Copyright (c) 2008 All rights reserved. http://works.bepress.com/kelvin_chan Recent documents in Kelvin Chan en-us Fri, 29 Aug 2008 04:49:37 PDT 3600 http://works.bepress.com/kelvin_chan/116 http://works.bepress.com/kelvin_chan/116 Wed, 27 Aug 2008 23:30:23 PDT A sensitive and accurate gas liquid chromatographic (GLC) method is described to determine pethidine and norpethidine in plasma of Chinese patients who received a single dose (1 mg/kg of total body weight) of pethidine intramuscularly. The chromatograph consists of a 3% w/w SP2250 on Chromosorb W glass column linked to a nitrogen-phosphorus detector. Sample preparation was simple, being based on a single extraction of basified plasma samples with n-hexane. The operating time of the assay was less than thirty minutes, which was suitable for routine pharmacokinetic studies of both pethidine and norpethidine. This method was sensitive to 5 ng/ml of pethidine and 10 ng/ml of norpethidine extracted from 1 ml plasma sample. Linearity was observed in the range of 10 to 500 ng/ml. The day-to-day variation at the concentration of 100 ng/ml of pethidine and norpethidine was 3.3 and 4.27% respectively. The mean ( ± S.D.) peak plasma concentration, the mean ( ± S.D.) time for maximum absorption, and the mean ( ± S.D.) elimination half-life of pethidine was 246.4 ± 65.9 ng/ml, 0.75 ± 0.31 hr., and 7.95 ± 2.22 hrs respectively. The N-demethylated metabolite, norpethidine, appeared in the plasma from 0.5 to 1 hour and the mean ( ± S.D.) peak plasma concentration was 28.8 ± 4.38 ng/ml. The mean elimination half-life (39.6 ± 19.3 hrs) was significantly greater than pethidine. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/115 http://works.bepress.com/kelvin_chan/115 Wed, 27 Aug 2008 23:21:12 PDT We measured pyrazinamide and rifampicin plasma concentrations in five patients with pulmonary tuberculosis and end stage renal failure treated by haemodialysis or continuous ambulatory peritoneal dialysis. Using conventional daily doses of oral pyrazinamide and rifampicin, we found that the drugs were removed efficiently by both dialysis methods, so that plasma levels were sub-optimal for maximal bactericidal action. These findings suggest that in patients with tuberculosis on maintenance dialysis, treatment should be either with higher doses of these two drugs, or with additional replacement doses given after each dialysis. Further detailed pharmacokinetic studies on larger numbers of patients are indicated. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/114 http://works.bepress.com/kelvin_chan/114 Wed, 27 Aug 2008 23:15:19 PDT The present study aims to investigate the preclinical intestinal absorption of bis(7)-tacrine (B7T) using different absorption models. In addition, potential intestinal and liver first-pass metabolism was evaluated by in vitro incubation of B7T with rat intestine and liver microsome. Results showed that the permeability of B7T across artificial membrane was pH dependent with rapid diffusion achieved at both pH 6.8 and 7.4. However, the absorptive permeability of B7T in Caco-2 cell model was substantially lower than that in the artificial membrane accompanied with over 56% of B7T being trapped within Caco-2 cells. In the rat in situ intestinal perfusion model, B7T was subject to an extensive intestinal extraction (>90%) with extremely low concentration of B7T detected in mesenteric blood, which was further found to be associated with the high tissue binding (99.9%) of B7T. In vitro incubation of B7T with rat liver and intestinal microsomes revealed that hydroxylation of B7T might mainly occur in rat liver rather than intestine. In conclusion, B7T is expected to have a low oral bioavailability in vivo, which may be due to its poor intestinal permeability, significant tissue binding and hepatic hydroxylation metabolism. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/113 http://works.bepress.com/kelvin_chan/113 Wed, 27 Aug 2008 23:08:38 PDT The method involves a single extraction of the drug and the internal standard, etidocaine, from alkalinized plasma with n-hexane. The gas chromatograph is equipped with a glass column (2.0 m x 2 mm) packed with 3% W/W SP2250 on Chromosorb W, (80/100 mesh) and a nitrogen sensitive detector. The method can accurately measure plasma bupivacaine concentrations down to 0.01 µg ml-1 using a sample size of 0.5 ml. The day-to-day variation of bupivacaine at 2.0 µg ml-1 is 6.90% (n = 10). The calibration graph is linear over the range 0.1 - 4.0 µg ml-1. The method is accurate, fast and sensitive and has been applied in a pharmacokinetic study of bupivacaine. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/112 http://works.bepress.com/kelvin_chan/112 Wed, 27 Aug 2008 22:53:37 PDT We here provide definitive evidence that ginsenoside- Rg1, the pharmacologically active component of ginseng, is a functional ligand of the glucocorticoid receptor (GR) as determined by fluorescence polarization assay. Rg1 increased the phosphorylation of GR, phosphatidylinositol-3 kinase (PI3K), Akt/PKB and endothelial nitric oxide synthase (eNOS) leading to increase nitric oxide (NO) production in human umbilical vein endothelial cell. Rg1-induced eNOS phosphorylation and NO production were significantly reduced by RU486, LY294,002, or SH-6. Also, knockdown of GR completely eliminated the Rg1-induced NO production. This study revealed that Rgl can indeed serve as an agonist ligand for GR and the activated GR can induce rapid NO production from eNOS via the non-transcriptional PI3K/Akt pathway. Kelvin Chan Chinese Medicine Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/111 http://works.bepress.com/kelvin_chan/111 Wed, 27 Aug 2008 22:47:13 PDT The urinary clearance of pyridostigmine was studied in six patients with myasthenia gravis. In three patients on pyridostigmine, alone, renal clearance ranged from 349 to 481 ml/min, corresponding to a pyridostigmine:creatinine clearance ratio of 2.64 to 3.46. In a patient on bendrofluazide as well as pyridostigmine, a similar clearance ratio was observed. By contrast, the urinary clearance of pyridostigmine and the pyridostigmine:creatinine clearance ratio was reduced in two myasthenic patients concurrently treated with other basic drugs. It is suggested that these results may reflect competition for renal tubular excretion. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/110 http://works.bepress.com/kelvin_chan/110 Wed, 27 Aug 2008 22:42:49 PDT The pharmacokinetics of pyrazinamide (PZA) in cerebrospinal fluid (CSF) and plasma of 10 rabbits were studied after separate intravenous (i.v.) and oral (p.o.) administration, in a cross-over study. Concentrations of PZA in biological fluids were determined by high-performance liquid chromatography (HPLC). After p.o. dose PZA was absorbed rapidly and peak plasma concentration was attained at 0.5 h post administration. After i.v. dose, the plasma PZA concentrations declined rapidly within 10 min and subsequently more slowly following a bi-exponential manner. No difference was observed int he area under plasma concentration-time curves indicating oral absorption was complete and no apparent first-pass metabolism occured. The (mean ± S.D.) elimination t1/2 after i.v. (1.04 ± 0.18 h) was significantly shorter (p = 0.0005) than that after oral (1.95 ± 0.63 h) dose and the apparent volume of distribution was also significantly smaller (P = 0.005) after i.v. (3.211 ± 0.412 l) than after oral (5.936 ± 1.607 l) administration. The elimination t1/2 of PZA in CSF was nearly identical to that in plasma after either i.v. (1.07 ± 0.20 h) or p.o. (1.84 ± 0.56 h) administration. There is no apparent barrier in rabbits for the penetration of PZA into CSF from the general circulation. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/109 http://works.bepress.com/kelvin_chan/109 Wed, 27 Aug 2008 22:34:17 PDT 219 surgical patients of either Caucasian, Chinese or Nepalese origin were given pethidine 1 mg/kg by intramuscular injection as pre-operative medication. Urine was collected for 24 h and analysed for pethidine, pethidinic acid, pethidinic scid conjugates, norpethidine, norpethidinic acid, and norpethidinic acid conjugates. The mean proportion of thc percentage of metabolites attributable to oxidative demethylation, hydrolysis and conjugation was almost identical in each ethnic gtoup (P > 0.2). It was concluded that there were no differences in the metabolic variability of the biotransformation of pethidine in Asians and Caucasians in whom the urine pH had not been acidified. Kelvin Chan http://works.bepress.com/kelvin_chan/108 http://works.bepress.com/kelvin_chan/108 Wed, 27 Aug 2008 22:27:14 PDT p-Aminobenzoic acid (PABA), p-acetamidobenzoic acid (PADB) and p-aminohippuric acid (PAH) have been separated and determined by a reversed phase, isocratic high performance liquid chromatographic (HPLC) procedure simultaneously. The mobile phase, at 1.5 ml min-1, used was 10 mM sodium hydrogen phosphate buffer, pH 3.5, containing 40% methanol. The eluent was detected at 270 nm. Linear relationship was obtained from 0 to 2.0 µg ml-1 of each compound with the corresponding peak-height ratio using p-methylamino-benzoic acid (PMAB) as the internal standard. Urine samples were obtained from healthy Chinese volunteers after oral dosing of 200 mg PABA which was used as a model substance for metabolic investigation of N-acetylation and other conjugation reactions. The 24 hour urinary recovery, from 43 healthy subjects, of PABA, PABA-COOH conjugates, PADB and PADB-COOH conjugates were (mean ± S.D.) 2.9 ± 1.5%, 5.2 ± 3.3%, 13.9 ± 4% and 42.9 ± 9.8% of the ingested dose respectively. These accounted for 64.9 ± 12.0% of total dose ingested in 24 hour. In contrast to previously reported findings on one Caucasian subject, no PAH was identified in the urine, and N-acetylation was the major route of metabolism of PABA apart from conjugation at the - COOH group in this group of Chinese volunteers. It is proposed that PABA metabolism may be a useful probe to study ethnic and geographic variation in N-acetylation. