Inflow cannula design for biventricular assist devices

Cardiovascular diseases are a leading cause of death throughout the developed world. With the demand for donor hearts far exceeding the supply, a bridge-to-transplant or permanent solution is required. This is currently achieved with ventricular assist devices (VADs), which can be used to assist the left ventricle (LVAD), right ventricle (RVAD), or both ventricles simultaneously (BiVAD). Earlier generation VADs were large, volume-displacement devices designed for temporary support until a donor heart was found. The latest generation of VADs use rotary blood pump technology which improves device lifetime and the quality of life for end stage heart failure patients. VADs are connected to the heart and greater vessels of the patient through specially designed tubes called cannulae. The inflow cannulae, which supply blood to the VAD, are usually attached to the left atrium or ventricle for LVAD support, and the right atrium or ventricle for RVAD support. Few studies have characterized the haemodynamic difference between the two cannulation sites, particularly with respect to rotary RVAD support. Inflow cannulae are usually made of metal or a semi-rigid polymer to prevent collapse with negative pressures. However suction, and subsequent collapse, of the cannulated heart chamber can be a frequent occurrence, particularly with the relatively preload insensitive rotary blood pumps. Suction events may be associated with endocardial damage, pump flow stoppages and ventricular arrhythmias. While several VAD control strategies are under development, these usually rely on potentially inaccurate sensors or somewhat unreliable inferred data to estimate preload. Fixation of the inflow cannula is usually achieved through suturing the cannula, often via a felt sewing ring, to the cannulated chamber. This technique extends the time on cardiopulmonary bypass which is associated with several postoperative complications. The overall objective of this thesis was to improve the placement and design of rotary LVAD and RVAD inflow cannulae to achieve enhanced haemodynamic performance, reduced incidence of suction events, reduced levels of postoperative bleeding and a faster implantation procedure. Specific objectives were: * in-vitro evaluation of LVAD and RVAD inflow cannula placement, * design and in-vitro evaluation of a passive mechanism to reduce the potential for heart chamber suction, * design and in-vitro evaluation of a novel suture-less cannula fixation device. In order to complete in-vitro evaluation of VAD inflow cannulae, a mock circulation loop (MCL) was developed to accurately replicate the haemodynamics in the human systemic and pulmonary circulations. Validation of the MCL’s haemodynamic performance, including the form and magnitude of pressure, flow and volume traces was completed through comparisons of patient data and the literature. The MCL was capable of reproducing almost any healthy or pathological condition, and provided a useful tool to evaluate VAD cannulation and other cardiovascular devices. The MCL was used to evaluate inflow cannula placement for rotary VAD support. Left and right atrial and ventricular cannulation sites were evaluated under conditions of mild and severe heart failure. With a view to long term LVAD support in the severe left heart failure condition, left ventricular inflow cannulation was preferred due to improved LVAD efficiency and reduced potential for thrombus formation. In the mild left heart failure condition, left atrial cannulation was preferred to provide an improved platform for myocardial recovery. Similar trends were observed with RVAD support, however to a lesser degree due to a smaller difference in right atrial and ventricular pressures. A compliant inflow cannula to prevent suction events was then developed and evaluated in the MCL. As rotary LVAD or RVAD preload was reduced, suction events occurred in all instances with a rigid inflow cannula. Addition of the compliant segment eliminated suction events in all instances. This was due to passive restriction of the compliant segment as preload dropped, thus increasing the VAD circuit resistance and decreasing the VAD flow rate. Therefore, the compliant inflow cannula acted as a passive flow control / anti-suction system in LVAD and RVAD support. A novel suture-less inflow cannula fixation device was then developed to reduce implantation time and postoperative bleeding. The fixation device was evaluated for LVAD and RVAD support in cadaveric animal and human hearts attached to a MCL. LVAD inflow cannulation was achieved in under two minutes with the suture-less fixation device. No leakage through the suture-less fixation device – myocardial interface was noted. Continued development and in-vivo evaluation of this device may result in an improved inflow cannulation technique with the potential for off-bypass insertion. Continued development of this research, in particular the compliant inflow cannula and suture-less inflow cannulation device, will result in improved postoperative outcomes, life span and quality of life for end-stage heart failure patients.

