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1.  Desferrioxamine decreases NAD redox potential of intact red blood cells: evidence for desferrioxamine as an inducer of oxidant stress in red blood cells 
Background
Desferrioxamine (DFO) is an important iron chelating agent. It has also been thought of as an agent with anti-oxidant potential as it chelates ferric iron in various parts of the body. However, there is evidence suggesting that it may paradoxically affect red blood cells (RBC) by inducing intracellular oxidant stress. To further understand the mechanism of DFO's interaction with RBC, we conducted a study to determine the effect of DFO upon RBC's redox status.
Methods
We examined NAD redox potential in intact RBC (N = 5) incubated with DFO. RBC were incubated with 6 mM DFO for 2 hours.
Results
Significant decreases in NAD redox potential were observed after incubation of RBC with 6 mM DFO. The mean decrease was 10.01 ± 1.98% (p < 0.0004).
Conclusions
The data confirm the oxidant effect of DFO on RBC.
doi:10.1186/1472-6904-2-8
PMCID: PMC134457  PMID: 12398791
red blood cells; desferrioxamine; NAD redox potential; oxidant stress; iron
2.  PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics 
Background
It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fwB). PKQuest, a new generic physiologically based pharmacokinetic software routine (PBPK), provides a novel approach to modeling capillary permeability in which the only adjustable parameter is the PS of muscle.
Methods
All the results were obtained by applying PKQuest to previously published human pharmacokinetic data.
Results
The PKQuest analysis suggests that the highly protein bound antibiotics dicloxacillin and ceftriaxone have a significant capillary permeability limitation. The human muscle capillary PS of inulin, dicloxacillin and ceftriaxone was 0.6, 13 and 6 ml/min/100 gm, respectively. The ceftriaxone protein binding is non-linear, saturating at high plasma concentrations. The experimental ceftriaxone data over a wide range of intravenous inputs (0.15 to 3 gms) was well described by PKQuest. PKQuest is the first PBPK that includes both permeability limitation and non-linear binding.
Conclusions
Because of their high degree of plasma protein binding, dicloxacillin and ceftriaxone appear to have a diffusion limited exchange rate between the blood and tissue and are not flow limited as had been previously assumed. PKQuest and all the examples are freely available at .
doi:10.1186/1472-6904-2-7
PMCID: PMC130020  PMID: 12323078
3.  Appetite suppressants and valvular heart disease – a systematic review 
Background
Although appetite suppressants have been implicated in the development of valvular heart disease, the exact level of risk is still uncertain. Initial studies suggested that as many as 1 in 3 exposed patients were affected, but subsequent research has yielded substantially different figures. Our objective was to systematically assess the risk of valvular heart disease with appetite suppressants.
Methods
We accepted studies involving obese patients treated with any of the following appetite suppressants: fenfluramine, dexfenfluramine, and phentermine. Three types of studies were reviewed: controlled and uncontrolled observational studies, and randomized controlled trials. Outcomes of interest were echocardiographically detectable aortic regurgitation of mild or greater severity, or mitral regurgitation of moderate or greater severity.
Results
Of the 1279 patients evaluated in seven uncontrolled cohort studies, 236 (18%) and 60 (5%) were found to have aortic and mitral regurgitation, respectively. Pooled data from six controlled cohort studies yielded, for aortic regurgitation, a relative risk ratio of 2.32 (95% confidence intervals 1.79 to 3.01, p < 0.00001) and an attributable rate of 4.9%, and for mitral regurgitation, a relative risk ratio of 1.55 (95% confidence intervals 1.06 to 2.25, p = 0.02) with an attributable rate of 1.0%. Only one case of valvular heart disease was detected in 57 randomized controlled trials, but this was judged unrelated to drug therapy.
Conclusions
The risk of valvular heart disease is significantly increased by the appetite suppressants reviewed here. Nevertheless, when considering all the evidence, valvulopathy is much less common than suggested by the initial, less methodologically rigorous studies.
doi:10.1186/1472-6904-2-6
PMCID: PMC126245  PMID: 12194699
4.  PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol 
Background
A "physiologically based pharmacokinetic" (PBPK) approach uses a realistic model of the animal to describe the pharmacokinetics. Previous PBPKs have been designed for specific solutes, required specification of a large number of parameters and have not been designed for general use.
Methods
This new PBPK program (PKQuest) includes a "Standardhuman" and "Standardrat" data set so that the user input is minimized. It has a simple user interface, graphical output and many new features: 1) An option that uses the measured plasma concentrations to solve for the time course of the gastrointestinal, intramuscular, intraperotineal or skin absorption and systemic availability of a drug – for a general non-linear system. 2) Capillary permeability limitation defined in terms of the permeability-surface area products. 4) Saturable plasma and tissue protein binding. 5) A lung model that includes perfusion-ventilation mismatch. 6) A general optimization routine using either a global (simulated annealing) or local (Powell) minimization applicable to all model parameters.
Results
PKQuest was applied to measurements of human propranolol pharmacokinetics and intestinal absorption. A meal has two effects: 1) increases portal blood flow by 50%; and 2) decreases liver metabolism by 20%. There is a significant delay in the oval propranolol absorption in fasting subjects that is absent in fed subjects. The oral absorption of the long acting form of propranolol continues for a period of more than 24 hours.
