Pharmacokinetic Basis for Using Saliva Matrine Concentrations as a Clinical Compliance Monitoring in Antitumor B Chemoprevention Trials in Humans.

This study reports the first clinical evidence of significantly high secretion of matrine in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. This is of high clinical significance as matrine can be used as a monitoring tool during longitudinal clinical studies to overcome the key limitation of poor patient compliance often reported in cancer chemoprevention trials. Both matrine and dictamine were detected in the saliva and plasma samples but only matrine was quantifiable after the oral administration of ATB tablets (2400 mg) in 8 healthy volunteers.

Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care.

When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer.

Development & validation of LC-MS/MS assay for 5-amino-1-methyl quinolinium in rat plasma: Application to pharmacokinetic and oral bioavailability studies.

5-Amino-1-methyl quinolinium (5-AMQ) is a potent Nicotinamide N-methyl transferase (NNMT) inhibitor. NNMT is an enzyme that catalyzes the N-methylation of the endogenous substrate nicotinamide, as well as exogenous xenobiotics. NNMT is fundamental to cellular metabolism; NNMT is overexpressed in select tissues (e.

Simultaneous quantification of vincristine and its major M1 metabolite from dried blood spot samples of Kenyan pediatric cancer patients by UPLC-MS/MS.

Vincristine (VCR) is an integral part of chemotherapy regimens in the US and in developing countries. There is a paucity of information about its disposition and optimal therapeutic dosing. VCR is preferentially metabolized to its major M1 metabolite by the polymorphic CYP3A5 enzyme, which may be clinically significant as CYP3A5 expression varies across populations.

Pharmacokinetic Model Analysis of Supralingual, Oral and Intravenous Deliveries of Mycophenolic Acid.

Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch.

Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.

Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials.

A polymeric micellar drug delivery system developed through a design of Experiment approach improves pancreatic tumor accumulation of calcipotriol and paclitaxel.

The aim of this study was to develop optimal micelles loaded with calcipotriol (Cal) and paclitaxel (PTX) for the treatment of pancreatic ductal adenocarcinoma (PDAC) using a Design of Experiment (DOE) approach. The central composite design (CCD), a type of DOE was used to tune the size and drug release properties of the drug-loaded micelles. This approach yielded optimal Cal and PTX co-loaded micelles (M-Cal/PTX) with size of 40-100 nm, a polydispersity index (PDI) of 0.

Sensitive and rapid UHPLC-MS/MS assay for simultaneous quantifications of calcipotriol and paclitaxel in rat whole blood and plasma samples.

Vitamin-D analogues have emerged as potential stroma-modulating agents for the treatment of pancreatic ductal adenocarcinoma (PDAC). One such agent, calcipotriol (Cal) has shown significant activity in in vitro and in vivo models of pancreatic ductal adenocarcinoma. Attempts in our lab have been focused on establishing the therapeutic merits of co-formulating this agent with the chemotherapeutic drug paclitaxel (PTX) in animal models.

Doxorubicin-loaded hollow gold nanospheres for dual photothermal ablation and chemoembolization therapy.

Background: Doxorubicin-loaded hollow gold nanospheres (Dox@HAuNS) are a promising technology for simultaneous trans-arterial tumor-targeted chemotherapy delivery and thermal ablation. We evaluated the efficacy of intra-arterial delivery of Dox@HAuNS followed by photothermal ablation (PTA) in a rabbit model of liver cancer. Adult New Zealand white rabbits (N=25) were inoculated with VX2 tumors into the left lobe of the liver.

Effects of inflammation on irinotecan pharmacokinetics and development of a best-fit PK model.

Irinotecan is a chemotherapeutic drug used in the treatment of advanced colorectal cancer and elevated blood concentrations of its active metabolite, SN-38 leads to increased gastrointestinal (GI) toxicity and diarrhea in patients. In this study, we investigated the effects of inflammation on the pharmacokinetics (PK) of irinotecan (CPT-11) and its active metabolite, SN-38. Mice were i.

Sustained delivery of a camptothecin prodrug - CZ48 by nanosuspensions with improved pharmacokinetics and enhanced anticancer activity.

We have synthesized a novel lactone-stabilized camptothecin (CPT) analog named CZ48 and demonstrated its potent anticancer effects via bioconversion to the active CPT in earlier studies. Herein, we aimed to develop, optimize and characterize CZ48 nanosuspensions, for a sustained delivery of this drug in humans with an intravenous (i.v.

Correction to: Longitudinal Impacts of Gastric Bypass Surgery on Pharmacodynamics and Pharmacokinetics of Statins.

In the original article the authors failed to include the following footnote.

Longitudinal Impacts of Gastric Bypass Surgery on Pharmacodynamics and Pharmacokinetics of Statins.

