Modeling Cyclosporine a Inhibition of the Distribution of a P-Glycoprotein PET Ligand, 11C-Verapamil, Into the Maternal Brain and Fetal Liver of the Pregnant Nonhuman Primate: Impact of Tissue Blood Flow and Site of Inhibition.

Modeling Cyclosporine A Inhibition of the Distribution of a P-Glycoprotein PET Ligand, 11C-Verapamil, into the Maternal Brain and Fetal Liver of the Pregnant Nonhuman Primate: Impact of Tissue Blood Flow and Site of Inhibition.

Filed under: Drug and Alcohol Rehabilitation

J Nucl Med. 2013 Jan 28;
Ke AB, Eyal S, Chung FS, Link JM, Mankoff DA, Muzi M, Unadkat JD

Through PET, our laboratory has studied the dynamic biodistribution of (11)C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood-brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling. METHODS: Thirteen pregnant macaques (gestational age, 71-159 d; term, ?172 d) underwent PET with (11)C-verapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic (11)C-verapamil brain or fetal liver (reporter of placental P-gp function) activity was assessed by a 1- or 2-tissue-compartment model. RESULTS: The 1-tissue-compartment model best explained the observed brain and fetal liver distribution of (11)C-radioactivity. When P-gp was completely inhibited, the brain and fetal liver distribution clearance (K(1)) approximated tissue blood flow (Q); that is, extraction ratio (K(1)/Q) was approximately 1, indicating that in the absence of P-gp function, the distribution of (11)C-verapamil radioactivity into these compartments is limited by blood flow. The potency of CsA to inhibit P-gp was tissue-independent (maternal BBB half-maximal inhibitory concentration [IC(50)], 5.67 ± 1.07 ?M, vs. BPB IC(50), 7.63 ± 3.16 ?M). CONCLUSION: We propose that on deliberate or inadvertent P-gp inhibition, the upper boundary of increase in human brain (or fetal) distribution of lipophilic drugs such as verapamil will be limited by tissue blood flow. This finding provides a means to predict the magnitude of P-gp-based drug interactions at the BBB and BPB when only the baseline distribution of the drug (i.e., in the absence of P-gp inhibition) across these barriers is available through PET. Our data suggest that P-gp-based drug interactions at the human BBB and BPB can be clinically significant, particularly in those P-gp substrate drugs for which P-gp plays a significant role in excluding the drug from these privileged compartments.
HubMed – drug

 

Barriers to Clinical Translation with Diagnostic Drugs.

Filed under: Drug and Alcohol Rehabilitation

J Nucl Med. 2013 Jan 28;
Josephson L, Rudin M

Radioactive imaging agents, like diagnostic drugs generally, undergo a drug development process that parallels that of therapeutic agents, with similar development times but substantially lower development costs and substantially smaller postapproval markets. Although rapid advances in genetic and expression profiling are furthering the development of expensive pharmacotherapies targeted to small patient populations, the commercial development of imaging agents for small patient populations is blocked by the limited revenues available with current per-dose pricing and the relatively small numbers of imaging procedures that would be performed. A wide-ranging discussion on the best approaches to allow new diagnostic imaging agents to become part of the health-care system, and benefit the patient, is needed.
HubMed – drug

 

Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model: a double-blind, randomized, placebo-controlled, five-arm crossover study.

Filed under: Drug and Alcohol Rehabilitation

J Pain Res. 2013; 6: 23-38
Ravn P, Secher EL, Skram U, Therkildsen T, Christrup LL, Werner MU

Opioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain. It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than ?-opioid receptor agonists. The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers. The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia, antihyperalgesia, and descending pain modulation.Twenty-eight healthy subjects were included. The study was a double-blind, randomized, placebo-controlled, five-arm crossover study with a multimodal (electrical, mechanical, and thermal stimuli) testing technique. After baseline assessments, intravenous infusions of morphine (10/20 mg), buprenorphine (0.3/0.6 mg), or placebo (normal saline) were administered over a 210-minute period, during which a cold pressor test, heat injury (47°C, 7 minutes, 12.5 cm(2)), and the first postburn assessment were done. After completion of the drug infusions, two additional postburn assessments were done. The subjects were monitored during each 8-hour session by an anesthesiologist.For nearly all tested variables, significant dose-dependent analgesic effects were demonstrated. The median antihyperalgesia/analgesia ratio (secondary hyperalgesia/heat injury relative to placebo) for low-dose morphine was 0.01 (interquartile range: -6.2; 9.9), 0.00 (-2.4; 2.1) for high-dose morphine, 0.03 (-1.8; 2.1) for low-dose buprenorphine, and 0.00 (-3.2; 1.1) for high-dose buprenorphine (P > 0.466). There were no significant differences in opioid responses between high and low pain-sensitive subjects (P > 0.286). High-dose buprenorphine, compared to placebo, was associated with a significantly enhanced action of the descending inhibitory pain control system (P = 0.004).The present study, using multimodal testing technique, could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia. Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system.
HubMed – drug

 

Synthesis of water-soluble poly(?-hydroxy acids) from living ring-opening polymerization of O-benzyl-L-serine carboxyanhydrides.

Filed under: Drug and Alcohol Rehabilitation

ACS Macro Lett. 2012 Apr 17; 1(4): 441-444
Lu Y, Yin L, Zhang Y, Zhonghai Z, Xu Y, Tong R, Cheng J

O-benzyl-L-serine carboxyanhydrides were synthesized via diazotization of O-benzyl-L-serine with sodium nitrite in aqueous sulfuric acid solution followed by cyclization of the resulting serine-based ?-hydroxy acid with phosgene. Degradable, water-soluble poly(?-hydroxy acids) bearing pendant hydroxyl groups were readily prepared under mild conditions via ring-opening polymerization of O-benzyl-L-serine carboxyanhydrides followed by removal of the benzyl group and showed excellent cell compatibility, suggesting their potential being used as novel materials in constructing drug delivery systems and as hydrogel scaffolds for tissue engineering applications.
HubMed – drug

 

How Frequently are “Classic” Drug-Seeking Behaviors Used by Drug-Seeking Patients in the Emergency Department?

Filed under: Drug and Alcohol Rehabilitation

West J Emerg Med. 2012 Nov; 13(5): 416-21
Grover CA, Elder JW, Close RJ, Curry SM

Drug-seeking behavior (DSB) in the emergency department (ED) is a very common problem, yet there has been little quantitative study to date of such behavior. The goal of this study was to assess the frequency with which drug seeking patients in the ED use classic drug seeking behaviors to obtain prescription medication.We performed a retrospective chart review on patients in an ED case management program for DSB. We reviewed all visits by patients in the program that occurred during a 1-year period, and recorded the frequency of the following behaviors: complaining of headache, complaining of back pain, complaining of dental pain, requesting medication by name, requesting a refill of medication, reporting medications as having been lost or stolen, reporting 10/10 pain, reporting greater than 10/10 pain, reporting being out of medication, and requesting medication parenterally. These behaviors were chosen because they are described as “classic” for DSB in the existing literature.We studied 178 patients from the case management program, who made 2,486 visits in 1 year. The frequency of each behavior was: headache 21.7%, back pain 20.8%, dental pain 1.8%, medication by name 15.2%, requesting refill 7.0%, lost or stolen medication 0.6%, pain 10/10 29.1%, pain greater than 10/10 1.8%, out of medication 9.5%, and requesting parenteral medication 4.3%. Patients averaged 1.1 behaviors per visit.Drug-seeking patients appear to exhibit “classically” described drug-seeking behaviors with only low to moderate frequency. Reliance on historical features may be inadequate when trying to assess whether or not a patient is drug-seeking.
HubMed – drug

 

Find More Drug And Alcohol Rehabilitation Information…