Conclusions
PKQuest provides a new general purpose, easy to use, freely distributed and physiologically rigorous PBPK software routine.
doi:10.1186/1472-6904-2-5
PMCID: PMC126244  PMID: 12182760
5.  PKQuest: measurement of intestinal absorption and first pass metabolism – application to human ethanol pharmacokinetics 
Background
PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose – PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption.
Methods
PKQuest was applied to previously published ethanol pharmacokinetic data.
Results
The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small.
Conclusions
The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at .
doi:10.1186/1472-6904-2-4
PMCID: PMC122094  PMID: 12182761
6.  An international survey of patients with thalassemia major and their views about sustaining life-long desferrioxamine use 
Background
Management of thalassemia major requires patients to have life-long access to a treatment regimen of regular blood transfusions coupled with iron chelation therapy. The objective of this study was to investigate patients' reasons for missing iron chelation therapy with desferrioxamine, and the support to sustain life-long adherence to treatment.
Methods
From October 1999 to May 2000 a survey of patients with thalassemia major was conducted in ten countries: Cyprus, Egypt, Greece, Hong Kong, India, Iran, Italy, Jordan, Taiwan, and the United States.
Results
1,888 questionnaires (65%) were returned. Most patients (1,573) used desferrioxamine, and 79% administered a dose at least 4 days a week. Inaccessibility of the drug was a common reason for missing a dose in India (51%), and in Iran (25%), whereas, in any other country, it was a reason for less than 17% of patients. Overall, 58% reported reasons for missing a dose related to their beliefs or feelings about the medication, and 42% drug-related side effects.
Conclusion
Many patients miss doses of desferrioxamine and an opportunity remains to develop interventions that provide more support to sustain use of desferrioxamine.
doi:10.1186/1472-6904-2-3
PMCID: PMC111194  PMID: 12015817
7.  Diclofenac does not interact with codeine metabolism in vivo: A study in healthy volunteers 
Background
Previously, we have demonstrated a marked inhibition of codeine glucuronidation by diclofenac in human liver tissue homogenate. We therefore aimed to investigate whether diclofenac inhibits glucuronidation of codeine also in vivo in healthy volunteers.
Methods
In a randomised, placebo-controlled, double-blind, cross-over study, 12 healthy volunteers received a singe of 100 mg codeine phosphate plus 50 mg diclofenac sodium or codeine phosphate plus placebo. Over a 36 hour period serum concentrations of codeine and its metabolites as well as urinary excretion were analysed using LC-mass spectrometry. Side effects were recorded and analgesic efficacy was determined using the cold pressor test (0–6 h).
Results
A single dose of diclofenac did not alter the formation of codeine-6-glucuronide in healthy volunteers. Metabolic clearance of codeine to morphine was not affected by diclofenac. In terms of side effects, both treatments were well tolerated. Diclofenac did not significantly influence the analgesic effects of codeine in the cold pressor test.
Conclusions
In contrast to recent in vitro data, a single oral dose of diclofenac did not alter the glucuronidation of codeine in healthy volunteers.
doi:10.1186/1472-6904-2-2
PMCID: PMC101395  PMID: 11943073
8.  LDL-cholesterol lowering effect of a generic product of simvastatin compared to simvastatin (Zocor™) in Thai hypercholesterolemic subjects – a randomized crossover study, the first report from Thailand 
Background
It is commonly agreed that people with a high blood LDL-cholesterol will have a higher risk of coronary artery disease (CAD) than people with low blood LDL-cholesterol. Due to the increasingly high costs of medication in Thailand, the government has set up several measures to combat the problem. One of such strategies is to promote the utilization of locally manufactured drug products, especially those contained in the National Drug List. Simvastatin, an HMG-CoA reductase inhibitor, is listed as an essential drug for the treatment of hypercholesterolemia. Here, we reported the study on the LDL-cholesterol-lowering effect of a generic simvastatin product in comparison with the Zocor©, in 43 healthy thai volunteers.
Method
The generic product tested was Eucor©, locally manufactured by Greater Pharma Ltd., Part, Thailand, and the reference product was Zocor© (Merck Sharp & Dohme, USA). The two products were administered as 10-mg single oral doses in a two-period crossover design. After drug administration, serial blood samples were collected every 4 weeks for 16 weeks. The major parameter monitored in this study was blood LDL-cholesterol.
Result
After taking the drugs for the first 8 weeks, no statistically significant difference was dedected in blood LDL-cholesterol between the first (Zocor©-treated) and the second (Eucor©-treated) groups. After crossover and taking drugs for further 8 weeks, a similar result was obtained, i.e., no significant difference in blood LDL-cholesterol between the first (Eucor©-treated) and the second (Zocor©-treated) groups was observed. Upon completion of the 16-week study, there was also no statisticaly significant difference in the changes of all tested blood parameters between the two products (randomized block ANOVA, N = 37). Only minor side effects, mainly dizziness and nausea, were observed in both products.
Conclusion
Our study demonstrated no significant differences in the therapeutic effect and safety between the generic and original simvastatin products.
doi:10.1186/1472-6904-2-1
PMCID: PMC65514  PMID: 11835697

Results 1-8 (8)