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/107 http://works.bepress.com/kelvin_chan/107 Wed, 27 Aug 2008 22:16:03 PDT The concentration-time profiles of ethmozine, a newly introduced anti-arrhythmic drug, in the cerebrospinal fluid (CSF) and plasma of six rabbits (New zealand white rabbits of both sexes, 4.0-5.0 kg) were studied after intravenous bolus administration. CSF samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg Kg-1) and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.3 ml) were obtained from the cisterna magna. The plasma concentrations of ethmozine in six rabbits declined rapidly after intravenous injection for up to 30 min then slowly over 12 h. Using non-compartmental analysis, the mean (± S.E.M.) elimination half-life, mean residence time, plasma clearance and volume of distribution at steady state were 13.9 ± 9.2h, 19.9 ± 13.4 h, 2.3 Lh-1 and 26.8 ± 7.9 L respectively. The mean CSF-plasma concentration ratios for ethmozine at 0.5, 1.0, 2.0, 4.0, 8.0 and 12.0 h were 0.17, 0.14, 0.16, 0.16, 0.23 and 0.22 respectively. The results suggest that ethmozine is able to penetrate into the CSF from the general circulation and this maybe related to its adverse effects on the central nervous system. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/106 http://works.bepress.com/kelvin_chan/106 Wed, 27 Aug 2008 22:02:16 PDT Danshen is a Chinese folk medicine commonly used in the Chinese population. The effects of Danshen on the pharmacokinetics and pharmacodynamics of warfarin were studied in rats. In the phamacokinetic study, single oral doses of warfarin were administered to rats or after 3 days treatment with Danshen intraperitoneally twice daily. Plasma warfarin concentrations were measured for 48 h after each of two warfarin doses by high performance liquid chromatography (HPLC). In the pharmacodynamic study, the treatments were similar to the pharmacokinetic study, the prothrombin time (PT) was measured daily both in the Danshen treatment period and after the warfarin doses for 4 days. The absorption rate (Ka), volume of distribution (Vd) and elimination half-life (T1/2) of warfarin were significantly decreased while Cmax and Tmax were significantly increased affer treatment with Danshen. There was no significant change in PT during the Danshen treatment period while the PTs were increased significantly in the first two days after warfarin doses. Our results suggested that Danshen can increase the initial bioavailability of warfarin and also affect the elimination of warfarin. It can also increase the PT further after the warfarin doses. The pharmacokinetic and pharmacodynamic interactions observed in this study indicate a clinically important interaction between Danshen and warfarin if these two agents are taken together. Kelvin Chan Chinese Medicine Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/105 http://works.bepress.com/kelvin_chan/105 Wed, 27 Aug 2008 21:48:49 PDT The present study reports findings on the disposition of epirubicin after an intrahepato-arterial administration of the Lipiodol-drug complex, prepared by mixing the drug-aqueous phase with the iodized oil by ultra-sonification, in 14 patients with histologically proven hepatoma or hepatomegaly with serum α-fetoprotein level above 500 µg.1-1. The volume of Lipiodol used was 5 ml and the epirubicin dose was 50mg.g-2. Blood samples were obstained at various time intervals up to 72 h post-dose. Serum concentrations of epirubicin were measured by liquid chromatography with fluorometric detection. The area under serum concentration-time curve (AUC) was higher in the Lipiodol-epirubicin group (n = 8) while the clearance was fater and elimination t1/2 and mean residence time shorter in the plain epirubicin group (n = 3). However, interindividual variation in metabolism of epirubicin would affect serum level of the drug. In three patients who were given intravenous and intrahepato-arterial injections (90 mg.m-2) or plain epirubicin and Lipiodol-drug complex, the relative bioavailability of Lipiodol-epirubicin complex (F = 0.76 and 0.45) was lower than that of plain epirubicin (F = 0.80 and 0.73) in two patients while it was approximately 100% (F = 1.06 and 1.20) in one patient. It is likely that liver function of the patients might be modified by the disease state over a period of 3 months in the cross-over study. Further studies with larger patient samples are required to confirm if there is a targeting effect of the Lipiodol-drug complex toward hepatoma using a better formulation of the drug in Lipiodol. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/104 http://works.bepress.com/kelvin_chan/104 Wed, 27 Aug 2008 04:00:31 PDT Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separiate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self medicate with Danggui or other TCM products while on chronic treatment with warfarin. Kelvin Chan Chinese Medicine Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/103 http://works.bepress.com/kelvin_chan/103 Wed, 27 Aug 2008 03:19:41 PDT In a residential Symposium on "Peptides as Targets for Drug Research" at Vanbrugh College, University of York, U.K. organized by the Society of Drug Research, several experts from academia and pharmaceutical industries presented concepts, reviews and possible applications on various aspects of peptides which may be important in the development of new targets for drug research. The following is a summary of some salient points in this rapidly growing field, with general references for readers' further pursuits. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/102 http://works.bepress.com/kelvin_chan/102 Wed, 27 Aug 2008 03:16:33 PDT One of the highlights of the scientific program of the 1st Scientific Meeting of the Hong Kong Pharmacology Society (HKPS), held on December 15th and 16th, 1987, was that of the Symposium on Modern Antimalarial Drug Therapy. Well-known researchers in this field from Southeast Asia and China were inivited speakers at the symposium. A concise overview of this symposium is given here. Kelvin Chan Chinese Medicine Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/101 http://works.bepress.com/kelvin_chan/101 Wed, 27 Aug 2008 03:10:44 PDT Using a high performance liquid chromatography assay, pyrazinamide and rifampicin concentrations were measured in paired samples of cerebrospinal fluid (CSF) and serum obtained 2, 5, and 8 hours after oral drug administration in 12 patients with tuberculous meningitis. Penetration of pyrazinamide into CSF was good, with the CSF concentration exceeding that of serum by five to eight hours. The maximum CSF concentration achieved was mcre than twice the minimum inhibitory concentration (MIC) for 85% of local strains of Mycobacterium tuberculosis. Penetration appeared greater at five hours in the earlier stages of the disease. By contrast, penetration of rifampicin was comparatively poor, the maximum concentration reached in the CSF being only one tenth that of serum at eight hours. Moreover, the level did not reach MICs for 20% of local strains of M tuberculosis. Penetration appeared to be proportional to the extent of meningeal inflammation as assessed by CSF protein concentration and white cell count. Use of steroids did not appear to influence either pyrazinamide or rifampicin penetration into the CSF. It is concluded that with the present oral dosages of pyrazinamide (31 to 33 mg/kg), adequate CSF levels are reached. However, for rifampicin, (mean dose, 11 to 12 mg/kg), the CSF concentration may not reach the MIC in a proportion of patients, so that further studies are needed to determine optimum dosage and method of drug administration in order to achieve therapeutic CSF levels. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/100 http://works.bepress.com/kelvin_chan/100 Wed, 27 Aug 2008 03:01:40 PDT Activity of Chinese Danggui (DG), the processed root of Angelica sinensis (Oliv.) Diels, is linked to the ferulic acid content but the stability of ferulic acid during extraction for medicinal use is not known. The stabilities of ferulic acid and coniferyl acid were evaluated in the extracts of DG using a variety of extraction solvents. Kelvin Chan Chinese Medicine Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/99 http://works.bepress.com/kelvin_chan/99 Wed, 27 Aug 2008 02:59:02 PDT Background: This paper describes the development of the Chinese Quality of Life Instrument (ChQOL) which is a self-report health status instrument. Chinese Medicine relies very much on asking subjective feelings of patients in the process of diagnosis and monitoring of treatment. For thousands of years, Chinese Medicine practitioners have accumulated a good wealth of experiences in asking questions about health of their patients based on the concept of health in Chinese Medicine. These experiences were then transformed into questions for the ChQOL. It is believed that ChQOL can contribute to the existing Patient Report Outcome measures. This paper outlines the concept of health and disease in Traditional Chinese Medicine, the building of the conceptual framework of the ChQOL, the steps of drafting, selecting and validating the items, and the psychometric properties of the ChQOL. Methods: The development of the ChQOL was based on the concept of health in Traditional Chinese Medicine with a theory driven approach. Based on the results of literature review, the research team developed an initial model of health which encompassed the concept of health in TCM. An expert panel was then invited to comment