An expressive-arts-based life-death education program for the elderly: A qualitative study.

This study endeavors to investigate how healthcare workers, equipped with expressive arts methods, could foster life-death education for the elderly. Forty-nine older adults aged 60 or above joined a 10-session expressive arts-based life-death education program that was led by social workers equipped with expressive arts methods. An ethnographic research approach, with a post-treatment focus group (n = 17), was conducted with the participants. The results showed that expressive arts methods could enhance reorganization of life experiences, promote dealing with ambivalent emotion regarding life-death issues, improve communicating life-death issues with family members, and induce ideas to prepare for death.

Poisoning by toxic plants in Hong Kong: a 15-year review.

INTRODUCTION: Hong Kong has a great diversity of plants, many of which are toxic to humans. The aim of this study was to identify the plant species most commonly involved in cases of plant poisoning in Hong Kong and to provide clinicians with a reference tool for the diagnosis and management of plant poisoning. METHODS: We retrospectively reviewed all plant poisoning cases referred to the Hospital Authority Toxicology Reference Laboratory from 1 January 2003 to 31 December 2017. Demographics, clinical presentation, laboratory findings, treatment and outcomes of patients, as well as morphological identification and analytical testing of the plant specimens, were investigated. RESULTS: A total of 62 cases involving 26 poisonous plant species were identified, among which Alocasia macrorrhizos (Giant Alocasia), Gelsemium elegans (Graceful Jessamine), and Rhododendron (Azalea) species were the three most commonly encountered. Gastrointestinal toxicity (n=30, 48%), neurological toxicity (n=22, 35%), and hepatotoxicity (n=6, 10%) were the three most common clinical problems. Forty-nine (79%) and eight (13%) patients had mild and moderate toxicity, respectively; they all recovered shortly with supportive treatment. The remaining five (8%) patients experienced severe toxicity requiring intensive care support. Most patients (n=61, 98%) used the plants intentionally: as a medicinal herb (n=31), as food (n=29), and for attempting suicide (n=1). Reasons for using the poisonous plants included misidentification (n=34, 55%), unawareness of the toxicity (n=20, 32%), and contamination (n=6, 10%). CONCLUSIONS: Although most plant exposure resulted in a self-limiting disease, severe poisonings were encountered. Epidemiology of plant poisonings is geographically specific. Clinicians should be aware of local poisonous plants and their toxicities.

Budd-Chiari syndrome secondary to toxic pyrrolizidine alkaloid exposure.

In this report, we describe a case of pyrrolizidine alkaloid-related Budd-Chiari syndrome in Hong Kong. A 10-month-old boy presented with ascites, right pleural effusion, and hepatomegaly after consumption of herbal drinks for 3 months. His clinical (including imaging) features were compatible with Budd-Chiari syndrome. Budd-Chiari syndrome is a rare disease entity in paediatric patients. In our case, extensive workup performed to look for the underlying cause of Budd-Chiari syndrome was unrevealing, except for toxic pyrrolizidine alkaloid exposure in his herbal drinks.

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass.

We conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg(-1) infused over 15 min followed by a 16 mg.kg(-1) .h(-1) infusion until chest closure with a 2 mg.kg(-1) load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined.

Lack of glutathione conjugation of melphalan in the isolated in situ liver perfusion in humans.

Tumor cell resistance against melphalan (LPAM) has been associated with increased cellular reduced glutathione (GSH) levels and glutathione S-transferase activity. Therefore, GSH conjugation of LPAM has been hypothesized to be a key factor in tumor cell resistance. In the present study, we evaluated GSH conjugation of LPAM by the perfused liver in patients with colorectal cancer metastases undergoing a Phase II study of isolated liver perfusion as well as in the rat. To evaluate whether LPAM-GSH conjugates were synthesized in the rat in vivo, LPAM was infused i.v. at a rate of 2.0 micromol/kg/min. In bile samples obtained during the infusion, two major GSH conjugates were identified by mass spectrometry: mono-hydroxy-mono-GSH-LPAM and di-GSH-LPAM. The maximum biliary excretion rate of these two conjugates accounted for only 1.3% of the LPAM infusion rate. In bile or perfusate samples from patients treated for 60 min initially with 0.3 mM LPAM in the perfusion medium via isolated liver perfusion (200 mg LPAM in approximately 2 liters perfusion medium), none of the above-mentioned conjugates were detected. When comparable rat liver perfusions were performed initially with 66 microM or 0.66 mM LPAM in the perfusion medium, bile samples did contain GSH-LPAM conjugates; the cumulative biliary excretion of the two conjugates amounted to 0.4 and 0.2% of the LPAM dose, respectively. These data suggest that both in rats and humans, hepatic GSH conjugation plays a very minor (if any) role in the elimination of LPAM and, therefore, that modulation of GSH levels is unlikely to affect the rate of elimination of this drug.

