Bioavailability of Echinacea Constituents: Caco-2 Monolayers and Pharmacokinetics of the Alkylamides and Caffeic Acid Conjugates

Many studies have been done over the years to assess the effectiveness of Echinacea as an immunomodulator. We have assessed the potential bioavailability of alkylamides and caffeic acid conjugates using Caco-2 monolayers and compared it to their actual bioavailability in a Phase I clinical trial. The caffeic acid conjugates permeated poorly through the Caco-2 monolayers. Alkylamides were found to diffuse rapidly through Caco-2 monolayers. Differences in diffusion rates for each alkylamide correlated to structural variations, with saturation and N-terminal methylation contributing to decreases in diffusion rates. Alkylamide diffusion is not affected by the presence of other constituents and the results for a synthetic alkylamide were in line with those for alkylamides found in an ethanolic Echinacea preparation. We examined plasma from healthy volunteers for 12 hours after ingestion of Echinacea tablets manufactured from an ethanolic liquid extract. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkylamides were detected in plasma 20 minutes after tablet ingestion and for each alkylamide, pharmacokinetic profiles were devised. The data are consistent with the dosing regimen of one tablet three times daily and supports their usage as the primary markers for quality Echinacea preparations.

The population pharmacokinetics of citalopram after deliberate self-poisoning: A Bayesian approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

Population pharmacokinetics of metformin in late pregnancy

The pharmacokinetic disposition of metformin in late pregnancy was studied together with the level of fetal exposure at birth. Blood samples were obtained in the third trimester of pregnancy from women with gestational diabetes or type 2 diabetes, 5 had a previous diagnosis of polycystic ovary syndrome. A cord blood sample also was obtained at the delivery of some of these women, and also at delivery of others who had been taking metformin during pregnancy but from whom no blood had been taken. Plasma metformin concentrations were assayed by a new, validated, reverse-phase HPLC method, A 2-compartment, extravascular maternal model with transplacental partitioning of drug to a fetal compartment was fitted to the data. Nonlinear mixed-effects modeling was performed in'NONMEM using FOCE with INTERACTION. Variability was estimated using logarithmic interindividual and additive residual variance models; the covariance between clearance and volume was modeled simultaneously. Mean (range) metformin concentrations in cord plasma and in maternal plasma were 0.81 (range, 0.1-2.6) mg/L and 1.2 (range, 0. 1-2.9) mg/L, respectively. Typical population values (interindividual variability, CV%) for allometrically scaled maternal clearance and volume of distribution were 28 L/h/70 kg (17.1%) and 190 L/70 ka (46.3%), giving a derived population-wide half-life of 5.1 hours. The placental partition coefficient for metformin was 1.07 (36.3%). Neither maternal age nor weight significantly influenced the pharmacokinetics. The variability (SD) of observed concentrations about model-predicted concentrations was 0.32 mg/L. The pharmacokinetics were similar to those in nonpregnant patients and, therefore, no dosage adjustment is warranted. Metformin readily crosses the placenta, exposing the fetus to concentrations approaching those in the maternal circulation. The sequelae to such exposure, ea, effects on neonatal obesity and insulin resistance, remain unknown.

Carboplatin administration in sulphur-crested cockatoos (Cacatua galerita): Clinical observations

To determine the clinical effect of systemic carboplatin administration in birds, 6 sulphur-crested cockatoos (Cacatua galerita) were anesthetized and infused intravenously or intraosseously with carboplatin at 5 mg/kg over 3 minutes. Four birds were euthanatized 96 hours after infusion and 2 birds given an intravenous dose were euthanatized 21 days after dosing. All birds tolerated the anesthesia and carboplatin infusion and recovered uneventfully. At 24 hours after dosing, all birds were bright and active. Within 12 hours of dosing, feed intake was reduced and 3 birds vomited, but these signs abated by 48 hours after dosing. Mean body weight decreased by 4% at 24 hours after dosing and continued to decrease, but not significantly, until 96 hours after dosing. Changes in packed cell volume (PCV) and plasma total solids reflected blood loss caused by sampling. The mean PCV decreased significantly by 6 hours after dosing, and the concentration of plasma total solids decreased significantly at 1 hour after dosing and continued to decrease until 12 hours after dosing before progressively and significantly increasing toward baseline values by 96 hours after dosing. At necropsy, myelosuppression was not observed in any bird and no evidence of carboplatin toxicity was found. These results provide veterinarians with useful data for formulating efficacious and safe protocols for platinum-containing compounds when treating neoplasia in parrots and other companion birds.

The effect of St John's wort extracts on CYP3A: a systematic review of prospective clinical trials

Aim The aim of this systematic review was to assess the quality and outcomes of clinical trials investigating the effect of St John's wort extracts on the metabolism of drugs by CYP3A. Methods Prospective clinical trials assessing the effect of St John's wort (SJW) extracts on metabolism by CYP3A were identified through computer-based searches (from their inception to May 2005) of Medline, Cinahl, PsycINFO, AMED, Current Contents and Embase, hand-searches of bibliographies of relevant papers and consultation with manufacturers and researchers in the field. Two reviewers selected trials for inclusion, independently extracted data and recorded details on study design. Results Thirty-one studies met the eligibility criteria. More than two-thirds of the studies employed a before-and-after design, less than one-third of the studies used a crossover design, and only three studies were double-blind and placebo controlled. In 12 studies the SJW extract had been assayed, and 14 studies stated the specific SJW extract used. Results from 26 studies, including all of the 19 studies that used high-dose hyperforin extracts (> 10 mg day(-1)), had outcomes consistent with CYP3A induction. The three studies using low-dose hyperforin extracts (< 4 mg day(-1)) demonstrated no significant effect on CYP3A. Conclusion There is reasonable evidence to suggest that high-dose hyperforin SJW extracts induce CYP3A. More studies are required to determine whether decreased CYP3A induction occurs after low-dose hyperforin extracts. Future studies should adopt study designs with a control phase or control group, identify the specific SJW extract employed and provide quantitative analyses of key constituents.

Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.

Short report: Lack of sex effect on the pharmacokinetics of primaquine

The pharmacokinetics of primaquine have been well defined in male volunteers, but there is little data on the disposition of the drug in women. We compared the kinetics of primaquine in nine male and nine female healthy Australian volunteers after the administration of a single oral dose (30 mg base) of primaquine. No statistical differences were observed in the following kinetic parameters of primaquine between men and women, respectively: maximum plasma concentration (93 +/- 26 and 115 +/- 38 ng/mL; 95% confidence interval [CI] of the mean difference: -55 to 10 ng/mL; P = 0.16), area under the curve (1.1 +/- 0.5 and 1.2 +/- 0.4 mu g.h/mL; 95% CI: -0.6 to 0.3 mu g.h/mL; P = 0.54), and clearance (0.34 +/- 0.12 and 0.39 +/- 0.14 L/h/kg; 95% CI: -0.17 to 0.08 L/h/kg; P = 0.46). The clinical relevance of such findings would suggest that sex does not have to be taken into account as a factor when prescribing primaquine for radical cure or terminal prophylaxis of Plasmodium vivax malaria.