and give suggestions for improvement of the initial model. According to their suggestions, the model was refined and a set of initial items for the ChQOL was drafted. The refined model, together with the key domains, facets and initial items of the ChQOL were then mailed to a sample of about 100 Chinese medicine practitioners throughout Mainland China for their comments and advice. A revised set of items were developed for linguistic testing by a convenience sample consisting of both healthy people and people who attended Chinese Medicine treatment. After that, an item pool was developed for field-testing. Field test was conducted on a convenience sample of healthy and patient subjects to determine the construct validity and psychometric properties of the ChQOL. Results: Construct validity was established by various methods, i.e. the internal consistency in all facets and domains were good; the correlation between facets to domain, and domains to overallChQOL correlation were high; confirmatory factor analysis showed that the structure fitness of all facets, domain and overall structure were good with CFI > 0.9. Test-retest reliability was also good, especially in the domain scores with ICC value ranging from 0.83 to 0.90. No ceiling or floor effect was noted which indicated that ChQOL can be applied to subjects with a wide range of health status. Most facet scores, domain scores and the overall CHQOL scores were able to discriminate groups of subjects with known differences in health status. The ChQOL had mild positive convergence with the other generic health related QOL measures, i.e. the WHOQOL-100 and the SF-36, with moderate correlations. Conclusion: In conclusion, the study indicated that the ChQOL is conceptually valid with satisfactory psychometric properties. It can provide additional information on health and QOL on top of the existing generic health related QOL measures. Furthermore, it forms basis for further testing and applications in clinical trials. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/98 http://works.bepress.com/kelvin_chan/98 Wed, 27 Aug 2008 02:57:22 PDT The major active constituents of ginseng are ginsenosides, and Rg1 is a predominant compound of the total extract. Recent studies have demonstrated that Rg1 can promote angiogenesis in vivo and in vitro. In this study, we used a DNA microarray technology to elucidate the mechanisms of action of Rg1. We report that Rg1 induces the proliferation of HUVECs, monitored using [3H]-thymidine incorporation and Trypan blue exclusion assays. Furthermore, Rg1 (150-600 nM) also showed an enhanced tube forming inducing effect on the HUVEC. Rg1 was also demonstrated to promote angiogenesis in an in vivo Matrigel plug assay, and increase endothelial sprouting in the ex vivo rat aorta ring assay. Differential gene expression profile of HUVEC following treatment with Rg1 revealed the expression of genes related to cell adhesion, migration and cytoskeleton, including RhoA, RhoB, IQGAP1, CALM2, Vav2 and LAMA4. Our results suggest that Rg1 can promote angiogenesis in multiple models, and this effect is partly due to the modulation of genes that are involved in the cytoskeletal dynamics, cell-cell adhesion and migration. Kelvin Chan Chinese Medicine Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/97 http://works.bepress.com/kelvin_chan/97 Wed, 27 Aug 2008 02:55:10 PDT Paeonia lactiflora Pall. (Ranunculaceae) root and Sinomenium acutum Rehder and Wilson (Menispermaceae) stem are two herbs widely used in Chinese medicine to treat rheumatoid arthritis. While, in theory, either herb could be used alone, in practice, Chinese medicine practitioners prescribe them together. Studies on pharmacokinetic interaction between the active constituents of these two herbs (paeoniflorin and sinomenine, respectively) provide empirical evidence to support their clinical practice.Asingle dose of paeoniflorin (150 mg/kg) alone and with sinomenine hydrochloride (90 mg/kg) was administered by gastric gavage to unrestrained conscious male Sprague-Dawley rats (n=6, 250-300 g). Blood samples were collected periodically via a jugular vein before and after dosing from 10 min to 12 h.Ahigh-performance liquid chromatographic (HPLC) assay was developed to determine the plasma concentrations of paeoniflorin. Non-compartmental pharmacokinetic profiles were constructed by using the software PK Solutions 2.0. The pharmacokinetic parameters were compared using unpaired Student t-test. After co-administration of sinomenine, the peak plasma concentration of paeoniflorin was elevated (P < 0.01), the peak time was delayed (P < 0.01), the AUC0-t was increased (P < 0.001), the mean residence time (MRT) was prolonged (P < 0.01), the CL was decreased (P < 0.01) and the Vd was reduced (P < 0.05). These results indicate that sinomenine hydrochloride at 90 mg/kg significantly improved the bioavailability of paeoniflorin in rats. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/96 http://works.bepress.com/kelvin_chan/96 Wed, 27 Aug 2008 02:52:46 PDT A systematic evaluation on the levels of organochlorine pesticide residues (OCP) was conducted on four selected, authentic Chinese materia medica, namely: Radix Angelicae Sinensis, Radix Notoginseng, Radix Salviae Miltiorrhizae and Radix Ginseng. Altogether ten representative batches of samples were analysed for each herb. Six batches were collected in the major cultivation areas of the Mainland whilst the remaining four batches were procured in the Hong Kong herbal market. All except Radix Angelicae Sinensis have been identified as containing quintozene and hexachlorocyclohexane in various levels. Hexachlorobenzene and lindane were also reported in samples of Radix Ginseng. The banned pesticide, DDT and its derivatives, was also observed in one of the Radix Notoginseng samples. The investigation will be continued for a target list of common used herbs in Hong Kong. All the results will be gathered and analysed for setting up regulatory permissible limits of OCP residues in Chinese materia medica used in Hong Kong. Kelvin Chan Herbal Medicines Chinese Medicine http://works.bepress.com/kelvin_chan/95 http://works.bepress.com/kelvin_chan/95 Wed, 27 Aug 2008 02:48:30 PDT The liver is the major organ for the metabolism of homocysteine (Hcy) and production of insulin-like growth factor 1 (IGF-1). Hcy metabolism and IGF-1 synthesis may be impaired in chronic liver diseases. The study investigated the regulatory effect of a Chinese medicinal suppository, Vitalliver, on Hcy and IGF-1, as well as their relationship in patients with hepatitis B infection. Forty patients with chronic hepatitis B virus (HBV) infection without cirrhosis, 25 males and 15 females, were observed for changes in Hcy and IGF-1 after the administration of Vitalliver (one nightly) for a period of 3 months. Serum levels of Hcy, IGF-1 and IGFBP-3 were measured at baseline, at 1 month and at 3 months after treatment. Vitalliver reduced Hcy levels significantly (p= 0.001) from 9.7 ± 2.8 to 9.0 ± 2.1 µmol/L after treatment of 3 months. Furthermore, the IGF-1 levels increased significantly (p= 0.001) from 170.2 ± 81.8 to 212.8 ± 80.9 ng/mL at 1 month and 187.5 ± 72.3 ng/mL at 3 months (p= 0.001) after treatment. In conclusion, it is speculated Vitalliver may have a self-regulatory effect on the release of IGF-1 in HBV patients without liver cirrhosis. with week 0, IGF-1 levels (192.5 ± 66.4 ng/ml) were significantly elevated at week 4 (211.7 ± 80.5, p < 0.05) and week 12 (226.6 ± 95.2 ng/ml, p = 0.01). No significant changes were observed for Hcy for the whole cohort from week 0 to week 16. When the cohort was divided into 2 groups using a Hcy level of 13.0 µmol/l as the cut-off, a significant (p < 0.05) difference in IGF-1 was observed between the 2 groups at week 12 only. The mean IGF-1 of 14 subjects with higher Hcy levels was lower than that of the 22 subjects with lower Hcy. We believe that VI-28 may exert a regulatory effect on the relationship between Hcy and IGF-1, at least in subjects with relatively low levels of Hcy. In addition, we also observed an apparent association of hyperhomocysteinemia (Hcy = 13.0 µmol/l) with decreased IGF-1. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/94 http://works.bepress.com/kelvin_chan/94 Wed, 27 Aug 2008 02:46:35 PDT Changes in serum homocysteine (Hcy), often related to stroke and vascular dementia, are negatively correlated with changes in serum insulin-like growth factor 1 (IGF-1) and growth hormone (GH) replacement decreases Hcy levels in men with GH deficiency. Very little information on the effects of Chinese medicines on GH and Hcy is available in the literature published in English. In this study, the effects of a Chinese medicine suppository, Vigconic VI-28 (VI-28), consisting of concentrated extracts of a composite mixture of herbal materials, on serum IGF-1 and Hcy were studied. In vivo observations after treatment with Chinese medicines have often indicated changes in biochemical profiles of measurable parameters related to those changes in endocrine secretions. Thirty six healthy males (age 47-66) were under observation over a 16-week schedule after using a VI-28 suppository from 0 to 12 weeks. Blood specimens were taken monthly (except at the end of week 8) for analysis of Hcy and IGF-1 levels. Compared with week 0, IGF-1 levels (192.5 ± 66.4 ng/ml) were significantly elevated at week 4 (211.7 ± 80.5, p < 0.05) and week 12 (226.6 ± 95.2 ng/ml, p = 0.01). No significant changes were observed for Hcy for the whole cohort from week 0 to week 16. When the cohort was divided into 2 groups using a Hcy level of 13.0 µmol/l as the cut-off, a significant (p < 0.05) difference in IGF-1 was observed between the 2 groups at week 12 only. The mean IGF-1 of 14 subjects with higher Hcy levels was lower than that of the 22 subjects with lower Hcy. We believe that VI-28 may exert a regulatory effect on the relationship between Hcy and IGF-1, at least in subjects with relatively low levels of Hcy. In addition, we also observed an apparent association of hyperhomocysteinemia (Hcy = 13.0 µmol/l) with decreased IGF-1. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/93 http://works.bepress.com/kelvin_chan/93 Wed, 27 Aug 2008 02:44:08 PDT Objective: To explore the application of factor analysis in creating a new health--related questionnaire for evaluating quality of life，the Chinese for Quality of Life Instrument (ChQOL). Methods: Two hundred and seventy three subjects selected from two provinces of North China (Ningxia) and South China(Guangdong) were investigated by ChQOL, and the preliminary version was completed with factor analysis． Results: Fifty items were developed using factor analysis．The final structure model of ChQOL was confirmed through the screening and verification of factor structural model on the 78 items of ChQOL，a new questionnaire with more rational structure was confirmed． Conclusion: Factor analysis is an effective method in developing new questionnaire. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/92 http://works.bepress.com/kelvin_chan/92 Wed, 27 Aug 2008 02:41:37 PDT Chinese medicine (CM), one of the oldest continuously surviving traditions, has been practised to maintain good health and treat diseases in the Chinese communities and recently by other ethnic groups worldwide. Chinese medicinal materials (Chinese materia medica, CMM) and proprietary CM products (PCM), acupuncture and related physical therapies, as well as special life styles are often used together in the practice, co-existing with orthodox medicine (OM) in China and some regions in the Far East. Increasing uses of CMM have created both skepticism and support of CM practice that have been the major debate since the successful randomised clinical trial of the 10-CM herbs prescription in relieving atopic eczema was published in 1992. Available in the West, some CMM are supplied with wrong species or wrong named herbs that possess liver and kidney toxicity and some PCM adulterated with OMdrugs. These do not give CMM the right reputation and recognition. These problems have been due to lack of recognition and regulation of the profession, qualified practitioners, quality-controlled CMM products and evidence-based clinical studies. Though practised widely, CM was not recognised officially in some regions such the EU and North America as part of the healthcare system run by western OM practice. Such circumstance has delayed the development of CM in these regions including Hong Kong comparing with that in Australia, Japan (As Kampo medicine), the UK, some European countries, and the USA. It can be considered as obstacles for proper development of CM in general. This paper addresses these key issues and attempts to propose ways for future research and development for CMM. The impact will certainly be modernisation in every aspect of CMM to cope with the fast growing demand in quality medicines in the 21st century. Several major areas are listed for discussion. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/91 http://works.bepress.com/kelvin_chan/91 Wed, 27 Aug 2008 02:39:48 PDT Homocysteine (Hcy) is a by-product of methionine metabolism. An imbalance of Hcy in the body may lead to hyperhomocysteinemia, a condition with elevated Hcy concentration in blood that may be one of the risk factors responsible for the development of several vascular diseases (thromboembolism, atherosclerosis, stroke, vascular diseases and dementia). Radix Salvia miltiorrhiza (Danshen), a well-known Chinese medicinal herb that can activate and improve blood microcirculation, is noticeable for its beneficial effect in treating cardiovascular diseases. The present study is to demonstrate the protective effect of Danshen extract against the homocysteine-induced adverse effect on human umbilical vein endothelial cell (HUVEC). Homocysteine (5 mM) not only decreased the cell viability but also caused the disruption of capillary-like structure formation in vitro. The protective effect of Danshen aqueous extract and its active compounds on endothelial cell function were demonstrated through an in vitro tube formation assay, which mimics the new blood vessel formation. To identify the active components in the aqueous extract of Danshen, the content was characterized by instrumental analysis using high performance liquid chromatography with diode array detector (DAD) and electrospray tandem mass spectrometry (ESI-MS/MS). Interestingly, Danshen extract and its pure compounds showed different effectiveness in protecting HUVEC against Hcy-induced injury according to the following descending order: Danshen aqueous extract, 3-(3,4-dihydroxy-phenyl)-2-hydroxy-propionic acid (Danshensu), protocatechuic acid, catechin and protocatechualdehyde. We believed that such findings might provide evidence in understanding the beneficial effects of Danshen on the cardiovascular system. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/90 http://works.bepress.com/kelvin_chan/90 Wed, 27 Aug 2008 02:25:29 PDT Different chromatographic and electrophoretic techniques commonly used in the instrumental inspection of herbal medicines (HM) are first conprehensively reviewed. Chemical fingerprints obtained by chromatographic and electrophoretic techniques, especially by hyphenated chromatographies, are strongly recommended for the purposes of quality control of herbal medicines, since they might represent appropriately the "chemical integrities" of the herbal medicines and therefore be used for authentification and identification of the herbal products. Based on the conception of phytoequivalence, the chromatographic fingerprints of herbal medicines could be utilized for addressing the problem of quality control of herbal medicines. Several novel chemometric methods for evaluating the fingerprints of herbal products, such as the method based on information theory, similarity estimation, chemical pattern recognition, spectral correlative chromatogram (SCC), multivariate resolution, etc. are discussed in detail with examples, which showed that the combination of chromatographic fingerprints of herbal medicines and the chemometric evaluation might be a powerful tool for the quality control of herbal products. Kelvin Chan Herbal Medicines http://works.bepress.com/kelvin_chan/89 http://works.bepress.com/kelvin_chan/89 Wed, 27 Aug 2008 02:21:26 PDT A reversed phase high-performance liquid chromatographic method was developed for quantifying E-ligustilide (1) and Z-ligustilide (3) in the roots of Angelica sinensis (Oliv.) Diels with confirmation using UV, atmospheric pressure chemical ionisation (APCI) MS and APCIMS- MS techniques. Based in the UV spectra of compounds 1, E-butylidenephthalide (2), 3 and Z-butylidenephthalide (4), the absorption at 350 nmwas chosen as measuringwavelength in which baseline separation of compounds 1 and 3 could be obtained but avoided the interference of compounds 2 and 4. The identity of compounds 1 and 3 in samples were unambiguously determined by the respective quasi-molecular ions ([M+H]+) in APCI-MS. According to the stability data, acetonitrile was chosen for the preparation of standard solutions in order to minimize the isomerization of compound 3. Compounds 1 and 3 were qualitatively and quantitatively analyzed in seven samples of the roots of Angelica sinensis (Oliv.) Diels, Angelica acutiloba Kitagawa, Angelica acutiloba Kitagawa var. sugiyamae Hikino and the rhizome of Ligusticum chuanxiong Hort. Analysis of an extract from a sample root of Angelica gigas Nakai using LC-MS for the first time could notdetect the presence of ligustilide in this herb. The overall analytical procedure is rapid and reproducible which is considered suitable for quantitative analysis of large number of samples. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/88 http://works.bepress.com/kelvin_chan/88 Wed, 27 Aug 2008 02:19:37 PDT At present, quality of life (QOL) has become a relevant measure of efficacy in clinical trials. It s use is spreading, and it s importance is growing as a valid indicator of effectiveness of a treatment (1). In 1985, QOL, recommended by Food and Drug Administration (FDA), is one of the primary efficacy parameters as a basis for approval of anticancer drugs. Some scholars in China are also interested in establishing a related parameter for measuring efficacy of new drugs in view of QOL (2). Without question, to improve QOL is one of the main goals in health care and social work. Kelvin Chan Chinese Medicine http://works.bepress.com/kelvin_chan/87 http://works.bepress.com/kelvin_chan/87 Wed, 27 Aug 2008 02:16:22 PDT A World Health Organisation survey indicated that about 70-80% of the world populations rely on non-conventional medicine mainly of herbal sources in their primary healthcare. In recent years, we have witnessed the increasing growth in popularity of over-the-counter (OTC) health foods, nutraceuticals and medicinal products from plants or other natural sources in developed countries. This indirectly indicates that the public is not satisfied with their orthodox medical (OM) treatment. Such increase in popularity has also brought concerns and fears over the professionalism of practitioners, and quality, efficacy and safety of their treatment methods and products from herbal and natural sources available in the market. Over the past decade several news-catching episodes in developed communities indicated adverse effects, sometimes life threatening, allegedly arisen consequential to taking of OTC herbal products or traditional medicines from various ethnic groups. These OTC products may be contaminated with