Purpose: Undergoing Roux-en-Y gastric bypass (RYGB) is expected to affect orally administered drug absorption. Statins are commonly prescribed to patients with obesity for the prevention of atherosclerotic cardiovascular diseases by lowering cholesterol. This is the first longitudinal prospective study on impacts of RYGB on weight loss, pharmacodynamics, and pharmacokinetics of atorvastatin, rosuvastatin, and simvastatin, and their active metabolites, up to 1-year post-surgery.

Development and validation of a rapid and sensitive UPLC-MS/MS assay for simultaneous quantification of paclitaxel and cyclopamine in mouse whole blood and tissue samples.

The prominent stromal compartment surrounds pancreatic ductal adenocarcinoma and protects the tumor cells from chemo- or radiotherapy. We hypothesized that our nano formulation carrying cyclopamine (CPA, stroma modulator) and paclitaxel (PTX, antitumor agent) could increase the permeation of PTX through the stromal compartment and improve the intratumoral delivery of PTX. In the present study a sensitive, reliable UPLC-MS/MS method was developed and validated to quantify PTX and CPA simultaneously in mouse whole blood, pancreas, liver and spleen samples.

Integrin αvβ3-Targeted [Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.

Copper sulfide (CuS) nanoparticles have been considered one of the most clinical relevant nanosystems because of their straightforward chemistry, small particle size, low toxicity, and intrinsic theranostic characteristics. In our previous studies, radioactive [Cu]CuS nanoparticles were successfully developed to be used as efficient radiotracers for positron emission tomography and for photothermal ablation therapy of cancer cells using near-infrared laser irradiation. However, the major challenge of CuS nanoparticles as a theranostic platform is the lack of a means for effective targeted delivery to the tumor site.

Stromal Modulation Reverses Primary Resistance to Immune Checkpoint Blockade in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to treat. It is refractory to most existing therapies, including immunotherapies, due to the presence of an excessive desmoplastic stroma, which restricts penetration of drugs and cytotoxic CD8 T cells. Stromal modulation has shown promising results in the enhancement of immune checkpoint blockade treatment in PDAC.

Rational design and development of a stable liquid formulation of riluzole and its pharmacokinetic evaluation after oral and IV administrations in rats.

Enterally administered riluzole is currently being investigated in a Phase II/III clinical trial for the treatment of acute spinal cord injury (SCI). Many SCI patients suffer from severe motor dysfunction and exhibit swallowing difficulties and cannot swallow riluzole tablets. The purpose of the present study was to develop a liquid solution formulation of riluzole, which can be administered more easily to this patient population with the capability to adjust the dose if needed.

Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay for simultaneous quantifications of CZ48, lactone-stabilized camptothecin, and camptothecin and their pharmacokinetic and biliary evaluations in rats.

CZ48, a prodrug of camptothecin (CPT), has a broad spectrum of antitumor activity against various types of human tumors without severe toxicity in preclinical human tumor-xenografted mouse models, which facilitates further preclinical and clinical pharmacokinetic (PK) evaluations of CZ48. In this study, a UHPLC-MS/MS method was developed and validated to simultaneously quantify CZ48 and CPT in rat plasma and bile. Detection was performed using the API 3200 Q Trap triple quadrupole mass spectrometer in a positive ion mode.

Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC.

UPLC-MS/MS assay of riluzole in human plasma and cerebrospinal fluid (CSF): Application in samples from spinal cord injured patients.

In the present study, a sensitive and robust LC-MS/MS method has been developed and validated for the quantification of riluzole in human plasma and cerebrospinal fluid (CSF) in clinical samples from patients with spinal cord injury (SCI). Riluzole and its labeled internal standard (IS) were isolated from plasma and CSF by liquid-liquid extraction using ethyl acetate. Riluzole (m/z 235→166) and IS (m/z 238→169) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode.

Clinical Pharmacokinetics of Mycophenolic Acid in Hematopoietic Stem Cell Transplantation Recipients.

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is widely used as a maintenance immunosuppressive regimen in solid organ transplant patients. It is increasingly used for the prophylaxis and treatment of graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT) patients. MPA displays extensive binding to serum albumin and glucuronidation to the inactive MPA-7-O-glucuronide (MPAG).

Simultaneous quantification of mycophenolic acid and its glucuronide metabolites in human plasma by an UPLC-MS/MS assay.

The aim of this study was to develop a reliable UPLC-MS/MS assay for accurate quantification of mycophenolic acid (MPA) and its glucuronide conjugates in human plasma. Plasma proteins were precipitated with acetonitrile and the chromatographic separation was achieved on a C18 column with a gradient elution. The detection was performed by a triple quadrupole mass spectrometer in the positive electrospray ionization and multiple reaction monitoring mode.

Pharmacokinetic Variability of Mycophenolic Acid in Pediatric and Adult Patients With Hematopoietic Stem Cell Transplantation.

The aim of this study was to evaluate the pharmacokinetic variations of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in both pediatric and adult patients following hematopoietic stem cell transplantation (HSCT). Twenty pediatric patients with a median age of 3 years (range 0.2-12 years) and 13 adult patients with a median age of 54 years (range 18-63 years) were enrolled.