Patty Fan-Havard

Cidofovir in the Treatment of Cytomegaloviral Disease

OBJECTIVE: To review the clinical pharmacology and microbiology of cidofovir in the therapy of cytomegalovirus (CMV) disease. DATA SOURCES: Pertinent literature was identified via a MEDLINE search (October 1986–February 1997), and data from abstracts presented at recent scientific meetings were also included; unpublished information was provided by the manufacturer. STUDY SELECTION: Antiviral activity data were included if widely accepted methodology was used. All clinical data currently available from human studies were also included. DATA SYNTHESIS: Cidofovir is similar to ganciclovir in mechanism of action; however, cidofovir does not require viral enzymes for activation. Although the half-life of cidofovir in plasma is only 2.6 hours, the intracellular half-life may be much longer, allowing efficacy with biweekly maintenance dosing. In vitro, cidofovir appears to be equally or more effective than the other agents currently available for the treatment of CMV. In vivo, cidofovir appears to be effective in delaying the progression of CMV retinitis, although no clinical trials to date have directly compared cidofovir with either ganciclovir or foscarnet. Current intravenous dose recommendations are 5 mg/kg once weekly for two doses (induction), and then 5 mg/kg once every other week (maintenance). Since cidofovir is cleared almost entirely by the kidneys, dosage adjustments must be made in patients with impaired renal function. Disadvantages of cidofovir primarily include its risks of adverse drug reactions, such as nephrotoxicity, which is likely to occur in up to 50% of patients if appropriate preventative measures are not taken. Neutropenia and constitutional reactions to probenecid are also commonly encountered during the course of cidofovir therapy. CONCLUSIONS: Cidofovir is the first acyclic phosphonate nucleoside antiviral agent to be approved for general use in the US. In addition to delaying the progression of CMV retinitis, cidofovir may provide some protective benefits to patients at risk for developing the disease and may be active against certain strains of virus resistant to other currently available therapies. Another advantage of cidofovir is its infrequent dosage schedule, which may prove beneficial in patients who are not compliant with daily intravenous dosing regimens. When determining the appropriate treatment for a patient with CMV retinitis, the benefits of using cidofovir must be weighed carefully against the risk of potentially serious adverse effects.

A liquid chromatography-tandem mass spectrometric method for quantification of curcumin-O-glucuronide and curcumin in human plasma.

Curcumin is a widely used herbal medicine for various human diseases including inflammation and cancer. The demonstration and optimization of curcumins activities in the clinical setting, however, have been compromised by its poor bioavailability and the lack of analytic methods to monitor its absorption. In this paper, we report the first validated liquid chromatography-tandem mass spectrometric method for simultaneous quantification of curcumin and its major metabolite: curcumin-O-glucuronide (COG), in the linear range of 2.0-2000 ng/mL in human plasma. The intra-day and inter-day accuracies of curcumin and COG in human plasma were in the range of 91.3-111.5% and 82.7-109.2% and their co-efficiency of variations were in the range of 3.5-12.7% and 3.1-11.3%, respectively. This method was capable of detecting only COG in human plasma samples from two healthy volunteers after an oral ingestion of curcumin.

A Sensitive and Specific Liquid Chromatography/Tandem Mass Spectrometry Method for Quantification of Nevirapine and Its Five Metabolites and Their Pharmacokinetics in Baboons

A highly sensitive and specific LC-MS/MS assay was developed and validated to quantify nevirapine (NVP) and its five metabolites [2-, 3-, 8-, 12-hydroxyl NVP (OHNVP) and 4-carboxyl NVP (CANVP)] simultaneously in baboon serum and the assay was used to characterize their pharmacokinetic studies of an oral-dose escalation study in baboon. The lower limit of quantification (LLOQ) for NVP and its four hydroxyl nevirapine metabolites was 1.0 ng/mL and for 4-CANVP was 5.0 ng/mL. The between-run and within-run precisions and accuracies at four quality control concentrations (1, 5, 50 and 500 ng/mL) were evaluated in baboon serum with less than 14% variation and 93-114% accuracies (n = 6), except for the LLOQ for 2-OHNVP, which had an accuracy of 115.8% for between-run validation. The pharmacokinetics of NVP and its five metabolites in non-pregnant baboons by a single-dose escalation study were also profiled. The major metabolites detected were 4-CANVP and 12-OHNVP. 3-OHNVP and 2-OHNVP were the minor metabolites with only a trace amount of 2-OHNVP detected in some pharmacokinetic samples. No 8-OHNVP was observed in all of the pharmacokinetic samples. In addition, the fragmentation for the four hydroxyl metabolite isomers is also discussed.

Fetal blood sampling in baboons (Papio spp.): Important procedural aspects and literature review

Background  The baboons (Papio cynocephalus) have similarities with human placentation and fetal development. Fetal blood sampling allows investigators to assess fetal condition at a specific point in gestation as well as transplacental transfer of medications. Unfortunately, assessing fetal status during gestation has been difficult and fetal instrumentation associated with high rate of pregnancy loss. Our objectives are to describe the technique of ultrasound guided cordocentesis (UGC) in baboons, report post‐procedural outcomes, and review existing publications.

Abstract 756: Pharmacokinetics of curcumin and curcumin O-glucuronide in healthy volunteers characterized by liquid chromatography-tandem mass spectrometry

Purpose: To develop and validate a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for simultaneous quantification of curcumin and curcumin O-glucuronide (COG) in human plasma, and to characterize the pharmacokinetics (PK) of curcumin and COG in healthy volunteers after separate oral administrations of Curcumin C3 Complex (CC3C) and nano-emulsion Curcumin (NEC) using this method. Methods: The study was conducted at The Ohio State University (OSU) with the approval of the OSU Institutional Review Board. CC3C and NEC were administered orally to four healthy volunteers and plasma levels of curcumin and COG were determined by a validated LC-MS/MS method. The pharmacokinetic parameters were calculated using WinNonlin computer software. Clinical safety assessment included vital signs and biochemical measurement on the day of each PK study and three weeks following each PK study to monitor potential toxicity. A mixed effect model was used for comparing the concentration of curcumin or COG at each time point after the oral consumption of CC3C or NEC across each donor using SAS 9.2 software. Results: An LC-MS/MS method for simultaneous quantification of curcumin and COG in human plasma with the lower limit of quantification of 2 ng/mL was established. The within-day and between-day validation parameters were consistent with the Food and Drug Administration9s (FDA) criteria for Good Laboratory Practice analytical methods. A cross-over pharmacokinetic study in the four healthy volunteers revealed that 2g NEC delivered much higher plasma concentrations of free curcumin (1.5-8.0 ng/mL vs. non-detectable, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 756. doi:1538-7445.AM2012-756

Fetal Blood Sampling During the Second and Third Trimester in Baboons

Background  The baboons (Papio cynocephalus) have similarities with human placentation and fetal development. Fetal blood sampling allows investigators to assess fetal condition at a specific point in gestation as well as transplacental transfer of medications. Unfortunately, assessing fetal status during gestation has been difficult and fetal instrumentation associated with high rate of pregnancy loss. Our objectives are to describe the technique of ultrasound guided cordocentesis (UGC) in baboons, report post‐procedural outcomes, and review existing publications.