excessive or banned pesticides, microbial contaminants, heavy metals, chemical toxins, and for adulterated with orthodox drugs. Excessive or banned pesticides, heavy metals and microbial contaminants may be related to the source of these herbal materials, if they are grown under contaminated environment or during collection of these plant materials. Chemical toxins may come from unfavourable or wrong storage conditions or chemical treatment due to storage. The presence of orthodox drugs can be related to unprofessional practice of manufacturers. Some of these environment related factors can be controlled by implementing standard operating procedures (SOP) leading to Good Agricultural Practice (GAP), Good Laboratory practice (GLP), Good Supply Practice (GSP) and Good Manufacturing Practice (GMP) for producing these medicinal products from herbal or natural sources. The public's belief that herbal and natural products are safer than synthetic medicines can only be ascertained by imposing regulatory standards on these products that should be manufactured using these Good Practices. Using Chinese medicines, as examples, this paper illustrates how advances in chemical and biomedical analysis would help to detect intentional and unintentional toxic contaminants in herbal substances. The paper also summarises how modernization and progress are being carried out to get the best out of Chinese medicines for public healthcare. Kelvin Chan Herbal Medicines Chinese Medicine http://works.bepress.com/kelvin_chan/86 http://works.bepress.com/kelvin_chan/86 Wed, 27 Aug 2008 02:14:28 PDT The study of protein binding of anti-tuberculous drugs is of clinical interest, since the degree of tissue penetration and possibly frequency of adverse drug reactions may be expected to be related to free drug concentration and, hence, inversely related to the degree of protein binding. Variations in free drug concentration may result from changes in plasma protein concentration with age or disease. Albumin and α-l-acid glycoprotein are two major drug binding proteins (1,2). Age and disease have been shown to affect the concentration of both proteins (3,4). To date there is little data on protein binding of isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZ). Information is available for isoniazid and rifampicin binding to serum proteins, but not to individual drug-binding proteins. Little information is available regarding percentage binding with changes in protein concentrations. Such data would be particularly relevant in treatment of tuberculosis in the elderly, where there is an increased incidence of side effects (5). It is known that age, disease, or malnutrition result in lower serum albumin concentrations, while α-1-acid glycoprotein increases with age (2,6). Although no difference in total plasma anti-tuberculous drug concentrations has been observed between young and elderly patients (7), the difference in serum drug-binding protein concentration may give rise to differences in free drug concentration, possibly contributing to the differences in incidences of adverse drug reactions in the young and elderly. In this study, we examined the degree of binding of INH, RIF, and PZ to plasma, albumin, and α-1-acid glycoprotein, and the effect of variations in protein concentration on the degree of binding. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/85 http://works.bepress.com/kelvin_chan/85 Wed, 27 Aug 2008 02:12:52 PDT The respiratory response to carbon dioxide was measured in 130 ASA 1 adult male patients from three ethnic groups, European, Nepalese, and Chinese, both before and after premedication with intramuscular morphine sulphate (200 µg/kg-1 bodyweight). Satisfactory results were obtained from 125 patients. Overall, there was no ethnic difference in the effect of morphine on the respiratory response to carbon dioxide, but initially the Chinese group appeared to be more sensitive in their response to carbon dioxide than the Europeans and Nepalese. However, there was a significant correlation between respiratory response to carbon dioxide and pulse rate and on restricting analysis to those patients with a pulse rate equal to or less than 72 beat.min-1, the ethnic difference in carbon dioxide response disappeared. It was concluded that there were no ethnic differences in the respiratory response to carbon dioxide before or after morphine in male Europeans, Nepalese and Chinese but that the respiratory response to carbon dioxide may be influenced by long term physical training. Kelvin Chan Anaesthesia http://works.bepress.com/kelvin_chan/84 http://works.bepress.com/kelvin_chan/84 Wed, 27 Aug 2008 02:10:59 PDT The international threshold for nandrolone in equine urine is reached when the ratio of 5α-estrane-3β,17α-diol to 5(l0)-estrene-3β,17α-diol exceeds one. When this ratio is exceeded, the sample is positive for administration of a nandrolone preparation. The present method for measuring the ratio requires hydrolysis of the urine sample followed by clean-up procedures, then analysis of the derivatized residue by gas chromatography-mass spectrometry (GC-MS). A quicker measurement of the ratio for screening purposes is desirable. A hybridoma that secretes monoclonal anti-5α-estrane-3β,17α-diol antibody has been developed. Using inhibition enzyme-linked immunosorbent assay (ELISA), this monoclonal antibody detects 5α-estrane-3β,17α-diol at 1ng ml-1 and is far more sensitive than a rabbit polyclonal antiserum. The monoclonal antibody is specific to 5α-estrane-3β,17α-diol, 5α-estrane-3β-ol-17-one and 5α-estrane-3β-ol-17-carboxymethyloxime. Slight cross-reactivity with other structurally related steroids is observed at concentrations higher than 200 ng ml-1. Work is in progress to raise a monoclonal antibody against 5(10)-estrene-3β,17α-diol. The two ELISAs should provide a rapid screening test to measure the nandrolone threshold ratio. Detailed GC-MS analysis would then only be required for confirmation. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/83 http://works.bepress.com/kelvin_chan/83 Wed, 27 Aug 2008 02:08:38 PDT We have studied simultaneously the pharmacokinetics of flumazenil and midazolam in 12 healthy Chinese children, aged 5 - 9 yr, undergoing circumcision. Two hours before operation each patient received midazolam 0.5 mg kg-1 orally for premedication and 0.5 mg kg-1 i.v. during induction. Six minutes after cessation of anaesthesia, a bolus of flumazenil 10 µg kg-1 was given i.v., followed by an infusion of flumazenil at 5 µg kg-1 min-1 which was maintained until the child could identify himself. Midazolam data were consistent with a three-compartment model with a mean (SD) elimination half-life of 107 (30) min, total body clearance of 15.4 (3.2) ml min-1 kg-1 and apparent volume of distribution at steady state of 1.9 (0.6) litre kg-1. Flumazenil data were best interpreted by a mono-exponential function, with a mean terminal elimination half-life of 35.3 (13.8) min, a total plasma clearance of 20.6 (6.9) ml min-1 kg-1 and apparent volume of distribution at steady state of 1.0 (0.2) litre kg-1. No unchanged midazolam was detected in the 24 h urine sample, but 5.8 - 13.8% of the flumazenil dose was recovered unchanged. At the time of self identification, 4.5 (1.4) min after flumazenil administration, the mean plasma concentrations of midazolam and flumazenil were 163/1 (43.7) and 29.9 (16.1) µg ml-1, respectively. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/82 http://works.bepress.com/kelvin_chan/82 Wed, 27 Aug 2008 02:05:20 PDT We have compared the pharmacokinetics of a bolus dose of propofol 2 mg kg-1 in eight patients undergoing Caesarean section with those in eight postpartum patients undergoing sterilization by mini-laparotomy. The Caesarean section group had a total body clearance of (median) 31.5 (range 24.4 - 53.3) ml min-1 kg-1, apparent volume of distribution at steady state 5.10 (2.46 - 6.61) litre kg-1 and mean residence time 161 (52.3 - 251) min; values for the postpartum group were 33.8 (21.5 - 47.2) ml min-1 kg-1, 5.17 (3.47 - 9.09) litre kg-1 and 163 (92.3 - 238) min, respectively. The 95% confidence interval for the umbilical venous to maternal venous ratio of propofol at delivery was 0.62 - 0.86. Plasma protein binding studies showed there was less unbound propofol in maternal plasma (1.28 - 2.29%) compared with umbilical plasma (2.08 - 3.88%) (P < 0.01 ). Neonatal concentrations of propofol were greater than maternal concentrations at 2 h and were in the range 0.05 -0.11 µg ml-1 at 4 h. Kelvin Chan Anaesthesia http://works.bepress.com/kelvin_chan/81 http://works.bepress.com/kelvin_chan/81 Wed, 27 Aug 2008 02:03:58 PDT The disposition of propofol was studied in women undergoing elective Caesarean section. Indices of maternal recovery and neonatal assessment were correlated with venous concentrations of propofol. After induction of anaesthesia with propofol 2.0 mg kg-1, ten patients received propofol 6 mg kg-1 hr-1, with nitrous oxide 50 per cent in oxygen (low group) and nine were given propofol 9 mg kg-1 hr-1 with oxygen 100 per cent (high group). Pharmacokinetic variables were similar between the groups. The mean ± SD Vss = 2 .38 ± 1.16 L kg-1, Cl = 39.2 ± 9.75 ml min-1 kg-1 and t1/2β = 126 ± 68.7 min. At the time of delivery (8-16 min), the concentration of propofol ranged from 1.91-3.82 µg ml-1 in the maternal vein (MV), 1.00-2.00µg ml-1 in the umbilical vein (UV) and 0.53- 1.66 µg ml-1 in the umbilical artery (UA). Neonates with high UV concentrations of propofol at delivery had lower neurologic and adaptive capacity scores 15 minutes later. The concentrations of propofol were similar between groups during the infusion but they declined at a faster rate in the low group postoperatively. Maternal recovery times did not depend on the total dose of propofol but the concentration of propofol at the time of eye opening was greater in the high group than the low group (1.74 ± 0.51 vs 1.24 ± 0.32 µg ml-1, P < 0.01). The rapid placental transfer of propofol during Caesarean section requires propofol infusions to be given cautiously, especially when induction to delivery times are long. Kelvin Chan Anaesthesia http://works.bepress.com/kelvin_chan/80 http://works.bepress.com/kelvin_chan/80 Wed, 27 Aug 2008 02:02:16 PDT The effects of ephedrine and phenylpropanolamine, (PPA) on the acute lethal toxicity of morphine and codeine in naive mice are reported. Moderate doses (20, 40, 80 mg kg-1, i.p.) of ephedrine or PPA led to no mortality on their own. Morphine had an LD50 of 267.8 (262.5-272.I) mg kg-1 after subcutaneous (s.c.) administration. On pretreatment with ephedrine, the LD50 of morphine decreased approximately 5-fold; while it decreased by between 3 to 5 times on pretreatment with PPA. The lethal toxicity of codeine was similarly enhanced by pretreatment with these sympathomimetics, in a clearly dose-dependent manner. The data suggest that these sympathomimetics enhance opioid toxicity. The possible clinical implications of these findings are discussed. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/79 http://works.bepress.com/kelvin_chan/79 Wed, 27 Aug 2008 02:00:24 PDT Bupivacaine 2.5 mg kg-1 (0.5 ml kg-1 of 0.5% solution), with or without adrenaline 5 µg ml-1, was administered by interpleural injection to 12 patients after elective cholecystectomy. Non-compartmental analysis indicated that the addition of adrenaline had no effect on total body clearance, apparent volume of distribution at steady state or elimination half-life of bupivacaine. However, peak plasma concentrations were lower in the adrenaline group (mean (SD) [range] : 2.57 (0.61) [1.52-3.11] vs 3.22 (0.27) [2.84-3.53] µg ml-1, P < 0.05) and the time to maximum concentration was delayed (median [range] : 25 [15-30] vs 15 [10-20] min, P < 0.05). Analgesia was variable and no differences were detected between the two groups. The addition of adrenaline appears prudent to minimize possible bupivacaine toxicity. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/78 http://works.bepress.com/kelvin_chan/78 Wed, 27 Aug 2008 01:57:48 PDT The effects of ephedrine and phenylpropanolamine on the antinociceptive activities of morphine and codeine were investigated. Both morphine and codeine exhibited dose-dependent antinociceptive activities in the tail flick test. Ephredrine (5, 10 and 20 mg/kg) and phenylpropanolamine (5, 10 and 20mg/kg) showed no antinociceptive effect when administered alone. The antinociceptive effects of morphine were enhanced in mice pretreated with ephedrine or phenylpropanolamine. Similarly, codeine antinociception was increased in mice pretreated with ephedrine or phenylpropanolamine. In all cases, the ED50 values and single dose comparisons were shifted in the same direction. These effects on the antinociceptive potencies of morphine and codeine were found to be dose-dependent, being statistically significant at the higher dose levels of ephedrine and phenylpropanolamine used in the present study. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/77 http://works.bepress.com/kelvin_chan/77 Wed, 27 Aug 2008 01:53:58 PDT Twenty women were given a bolus induction of propofol 2.0 mg.kg-1 for elective caesarean section. Induction to delivery times ranged from five to fourteen minutes. At delivery the maternal venous (MV) concentrations of propofol ranged from 0.53 to 1.48 µg.ml-1 umbilical vein (UV) 0.39 to 1.4 µg.ml-1 and umbilical artery (UA) 0.34 to 0.68 µg.ml-1. MV propofol concentrations were always higher than corresponding UV concentrations. The mean (95% confidence interval) UV/MV ratio was 0.65 (0.56-0.74) and the mean UA/UV ratio was 1.07 (0.99-1.15). Neither ratio was shown to be correlated with induction to delivery time. Distribution of propofol is rapid across the placenta and in the fetus. Apgar scores were higher with shorter incision to delivery times but were not correlated to umbilical levels of propofol. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/76 http://works.bepress.com/kelvin_chan/76 Wed, 27 Aug 2008 01:52:10 PDT The single-dose pharmacokinetics of 50 U/kg body weight of recombinant human erythropoietin (rHuEPO) given by either the subcutaneous (s.c.) or the intraperitoneal (i.p.) route were studied in 20 anemic patients maintained on continuous ambulatory peritoneal dialysis. Their baseline haemoglobin levels were less than 9 g/dl. The absorption of rHuEPO via the i.p. route was limited. The serum erythropoietin (EPO) level was only slightly elevated from a baseline value of 27 ± 3 mU/l to a plateau of 36 ± 4 mU/l at 12-24 hours. In comparison, after s.c. injection, a peak EPO level of 81 ± 13 mU/l was obtained after 24 hours. The areas under the concentration-time curve from 0-24 hours were 803 ± 67 and 1492 ± 165 mU/l h for the i.p. and s.c. group respectively (p < 0.003). The same two groups of patients were then given rHuEPO by either the s.c. or the i.p. route over a period of 16 weeks. In the s.c. group, the haemoglobin increased significantly from 6.9 ± 0.3 g/dl to 9.8 ± 0.6 g/dl (p < 0.004). The mean rHuEPO dosage was 84 ± 9 U/kg body wt/week. In the i.p. group, despite relatively higher rHuEPO dosage (133 ± 7 U/kg body wt/week), haemoglobin levels did not increase significantly (7.0 ± 0.4 g/dl to 8.0 ± 0.4 g/dl, p = 0.09). Subcutaneous administration of rHuEPO is effective and convenient for patients maintained on continuous ambulatory peritoneal dialysis. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/75 http://works.bepress.com/kelvin_chan/75 Wed, 27 Aug 2008 01:49:16 PDT The pharmacokinetics of propofol were studied in 12 healthy Chinese children, aged 4-12 yr, undergoing circumcision under inhalation anaesthesia. All patients received a single i.v. bolus dose of propofol 2.5 mg kg-1 and blood concentrations of propofol over the subsequent 24 h were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistent with a three-compartment model with a mean (SEM) elimination half-life of 209 (29) min and total body clearance of 40.4 (3.6) ml min-1 kg-1. The mean (SEM) apparent volume of distribution at steady state was 5.0 (2.7) litre kg-1 and volume of the central compartment was 0.6 (0.1 ) litre kg-1. The mean (SEM) ratio of k12:k21 was 1.4 (0.2), suggesting that, after injection of a single bolus dose in children, propofol is distributed rapidly to the shallow compartment. The mean ratio of k31:k10 suggests that lipophilicity constrains return of the drug to the central compartment. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/74 http://works.bepress.com/kelvin_chan/74 Wed, 27 Aug 2008 01:47:08 PDT We have compared the pharmacokinetics of a bolus induction dose of propofol 2 mg kg-1 in 10 Chinese women undergoing elective Caesarean section with those in six non-pregnant Chinese women having laparoscopic sterilization. Blood propofol concentrations were measured using high pressure liquid chromatography with fluorimetric detection. Pharmacokinetic data were analysed by a model independent method based on statistical moment theory. Data from the laparoscopy group also underwent compartmental analysis, which produced similar kinetic results. Non-compartmental analysis estimated that the women undergoing Caesarean section had a similar elimination half-life (mean 81.27 (SD 18.87) min) and apparent volume of distribution at steady state (2.66 (0.63) litre kg-1) as non-obstetric patients (99.45 (29.40) min and 3.36 (1.87) litre kg-1). Clearance was more rapid in the Caesarean section group (39.32 (8.07) ml min-1 kg-1 vs 29.40 (8.72) ml min-1 kg-1) (P < 0.05). The increased total body clearance may result from blood loss and delivery of the fetus and placenta at operation, although an increase in extrahepatic clearance is also possible. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/73 http://works.bepress.com/kelvin_chan/73 Wed, 27 Aug 2008 01:45:28 PDT Two propofol infusion regimens and a standard general anaesthetic were compared in thirty Chinese women undergoing elective Caesarean section. After induction of anaesthesia with propofol 2 mg-1 kg-1, ten patients received propofol 6 mg-1 kg-1 hr-1 and nitrous oxide 50 per cent in oxygen while ten were given propofol 9 mg-1 kg-1 hr-1 with 100 per cent oxygen. The other ten patients received thiopentone 4 mg-1 kg-1 and nitrous oxide 50 per cent in oxygen with enflurane one per cent. Maternal recovery times and psychomotor performance were recorded. Neonates were assessed by Apgar scores, neurologic and adaptive capacity scores (NACS) and umbilical cord blood gas analysis. Haemodynamic changes were similar immediately following induction but the low propofol infusion group had the best haemodynamic stability subsequently. Recovery times were fastest in the low-infusion group but there were no differences in later postbox testing. Neonatal Apgar scores and umbilical blood gas analysis were similar but NACS at two hours were poorer in the high infusion group. A propofol infusion coupled with nitrous oxide appears to be a satisfactory technique for Caesarean section. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/72 http://works.bepress.com/kelvin_chan/72 Wed, 27 Aug 2008 01:43:15 PDT The pKa value, partition coefficients between n-heptane-, octanol- and dichloromethane- phosphate buffer, and buccal absorption of ethmozine have been determined. The pKa of ethmozine was 5.65, indicating that it is a very weak base. The partition coefficient between n-heptane and buffer was 0.46, but the drug is almost completely transferred into octanol and dichloromethane with partition coefficients approaching infinity. The buccal aborption of ethmozine increased as the buffer pH increased until a plateau absorption level (around 36%) was reached at pH 7.4. The physicochemical properties and buccal absorption of ethmozine reported in this study should be helpful in understanding its disposition and action in the body. It is likely that the renal elimination of ethmozine would be influenced by urinary pH. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/71 http://works.bepress.com/kelvin_chan/71 Wed, 27 Aug 2008 01:41:07 PDT Alfentanil requirements were compared in thirty-six Asian and forty-three European patients during general anaesthesia with muscle relaxants. Alfentanil infilsion at 5 µg/kg/min was started immediately after induction with thiopentone and alcuronium. The infusion rate was reduced to 0.5 µg/kg/min after ten minutes. An incremental dose of 5 µg/kg/min for five minutes was given on each occasion when anaesthesia was clinically judged to be inadequate. Recovery parameters were recorded. Pharmacokinetics were also studied in five Europeans, four Chinese and four Nepalese. The dosage of alfentanil required was comparable in both Asian and European patients, but recovery was slower in the Asian patients. The elimination half-life in the Chinese and the Nepalese were both significantlv shorter than that of the Europeans (P < 0.05), but at the time of recovery of spontaneous ventilation, the mean plasma concentrations were not significantly different. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/70 http://works.bepress.com/kelvin_chan/70 Wed, 27 Aug 2008 01:39:31 PDT A gas liquid chromatography (GLC) for the determination of alfentanil in plasma of surgical patients is described. The assay involved a preliminary ethereal extraction of alfentanil and fentanyl (as internal standard) in a 0.5 ml plasma sample under alkaline conditions. The dried extract was dissolved in n-heptane (10 µl) and 1µl-aliquot was analysed by a Varian GLC system consisting of a SE-30 capillary column (16 m x 0.25 mm) linked to a nitrogen selective detector. The recovery of alfentanil from plasma samples at 250 ng ml-1 ranged from 84 to 92% (n = 10, mean 88%) with a coefficient of variation of 2.7%. Calibration graphs, over the concentration range of 5 to 500 ng ml-1, relating the peak height ratios of alfentanil to the internal standard were linear (n = 6; coefficients of variation ranging from 2.4 to 5.7%). The assay was used to measure the plasma concentrations of alfentanil in 4 surgical patients during and after its intravenous infusion and when spontaneous ventilation was re-established at the end of surgery. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/69 http://works.bepress.com/kelvin_chan/69 Wed, 27 Aug 2008 01:37:57 PDT A liquid chromatographic assay was modified for the simultaneous determination of rifampin (R) and its major metabolite, 25- desacetylrifampin (2S-DR1 in cerebrospinal fluid (CSF) and plasma in the rabbit. R, 25-DR and the internal standard, p-methylaminobenzoic acid (PMAB), were in an acidified sample at pH 4.2 containing 2% ascorbic acid as anti-oxidant and extracted into organic solvent (dicthylether: dichloromethane, 3:2). The residue of the solvent extract was dissolved in 75µl methanol. The concentration was analysed by a liquid chromatograph consisting of a LDC pump using a reversed phase pre-column (30 µm C8) linked to a radial pak column (10 µm C9) The compounds were eluted with acetonitrile-10 mmol/L phosphate buffer, KH2PO4, at pH 3.5 (40:60, vol : vol). The eluates are detected at 254 nm. The assay has been used to investigate the disposition of R and 25-DR in CSF and plasma of the rabbits. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/68 http://works.bepress.com/kelvin_chan/68 Wed, 27 Aug 2008 01:25:42 PDT The influence of anaesthesia on the pharmacokinetics of pyrazinamide (PZA) in cerebrospinal fluid (CSF) and plasma of rabbits was investigated. In a cross-over study, seven New Zealand white rabbits were given oral pyrazinamide (30 mg kg-1) on 2 occasions, with intermittent thiopentone and with continuous pentobarbitone anaesthesia. PZA concentrations in CSF and plasma were determined by high performance liquid chromatography (HPLC). The elimination of PZA after rapid absorption, in both occasions, followed a one compartment kinetics. Plasma elimination t1/2 (1.81 ± 0.52 h and 1.34 ± 0.11 h; p < 0.0025) and apparent volume of distribution (1.804 ± 0.836 and 1.542 ± 0.485 L kg-1; p < 0.10) were larger in the continuously anaesthetised group. The rate and peak of absorption were not different. Ratios of CSF to plasma PZA at 0.5 h (0.96 ± 0.07, 1.01 ± 0.15), 1 h (1.03 ± 0.07, 1.05 ± 0.04), 4 h (0.96 ± 0.13, 0.97 ± 0.16), and 6 h (1.17 ± 0.37, 1.12 ± 0.11), with intermittent and continuous anaesthesia respectively, were similar. Thus, continuous anaesthesia may prolong PZA elimination but does not affect its penetration into CSF from the general circulation in rabbits. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/67 http://works.bepress.com/kelvin_chan/67 Wed, 27 Aug 2008 01:22:45 PDT The concentration-time profiles of rifampicin and pyrazinamide in the cerebrospinal fluid (CSF) and plasma of the rabbit (New Zealand white rabbits of both sex, 4.0-5.5 kg) were studied after oral administration. CSF samples and simultaneous blood samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg kg -1) : and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.2 ml) were obtained from the cisterna magna. Using this rabbit model, 8 CSF and 20 blood samples can be obtained from the rabbit in a 24 h period after drug administration. In 6 rabbits the mean CSF-plasma ratios for pyrazinamide at 0.5, 1, 4, 6 and 24 h was 1.23, 1.13. 1.05. 1.19 and 0.75, respectively, while in 4 rabbits after oral rifampicin dose, the ratios were 0.52, 0.76, 1.17, 0.89 and 0.78 at 0.5, 1, 4, 6 and 12 h, respectively. The results indicate that the small pyrazinamide molecule with good lipid solubility penetrates readily into the CNS while rifampicin traverses the blood brain barrier with difficulty due perhaps to its bulky molecule and low water solubility. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/66 http://works.bepress.com/kelvin_chan/66 Wed, 27 Aug 2008 01:20:24 PDT The disposition and elimination of phenoperidine was studied in five normal subjects, and in six patients with hepatic disease. Plasma concentrations of phenoperidine were generally higher in patients with hepatic dysfunction. Secondary peaks were observed between 15 and 105 min (particularly in patients with liver disease). In the patients the terminal half-life of phenoperidine was prolonged by approximately 50%, mainly because of a decrease in the clearance of the drug. There was little or no change in the total apparent volume of distribution. However, the differences between normal subjects and patients with hepatic disease were not statistically significant. The results suggest that slight or moderate impairment of hepatic function does not significantly affect the kinetics of the drug, and that modification of its dosage may not be required. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/65 http://works.bepress.com/kelvin_chan/65 Wed, 27 Aug 2008 01:18:42 PDT Preparations of indomethacin and indomethacin in combination with PEG 6000 were administered in solid form by the oral route to male rats. No significant differences in anti-oedema activity were observed between the different preparations of indomethacin, but high blood levels of drug were observed following dosing with indomethacin, in a PEG 6000 melt. Rapid dispersion formulations of indomethacin were also found to be gastro-toxic. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/64 http://works.bepress.com/kelvin_chan/64 Wed, 27 Aug 2008 01:16:36 PDT The effect of antacids on the plasma concentration of phenoperidine was studied in six volunteers. All subjects received the same dose of phenoperidine (15µg kg-1) on different occasions in the presence, and absence of, an antacid preparation. In control studies, secondary peaks in the plasma concentration of phenoperidine were invariably observed; these were entirely eliminated, or modified substantially, by the concurrent administration of antacids. In the latter conditions, plasma concentrations of phenoperidine were greater during the first 20min, and the area under the plasma concentration-time curve between 0 and 20 min was significantly greater than in control studies. In contrast, the plasma clearance of the drug was almost identical in control conditions and during treatment with antacids. After the oral administration of phenoperidine to two subjects, the systematic bioavailability of the drug was 9 .9% and 13.9a% respectively. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/63 http://works.bepress.com/kelvin_chan/63 Wed, 27 Aug 2008 01:14:56 PDT The effect of urine pH ont he plasma concentration and elimination of phenoperidine and its main metabolites was studied in six volunteers. The clearance of unchanged phenoperidine in acid urine was significantly greater than in neutral or alkaline urine. By contrast, the elimination of its basic metabolites was enhanced in uncontrolled or alkaline urine. Other pharmacokinetic parameters were not significantly affected. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/62 http://works.bepress.com/kelvin_chan/62 Wed, 27 Aug 2008 01:12:23 PDT The plasma concentrations of pyridostigmine were measured in eight patients during the antagonism of non-depolarizing neuromuscular blockade. After the injection i.v. of pyridostigmine bromide 14.6 mg/70kg, the concentration of the drug rapidly decreased between 2 and 7 min, and then declined more slowly. After 2 h, significant amounts of pyridostigmine were still present in the plasma of all subjects. In the eight patients studied, the initial half-life was 1.0 ± 0.3min and the terminal half-life was 46.4 ± 6.5min (mean ± SEM). Total body clearance of pyridostigmine was 8.7 ± 1.5ml min-1 kg-1, and the total apparent volume of distribution was 536 ± 80 ml kg -1. Possible explanations for the differences between these results and previous studies are considered. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/61 http://works.bepress.com/kelvin_chan/61 Wed, 27 Aug 2008 01:09:33 PDT The plasma concentrations of phenoperidine were measured in five patients during general anaesthesia. The concentration of the drug decreased rapidly between 2 and 40 min and then declined more slowly. Detectable concentrations of phenoperidine were present in plasma for at least 3 h. In the five patients, the distribution half-life of the drug ranged from 3.19 to 14.23 min and the climination half-life from 47.31 to 162.30 min. Unchanged phenoperidine and two identified metabolites (pethidine and norpethidine) were present in urine. Kelvin Chan Pharmacokinetics, Biochemistry Anaesthesia http://works.bepress.com/kelvin_chan/60 http://works.bepress.com/kelvin_chan/60 Wed, 27 Aug 2008 01:01:52 PDT The relation between the plasma concentration of pyridostigmine and its effects was studied in 5 patients with myasthenia gravis. In 4 patients with typical electromyographic decrement in the adductor pollicis, there was a positive correlation between the concentration of pyridostigmine in plasma and the effect on neuromuscular transmission. The plasma concentration of pyridostigmine required to restore transmission to normal (as calculated from the regression line relating plasma concentration to neuromuscular function) varied over a 5-fold range, reflecting the variable severity of the disease. In another myasthenic patient with purely ocular symptoms, there was a significant correlation between the plasma concentration of the drug and the diameter of the palpebral fissure. It is suggested that the routine measurement of the plasma concentration of pyridostigmine may be of value in the management of myasthenia gravis. A method to calculate the optimal daily dose of pyridostigmine in individual myasthenis patients is described. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/59 http://works.bepress.com/kelvin_chan/59 Wed, 27 Aug 2008 00:53:33 PDT Plasma concentrations of pyridostigmine were measured in 7 patients with myasthenia gravis. Six subjects on oral pyridostigmine bromide were stabilized on widely different doses of the drug (60 to 660 mg/day). Nevertheless, the concentration of the quaternary amine in plasma was maintained within a relatively narrow range (usually between 20 and 60 ng/ml). In 3 myasthenic patients, the area under the plasma concentration-time curve was relatively constant for 4 hr after the same oral dose of pyridostigmine (60 mg). Despite this similarity, there were in general considerable interindividual differences in teh bioavailability of pyridostigmine in myasthenic patients. In 1 subject, the bioavailability of the quaternary amine was increased sixfold by doubling the oral dose from 30mg to 60 mg. After oral administration of pyridostigmine, the half-life of the drug in one subject (4.25 hr) was almost three times as great as after intramuscular administration in a different patient (1.49 hr). Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/58 http://works.bepress.com/kelvin_chan/58 Wed, 27 Aug 2008 00:48:09 PDT 1 The pharmacokinetics of neostigmine was studied in six patients during the reversal of neuromuscular block induced by tubocurarine chloride. The effect of the drug on neuromuscular function was simultaneously assessed by electromyography. 2 Neostigmine was rapidly eliminated from plasma after intravenous administration. The decline in the plasma concentration of the drug was invariably resolved into two exponential components. The fast disposition (distribution) half-life of the drug wis invariably less than I min; the slow disposition (eliminition) half-life ranged from 15.4-31.7 min. 3 Neostigmine usually increased the amplitude of the compound muscle action potential and diminished electromyographic decrement within 2 min of intravenous injection. The pharmacological effect of neostigmine was usually maximal between 7 and 15 min. There was an inverse relationship between the plasma concentration of the drug and the facilitation of neuromuscular transmission. 4 Red cell acetylcholinesterase activity was almost completely inhibited within 2-3 min of intravenous injection of neostigmine. Enzyme activity recovered to approximately 28% of control values by 30 min and to 55% by 60 min. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/57 http://works.bepress.com/kelvin_chan/57 Wed, 27 Aug 2008 00:46:01 PDT The plasma concentration of neostigmine was measured in five patients during the antagonism of neuromuscular block. The concentration of the drug decreased rapidly between 2 and 5 min after administration, and then more slowly. Detectable concentrations of neostigmine were present in plasma after 60 min. In the five patients the distribution half-life of neostigmine was less than 1 min; the elimination half-life ranged from 15.4 to 30.1 min. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/56 http://works.bepress.com/kelvin_chan/56 Wed, 27 Aug 2008 00:41:41 PDT 1. The pharmacokinetics of neostigmine and pyridostigmine was studied in conscious dogs by the use of a cross-over design. 2. Both neostigmine and pyridostigmine were cleared from plasma in a biexponential manner. 3. The apparent volume of distribution of pyridostigmine was invariably greater than that of neostigmine, and its fast disposition half-life was approximately three times longer. 4. The whole body clearance and the urinary elimination of pyridostigmine was approximately twice that of neostigmine. 5. the slow disposition half-life of pyridostigmine was approximately three times longer than that of neostigmine, suggesting that the longer duration of action of pyridostigmine is related to the differential clearance of the two quaternary amines from plasma. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/55 http://works.bepress.com/kelvin_chan/55 Wed, 27 Aug 2008 00:38:47 PDT 1. Plasma pethidine levels have been monitored after the administration of 1.5 mg/kg intramuscularly to a group of young (under 30) and old (over 70) subjects. 2. Plasma levels were consistently higher in the old group, this was most marked for the first three hours but for most of the study there was a more than two-fold difference. 3. Differences in uptake from muscle and in metabolism were small and appeared unimportant. 4. Less pethidine was excreted in the elderly and this contributed to the overall differences in serum levels but was not important in explaining the marked disparity noted over the first three hours. 5. Red cell binding of pethidine by the young was much greater than by the old and if the differences in drug binding also applies to other tissues this would explain the high serum levels in the old and the increased incidence of side effects. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/54 http://works.bepress.com/kelvin_chan/54 Wed, 27 Aug 2008 00:37:41 PDT 1. Plasma pethidine levels have been monitored after the administration of 1.5 mg/kg intramuscularly to a group of young (under 30) and old (over 70) subjects. 2. Plasma levels were consistently higher in the old group, this was most marked for the first three hours but for most of the study there was a more than two-fold difference. 3. Differences in uptake from muscle and in metabolism were small and appeared unimportant. 4. Less pethidine was excreted in the elderly and this contributed to the overall differences in serum levels but was not important in explaining the marked disparity noted over the first three hours. 5. Red cell binding of pethidine by the young was much greater than by the old and if the differences in drug binding also applies to other tissues this would explain the high serum levels in the old and the increased incidence of side effects. Kelvin Chan Pharmacokinetics, Biochemistry http://works.bepress.com/kelvin_chan/47 http://works.bepress.com/kelvin_chan/47 Sat, 23 Aug 2008 02:29:54 PDT Astragalus memebranaceus is used as immunomodulating agent in treating immunodeficiency diseases and to alleviate the adverse effects of chemotherapeutic drugs. In recent years, it has been proposed that Astragalus may possess anti-tumorigenic potential in certain cancer cell types. In this study, the anti-carcinogenic effects of Astragalus saponin extract were investigated in HT-29 human colon cancer cells and tumor xenograft. Our findings have shown that Astragalus saponins (AST) inhibit cell proliferation through accumulation in S phase and G2/M arrest, with concomitant suppression of p21 expression and inhibition of cyclindependent kinase activity. Besides, AST promotes apoptosis in HT-29 cells through caspase 3 activation and poly(ADP-ribose) polymerase cleavage, which is indicated by DNA fragmentation and nuclear chromatin condensation. evertheless, we also demonstrate the anti-tumorigenic effects of AST in vivo, of which the reduction of tumor volume as well as pro-apoptotic and antiproliferative effects in HT-29 nude mice xenograft are comparable with that produced by the conventional chemotherapeutic drug 5-fluorouracil (5-FU). In addition, the side effects (body weight drop and mortality) associated with the drug combo 5-FU and oxaliplatin are not induced by AST. These results indicate that AST could be an effective chemotherapeutic agent in colon cancer treatment, which might also be used as an adjuvant in combination with other orthodox chemotherapeutic drugs to reduce the side effects of the latter compounds. Kelvin Chan Chinese Medicine