Discovery and preclinical evaluation of a novel class of cytotoxic propynoic acid carbamoyl methyl amides (PACMAs).

Herein, we discovered a series of propynoic acid carbamoyl methyl-amides (PACMAs) with potent cytotoxicity against a panel of cancer cell lines. These compounds interrupted cell cycle progression at low micromolar concentrations and induced early and late stage apoptosis. A representative compound suppressed tumor growth without apparent toxicity in an MDA-MB-435 mouse xenograft model. We used a Kinexus 628-antibody microarray and the Ingenuity Pathway Analysis (IPA) bioinformatics tools to better understand their mechanisms. The IPA analysis revealed the initiation of Nrf2-mediated oxidative stress through modulating the expression of SOD1 and STIP1 by compound 1. The involvement of the oxidative stress pathway was further validated by measuring the levels of the PACMA-induced mitochondrial superoxide species. To our knowledge, this is the first report on the discovery and biological evaluations of PACMAs as anticancer agents. Their broad-spectrum in vitro cytotoxicity, possibly through an oxidative stress-mediated pathway, and in vivo efficacy warrant further preclinical investigations.

Estimation of glomerular filtration rate by using serum cystatin C and serum creatinine concentrations in patients with human immunodeficiency virus.

STUDY OBJECTIVE: To compare the predictive performance of four equations for estimating glomerular filtration rate (GFR) relative to the gold standard measurement, iothalamate clearance, in patients with human immunodeficiency virus (HIV) who have various degrees of kidney function. DESIGN: Prospective, cross-sectional analysis. SETTING: General clinical research center. PATIENTS: Twenty-two adult (mean age 51 yrs) HIV-positive patients with various degrees of stable kidney function and with lean body mass considered normal for a well-nourished person. INTERVENTION: Patients were administered a single dose of intravenous iothalamate 456 mg as a rapid infusion over 3 minutes, 1 hour after an oral fluid load of 600 ml of caffeine-free, sugar-free liquids. MEASUREMENTS AND MAIN RESULTS: Serial blood and urine samples were obtained for determination of measured GFR. Estimated GFR values were calculated by using four equations: the Cockcroft-Gault equation, the simplified Modification of Diet in Renal Disease Study (MDRD) equation, an equation that incorporates serum creatinine and cystatin C concentrations, and an equation incorporating only serum cystatin C concentration. The predictive performance of the equations was determined by comparing the bias, accuracy, and precision of the estimates with the measured values. Body composition was determined by dual-energy x-ray absorptiometry. The four predictive equations underestimated the measured GFR obtained by the iothalamate method, but the differences were not statistically significant. The MDRD equation and the equation that included both serum cystatin C and creatinine concentrations, as well as age, sex, and race, provided the least bias, most precision, and best accuracy in estimating the measured GFR. CONCLUSION: The MDRD equation and the equation that included both serum cystatin C and creatinine concentrations appear to provide accurate, precise, and relatively unbiased estimates of GFR in patients with HIV. Larger studies are needed that include patients with muscle wasting and lipodystrophy in order to validate these preliminary observations and the effects of body composition on the predictability of GFR with use of these equations.

Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents?

Currently, therapeutic drug monitoring (TDM) of antiretroviral therapy (ART) is not performed in the United States as part of routine clinical care of an HIV-infected adolescent patient. TDM is recommended to rule out subtherapeutic drug concentrations and to differentiate among malabsorption, drug interactions, poor adherence, or increased drug metabolism or clearance as possible causes of decreased drug exposure. The use of TDM is also considered to assist in finding the optimal dose of a drug in patients whose virus has shown reduced susceptibility to that drug. The dosing of antiretroviral (ARV) drugs in adolescent patients with HIV infection depends on the chronologic age, weight, height, and the stage of sexual maturation. As a result of the limited data on the pharmacokinetics of ART during puberty, the transition of a dosing regimen from higher pediatric (weight and surface-based) to adult (fixed) range is not well defined. Developmental pharmacokinetic differences contribute to high variability in pediatric and adolescent patients and an increased frequency of suboptimal ARV exposure as compared to in adults. Individualized, concentration-targeted optimal dosing of ARV medications can be beneficial to patients for whom only limited dosing guidelines are available. This article describes three cases of the application of TDM in treatment-experienced adolescent patients whose ART was optimized using ARV TDM. TDM of ARV drugs is useful in managing the pharmacotherapy of HIV in adolescent patients and is well received by the adolescent patients with HIV and their families. Among others, the benefits of TDM provide evidence for adherence interventions and create grounds for enhanced education of the adolescent patient and involved adult caregivers about ART. Finally, TDM in adolescents provides valuable information about the clinical pharmacology of ART during puberty.