Kinetics of sulfation and glucuronidation of harmol in the perfused rat liver preparation. Disappearance of aberrances in glucuronidation kinetics by inhibition of sulfation.

Harmol is conjugated by glucuronidation and sulfation when it is given to the rat in vivo. In the once-through perfused rat liver preparation glucuronidation of harmol shows kinetic aberrances [Pang et al., J. Pharmac. exp. Ther. 219, 134 (1981)]. In order to further delineate the mechanism behind this, sulfation was inhibited to about 10% of control by 2,6-dichloro-4-nitrophenol. The loss of sulfation was compensated by an increase in the rate of glucuronidation, keeping the total clearance by the liver virtually constant in spite of the loss of sulfation. The inhibition of sulfation eliminated the previously observed lag-phase in the kinetics of glucuronidation; the rate of glucuronidation was now almost linear with the input concentration of the substrate harmol. The constant clearance of harmol in spite of inhibition of sulfation, the occurrence of the lag-phase in glucuronidation in the presence of sulfation, and the disappearance of this lag-phase in the absence of sulfation can be explained by either diffusion-limited metabolism of harmol or a heterogeneous sub-lobular distribution of the sulfating and glucuronidating systems. Activation of glucuronidation by harmol at high concentration can be excluded.

Selective inhibition of sulfate conjugation in the rat: pharmacokinetics and characterization of the inhibitory effect of 2,6-dichloro-4-nitrophenol.

The pharmacokinetics of 2,6-dichloro-4-nitrophenol (DCNP) have been studied in the rat. Upon i.v. injection the plasma decay curve of DCNP showed a rapid distribution phase. After 30 min the plasma concentration reached a value that was constant for at least 90 min, indicating very slow elimination of DCNP. The volume of distribution was 88 ml/kg and a high degree of binding (over, 99%) of DCNP in vitro to bovine serum albumin was found. The concentration of DCNP in the liver was between 30 and 50% of the plasma values. While in vivo the effect of DCNP persisted for a long time, its action was readily reversible in the single-pass perfused rat liver. In vivo, the effect of the dose of DCNP on the inhibition of sulfation of the phenolic compound harmol was investigated. Upon the i.v. injection of 26 mumole DCNP/kg an instantaneous and complete inhibition of sulfation of harmol was found. Using this property of DCNP, the rate of sulfation of harmol in vivo was evaluated in relation to the dose and the time after injection of the substrate. Saturation of sulfation apparently occurred because the consumption of inorganic sulfate was extremely small.

Glucuronidation and sulfation in the rat in vivo. The role of the liver and the intestine in the in vivo clearance of 4-methylumbelliferone.

The role of the liver in the conjugation of 4-methylumbelliferone (4MU), mainly glucuronidation, was investigated in the rat in vivo. The liver extracted 4MU almost completely (97%) during steady-state infusion, as measured by the difference between 4MU concentration in portal and hepatic venous blood. Previously, it was shown that the intestinal region extracts 40% of the 4MU of the incoming arterial blood. The liver and the gastrointestinal region are so efficient that their conjugation activity can account for total body clearance of 4MU (50-60 ml/min per kg). These results and other evidence on extrahepatic conjugation of phenolic substrates suggest that glucuronidation may be limited to the liver, (the kidney) and the gastrointestinal region, while sulfation may occur more widespread throughout the body. Protein binding studies showed the sulfate conjugate to be even more protein-bound than unconjugated 4MU, while 4MU glucuronide was much less bound to rat plasma proteins.

Extrahepatic sulfation and glucuronidation in the rat in vivo. Determination of the hepatic extraction ratio of harmol and the extrahepatic contribution to harmol conjugation.

The phenolic compound, harmol, is metabolized by sulfation and glucuronidation in the rat in vivo. In the present study, various harmol infusion rates into the jugular vein were used to delineate first-order conditions whereby total body clearance was maximal and constant; at low infusion rates the steady state harmol concentration in blood varied proportionally with the infusion rate. At infusion rates of 167 nmole/min and below, the steady state clearance of harmol was 60 ml/min or 200 ml/min/kg. Because this value for total body clearance greatly exceeded the value for hepatic blood flow rate (20 ml/min for a 300 g rat), considerable extrahepatic conjugation of harmol was suggested. At higher harmol infusion rates the total clearance decreased. Since an intraportal infusion of 167 nmole/min to the rat yielded, during steady state, the same arterial harmol blood concentration as a 52 nmole/min jugular infusion, the hepatic extraction ratio of harmol in vivo was 0.7. Extrahepatic clearance, therefore, constituted about 77% of total body clearance (after taking the difference between total body clearance and hepatic clearance). Total sulfation clearance was 52 ml/min, and greatly exceed the value for hepatic clearance (14 ml/min). Extrahepatic clearance for sulfation (at least 38 ml/min) therefore accounted for a major proportion of the sulfation activity. Blood platelets did not seem to contribute to sulfation or glucuronidation in vivo.