The structure of Pavlovian fear conditioning in the amygdala

Do different brains forming a specific memory allocate the same groups of neurons to encode it? One way to test this question is to map neurons encoding the same memory and quantitatively compare their locations across individual brains. In a previous study, we used this strategy to uncover a common topography of neurons in the dorsolateral amygdala (LAd) that expressed a learning-induced and plasticity-related kinase (p42/44 mitogen-activated protein kinase; pMAPK), following auditory Pavlovian fear conditioning. In this series of experiments, we extend our initial findings to ask to what extent this functional topography depends upon intrinsic neuronal structure. We first showed that the majority (87 %) of pMAPK expression in the lateral amygdala was restricted to principal-type neurons. Next, we verified a neuroanatomical reference point for amygdala alignment using in vivo magnetic resonance imaging and in vitro morphometrics. We then determined that the topography of neurons encoding auditory fear conditioning was not exclusively governed by principal neuron cytoarchitecture. These data suggest that functional patterning of neurons undergoing plasticity in the amygdala following Pavlovian fear conditioning is specific to memory formation itself. Further, the spatial allocation of activated neurons in the LAd was specific to cued (auditory), but not contextual, fear conditioning. Spatial analyses conducted at another coronal plane revealed another spatial map unique to fear conditioning, providing additional evidence that the functional topography of fear memory storing cells in the LAd is non-random and stable. Overall, these data provide evidence for a spatial organizing principle governing the functional allocation of fear memory in the amygdala.

Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis

Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobarichypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 ± 1.4 versus 13.8 ± 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 ± 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B2 excretion increased following hypoxia (44.6 ± 11.1 versus 14.7 ± 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 ± 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin1α excretion following hypoxia was reduced by COX-2 gene disruption (29 ± 3 versus 52 ± 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA2/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA2, and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment : the M77001 study group

Purpose: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: Patients were randomly assigned to six cycles of docetaxel 100 mg/m 2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity. © 2005 by American Society of Clinical Oncology.

Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer : a review of the existing clinical trials and results of the expanded access programme in the UK

Trastuzumab is a humanised monoclonal antibody against the extracellular domain of HER2 (human epidermal growth factor receptor-2) that is overexpressed in about 25% of human breast cancers. It has shown clinical benefit in HER2-positive breast cancer cases when used alone or in combination with chemotherapy. Trastuzumab increases the response rate to chemotherapy and prolongs survival when used in combination with taxanes. In this article, we review the clinical trials where trastuzumab has been administered together with docetaxel, and we present the results of the trastuzumab expanded access programme (EAP) in the UK. Combination of trastuzumab with docetaxel results in similar response rates and time-to-progression with the trastuzumab/paclitaxel combinations. The toxicity of the combination and the risk of heart failure are low. The clinical data for the docetaxel/trastuzumab combination indicate a favourable profile from both the efficacy and the safety point of view and confirm the feasibility and safety of trastuzumab administration both as monotherapy and in combination with docetaxel. © 2004 Blackwell Publishing Ltd.

Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder

Muscle invasive transitional cell carcinoma (TCC) of the bladder is associated with a high frequency of metastasis, resulting in poor prognosis for patients presenting with this disease. Models that capture and demonstrate step-wise enhancement of elements of the human metastatic cascade on a similar genetic background are useful research tools. We have utilized the transitional cell carcinoma cell line TSU-Pr1 to develop an in vivo experimental model of bladder TCC metastasis. TSU-Pr1 cells were inoculated into the left cardiac ventricle of SCID mice and the development of bone metastases was monitored using high resolution X-ray. Tumor tissue from a single bone lesion was excised and cultured in vitro to generate the TSU-Pr1-B1 subline. This cycle was repeated with the TSU-Pr1-B1 cells to generate the successive subline TSU-Pr1-B2. DNA profiling and karyotype analysis confirmed the genetic relationship of these three cell lines. In vitro, the growth rate of these cell lines was not significantly different. However, following intracardiac inoculation TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2 exhibited increasing metastatic potential with a concomitant decrease in time to the onset of radiologically detectable metastatic bone lesions. Significant elevations in the levels of mRNA expression of the matrix metalloproteases (MMPs) membrane type 1-MMP (MT1-MMP), MT2-MMP and MMP-9, and their inhibitor, tissue inhibitor of metalloprotease-2 (TIMP-2), across the progressively metastatic cell lines, were detected by quantitative PCR. Given the role of MT1-MMP and TIMP-2 in MMP-2 activation, and the upregulation of MMP-9, these data suggest an important role for matrix remodeling, particularly basement membrane, in this progression. The TSU-Pr1-B1/B2 model holds promise for further identification of important molecules.