The multiple indicator dilution method and its utility in risk assessment.

The multiple-indicator dilution (MID) technique entails the injection of a mixture of labeled indicators into the blood vessel immediately at the entrance of an organ, e.g., the liver, kidney, heart, or lung, and characterization of outflow dilution profiles from timed venous samples. The mathematical basis of the method encompasses linear systems of partial differential equations that are formulated for flow- or barrier-limited transport combined with intracellular metabolism/excretion. The concept can be generalized to include metabolites. MID experiments are useful for determining tissue partition coefficients as well as kinetic parameters such as membrane permeabilities or metabolic/excretory intrinsic clearances, factors that affect the mean residence times or exposure of solutes to the organ. The main utility of the MID method lies in its role in identifying the basic mechanisms of the interaction of organs with vascular components. The concentration dependence in transport and removal is revealed by the rate coefficients upon varying the input concentrations of unlabeled substances into the organ at steady state. The data obtained with MID experiments can be incorporated into physiologically based pharmacokinetic (PBPK) models such as those used for biological risk assessment. This is especially pertinent in the case where diffusional barriers appear within organs. The insight gained from the MID organ approach may be useful for PBPK models with more realistic representation of organ kinetics.

Transport, binding, and metabolism of sulfate conjugates in the liver.

Sulfate conjugates are a heterogeneous class of polar, anionic metabolites that result from the conjugation of endogenous and exogenous compounds. Sulfate conjugates exhibit a high degree of binding to albumin, the extent of which usually exceeds those of their parent compounds. Preponderant direct and indirect evidence suggests that sulfation activity is slightly higher in the periportal than in the perivenous (centrilobular) region of the liver, but recent immunohistochemical studies imply that specific isoforms of the sulfotransferases may also be preferentially localized in the perivenous region. Entry of sulfate conjugates into the liver cell is poor unless discrete carriers are present. Although known transport carriers exist for the sulfated bile acids, the specificity of the carriers for drug sulfate conjugates is presently unknown. The removal of sulfates is usually by way of biliary excretion while, on occasion, sulfates can be desulfated and participate in futile cycling with their parent compounds. The binding, transport, and hepatic elimination of various drug sulfate conjugates are examined. Non-recirculating studies carried out in the perfused rat liver with the multiple indicator dilution technique under varying input sulfate conjugate concentrations have provided essential information on the effects of vascular (red blood cells and plasma protein) binding on transport and removal of the conjugates. These studies clearly demonstrate the need to study protein binding, transmembrane transfer characteristics across the liver basolateral (sinusoidal) and canalicular membranes, and enzyme zonation in a distributed-in-space fashion in order to properly define the handling of sulfate conjugates in the liver.

Theoretical relationships between area under the curve and route of administration of drugs and their precursors for evaluating sites and pathways of metabolism.

The bioavailability of a drug administered extrasystemically is a measure of the initial extraction of a compound by a series of eliminating events involving the intestinal mucosal enzymes, the gut bacterial microflora, the liver, and the lung. A theoretical analysis is presented to differentiate the process of gut wall elimination and hepatic removal of a drug during this first-pass effect. The area under the blood concentration--time curve (AUC) for a drug and its metabolite is shown to be useful in determining the presence of these processes when a drug and its metabolite are administered concomitantly by different routes of administration. Furthermore, the fraction of a precursor transformed to its metabolite also can be determined by pharmacokinetic analysis of the AUC of a drug and its metabolite after administration of both substances.

Implantation metastasis in a 13-year-old girl: a case report.

We report a case of a 13-year-old girl with an osteosarcoma of the right humerus, which had been diagnosed as an aneurysmal bone cyst at our institution. She underwent curettage and bone grafting of the lesion, which resulted in implantation metastasis of the tumour to the ilium. She died 15 months after presentation owing to pulmonary metastases. This report highlights the possibility of metastasis occurring by direct implantation to a graft donor site. We strongly recommend that a biopsy be performed in cases of presumed benign lesions before proceeding with the definitive surgery.

ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans.

This white paper provides a critical analysis of methods for estimating transporter kinetics and recommendations on proper parameter calculation in various experimental systems. Rational interpretation of transporter-knockout animal findings and application of static and dynamic physiologically based modeling approaches for prediction of human transporter-mediated pharmacokinetics and drug-drug interactions (DDIs) are presented. The objective is to provide appropriate guidance for the use of in vitro, in vivo, and modeling tools in translational transporter science.

Transport of 5,5-diphenylbarbituric acid and its precursors and their effect on P-gp, MRP2 and CYP3A4 in Caco-2 and LS180 cells.

AIM: To examine the transport of 5,5-diphenylbarbituric acid sodium (T2007) and its mono- (MMMDPB) and di- (T2000) methoxymethylated precursors and their inducibility potential in Caco-2 and LS180 cells. METHODS: Transport studies of T2000, MMMDPB and T2007 in Caco-2 cells were performed in Transwells. P-gp and CYP3A4 activities were assayed by [(3)H]digoxin and rhodamine 123 cellular retention and testosterone 6ß-hydroxylation, respectively. Expressions of PXR, VDR and CAR mRNA and CYP3A4, MDR1/P-gp and MRP2 mRNA and protein were determined by qPCR and Western blotting, respectively. PXR siRNA was used to assess the involvement of PXR. RESULTS: The P(app(A→B))s and P(app(B→A))s of T2000, MMMDPB and T2007 were similar (30-35×10(-6)cm/s) in Caco-2 cells. Treatment for 3 days with T2000 (15µM), MMMDPB (70µM) and T2007 (300µM) generally furnished a greater induction in LS180 cells over the Caco-2 cells due to the higher, natural abundance of PXR. Changes in expression were confined mostly to MDR1 and CYP3A4: in LS180 cells, treatment for 3 days increased MDR1 and CYP3A4 but not MRP2 mRNA, and elevated P-gp and CYP3A4 protein expression that led to decreased cellular accumulation of [(3)H]digoxin and rhodamine 123, and enhanced testosterone 6ß-hydroxylase activity towards T2007, respectively. The silencing of PXR by PXR siRNA in LS180 cells significantly attenuated the induction of MDR1 and CYP3A4. CONCLUSIONS: T2000, MMMDPB, and T2007 exhibited high permeabilities but are not P-gp substrates. T2007 and its analogs upregulated CYP3A4 and MDR1 modestly via the PXR.

Kinetics of sequential metabolism. Contribution of parallel, primary metabolic pathways to the formation of a common, secondary metabolite.

Interpretation of rate constants in the sequential metabolism of two different primary metabolites (MIA and MIB) for formation of a common, secondary metabolite (MII) after drug administration requires theoretical development of formulations that govern mass transfer during intravenous and oral administrations. Two cases (a and b) were presently considered for metabolism occurring only in the first-pass organs (intestine and liver) for flow-limited drugs and primary and secondary metabolites: (case a) wherein drug formed only the two primary metabolites, with the fractions of total body clearance that formed MIA and MIB, being denoted by f1 and f2, respectively, and (case b) wherein other additional elimination pathways for drug were present. MIA and MIB only partially formed MII (denoted by fMIA and fMIB, respectively), because provision was made for alternate elimination pathways; the fractional clearance in the formation of MII from MIA and MIB were fMIA and fMIB, respectively. Drug was metabolized to MIA than MII within the gut lumen with oral drug administration; the MIA and MII formed were further absorbed. Triangular matrices were found to result from mass transfer equations for first-order conditions with oral and intravenous administrations. Upon inversion of the matrices, the areas under the curve for drug and metabolite species were obtained after multiplication by the administered dose and division by the volume of the species considered. However, the dose-corrected area under the curve was used as the basis for comparison. Case-independent solutions were obtained for the fractions absorbed (Fa, FaMIA, FaMIB) and the availabilities (F, F(MIA), F(MIB)) of drug and the primary metabolites, and for f1, f2, f1/f2, fMIA/fMIB, and (f1fMIA)/(f2fMIB) (ratio of effective clearances of MII formation from D via MIA and MIB). Case-dependent solutions also existed. For case a (f1 + f2 = 1), the fraction of total body clearance that formed MIA (f1) or MIB (f2) was solved with the area under the curve of MII after intravenous D, MIA, and MIB administrations. For case b, however, the same constants were obtained after greater manipulation, and entailed oral administration of the metabolites. Although solutions for the ratios of f1/f2 and (f1fMIA)/(f2fMIB) were found, the fractional clearances in formation of MII from MIA (fMIA) and MIB (fMIB) were, however, not provided in both cases unless MII was completely absorbed.