Human breast cancer cell metastasis to long bone and soft organs of nude mice : a quantitative assay

Bone is a common metastatic site in human breast cancer (HBC). Since bone metastasis occurs very rarely from current spontaneous or experimental metastasis models of HBC cells in nude mice, an arterial seeding model involving the direct injection of the cells into the left ventricle has been developed to better understand the mechanisms involved in this process. We present here a sensitive polymerase chain reaction (PCR) method to detect and quantitate bone and soft organ metastasis in nude mice which have been intracardially inoculated with Lac Z transduced HBC cells. Amplification of genomically incorporated Lac Z sequences in MDA-MB-231-BAG HBC cells enables us to specifically detect these cells in mouse organs and bones. We have also created a competitive template to use as an internal standard in the PCR reactions, allowing us to better quantitate levels of HBC metastasis. The results of this PCR detection method correlate well with cell culture detection from alternate long bones from the same mice, and are more sensitive than gross Lac Z staining with X-gal or routine histology. Comparable qualitative results were obtained with PCR and culture in a titration experiment in which mice were inoculated with increasing numbers of cells, but PCR is more quantifiable, less time consuming, and less expensive. This assay can be employed to study the molecular and cellular aspects of bone metastasis, and could easily be used in conjunction with RT-PCR-based analyses of gene products which may be involved with HBC metastasis.

An MMP13-selective inhibitor delays primary tumor growth and the onset of tumor-associated osteolytic lesions in experimental models of breast cancer

We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.

Left ventricular volume and valve gradient analysis using an Apple Macintosh computer

A description of a computer program to analyse cine angiograms of the heart and pressure waveforms to calculate valve gradients.

Letter: Brain natriuretic peptide is a potentially useful screening tool for the detection of cardiovascular disease in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) have a significantly higher risk of coronary heart disease, despite being less likely to report symptoms of angina, and are more likely to experience unrecognised myocardial infarction and sudden cardiac death than non-RA controls.1 Furthermore, left ventricular diastolic dysfunction has been described in up to 40% of patients with RA.2...

Feasibility of perflutren microsphere contrast transthoracic echocardiography in the visualization of ventricular endocardium during venovenous extracorporeal membrane oxygenation in a validated ovine model

Background: Transthoracic echocardiography (TTE) during extra corporeal membrane oxygenation (ECMO) is important but can be technically challenging. Contrast-specific TTE can improve imaging in suboptimal studies. These contrast microspheres are hydrodynamically labile structures. This study assessed the feasibility of contrast echocardiography (CE) during venovenous (VV) ECMO in a validated ovine model. Method: Twenty-four sheep were commenced on VV ECMO. Parasternal long-axis (Plax) and short-axis (Psax) views were obtained pre- and postcontrast while on VV ECMO. Endocardial definition scores (EDS) per segment were graded: 1 = good, 2 = suboptimal 3 = not seen. Endocardial border definition score index (EBDSI) was calculated for each view. Endocardial length (EL) in the Plax view for the left ventricle (LV) and right ventricle (RV) was measured. Results: Summation EDS data for the LV and RV for unenhanced TTE (UE) versus CE TTE imaging: EDS 1 = 289 versus 346, EDS 2 = 38 versus 10, EDS 3 = 33 versus 4, respectively. Wilcoxon matched-pairs rank-sign tests showed a significant ranking difference (improvement) pre- and postcontrast for the LV (P < 0.0001), RV (P < 0.0001) and combined ventricular data (P < 0.0001). EBDSI for CE TTE was significantly lower than UE TTE for the LV (1.05 ± 0.17 vs. 1.22 ± 0.38, P = 0.0004) and RV (1.06 ± 0.22 vs. 1.42 ± 0.47, P = 0.0.0006) respectively. Visualized EL was significantly longer in CE versus UE for both the LV (58.6 ± 11.0 mm vs. 47.4 ± 11.7 mm, P < 0.0001) and the RV (52.3 ± 8.6 mm vs. 36.0 ± 13.1 mm, P < 0.0001), respectively. Conclusions: Despite exposure to destructive hydrodynamic forces, CE is a feasible technique in an ovine ECMO model. CE results in significantly improved EDS and increased EL.

Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

The beta-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 mu M) or PDE4-selective inhibitor rolipram (1 mu M) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through beta(1)-adrenoceptors (beta(2)-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through beta(2)-adrenoceptors (beta(1)-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from -logEC(50)s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-beta-blocker-treated patients, consistent with the previously reported beta(2)-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular beta(2)-adrenoceptors compared to beta(1)-adrenoceptors. The beta(2)-adrenoceptor-selectivity of carvedilol may provide protection against beta(2)-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control beta(1)- and beta(2)-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.

Pimelea trichostachya poisoning (St George disease) in horses

A dense population of Pimelea trichostachya plants (Family Thymelaeaceae) in pasture poisoned a horse herd in southern inland Queensland in October-November 2005. Plant density was 2 to 45 g wet weight/m2 (mean 16 g/m2) from 5 to 69 plants/m2 (mean 38 plants/m2) representing 3 to 20% (mean 9%) of the volume of pasture on offer. Ten of 35 mares, fillies and geldings were affected. Clinical signs were loss of body weight, profound lethargy, serous nasal discharge, severe watery diarrhoea and subcutaneous oedema of the intermandibular space, chest and ventral midline. Pathological findings were anaemia, leucocytopenia, hypoproteinaemia, dilatation of the right ventricle of the heart, dilated hepatic portal veins and periportal hepatic sinusoids (peliosis hepatis), alimentary mucosal hyperaemia and oedema of mesenteric lymph nodes. Cattle grazing the same pasture were affected by Pimelea poisoning simultaneously. Removal of the horses to Pimelea-free pasture initiated recovery. The one other incident of this syndrome, previously only recognised in cattle in Australia, occurred in horses, in South Australia in 2002, with access to a dense Pimelea simplex population.

Levosimendan: Studies on its mechanisms of action and beyond

Acute heart failure syndrome represents a prominent and growing health problem all around the world. Ideally, medical treatment for patients admitted to hospital because of this syndrome, in addition to alleviating the acute symptoms, should also prevent myocardial damage, modulate neurohumoral and inflammatory activation, and preserve or even improve renal function. Levosimendan is a cardiac enhancer having both inotropic and vasodilatory effects. It is approved for the short-term treatment of acutely decompensated chronic heart failure, but it has been shown to have beneficial clinical effects also in ischemic heart disease and septic shock as well as in perioperative cardiac support. In the present study, the mechanisms of action of levosimendan were studied in isolated guinea-pig heart preparations: Langendorff-perfused heart, papillary muscle and permeabilized cardiomyocytes as well as in purified phosphodiesterase isoenzyme preparations. Levosimendan was shown to be a potent inotropic agent in isolated Langendorff-perfused heart and right ventricle papillary muscle. In permeabilized cardiomyocytes, it was demonstrated to be a potent calcium sensitizer in contrast to its enantiomer, dextrosimendan. It was additionally shown to be a very selective phosphodiesterase (PDE) type-3 inhibitor, the selectivity factor for PDE3 over PDE4 being 10000 for levosimendan. Irrespective of this very selective PDE3 inhibitory property in purified enzyme preparations, the inotropic effect of levosimendan was demonstrated to be mediated mainly through calcium sensitization in the isolated heart as well as the papillary muscle preparations at clinically relevant concentrations. In the isolated Lagendorff-perfused heart, glibenclamide antagonized the levosimendan-induced increase in coronary flow (CF). Therefore, the main vasodilatory mechanism in coronary veins is believed to be the opening of the ATP-sensitive potassium (KATP) channels. In the paced hearts, CF did not increase in parallel with oxygen consumption (MVO2), thus indicating that levosimendan had a direct vasodilatory effect on coronary veins. The pharmacology of levosimendan was clearly different from that of milrinone, which induced an increase in CF in parallel with MVO2. In conclusion, levosimendan was demonstrated to increase cardiac contractility by binding to cardiac troponin C and sensitizing the myofilament contractile proteins to calcium, and further to induce coronary vasodilatation by opening KATP channels in vascular smooth muscle. In addition, the efficiency of the cardiac contraction was shown to be more advantageous when the heart was perfused with levosimendan in comparison to milrinone perfusion.

Cyanidin 3-glucoside improves diet-induced metabolic syndrome in rats

Increased consumption of dark-coloured fruits and vegetables may mitigate metabolic syndrome. This study has determined the changes in metabolic parameters, and in cardiovascular and liver structure and function, following chronic administration of either cyanidin 3-glucoside (CG) or Queen Garnet plum juice (QG) containing cyanidin glycosides to rats fed either a corn starch (C) or a high-carbohydrate, high-fat (H) diet. Eight to nine-week-old male Wistar rats were randomly divided into six groups for 16-week feeding with C, C with CG or QG, H or H with CG or QG. C or H were supplemented with CG or QG at a dose of ∼8 mg/kg/day cyanidin glycosides from week 8 to 16. H rats developed signs of metabolic syndrome including visceral adiposity, impaired glucose tolerance, hypertension, cardiovascular remodelling, increased collagen depots in left ventricle, non-alcoholic fatty liver disease, increased plasma liver enzymes and increased inflammatory cell infiltration in the heart and liver. Both CG and QG reversed these cardiovascular, liver and metabolic signs. However, no intact anthocyanins or common methylated/conjugated metabolites could be detected in the plasma samples and plasma hippuric acid concentrations were unchanged. Our results suggest CG is the most likely mediator of the responses to QG but that further investigation of the pharmacokinetics of oral CG in rats is required.