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Biomedical subjects

P K Yeung

Publications and source records attributed to P K Yeung.

At least 19 recordsLinked to original sources
PubMed2001

Effect of administration route and length of exposure on pharmacokinetics and metabolism of diltiazem in dogs.

The objective of this study was to systematically determine the pharmacokinetics and metabolism of diltiazem (DTZ) after a single i.v. dose, and after single and multiple oral (p.o.) doses. Four mongrel dogs (3 M, 1 F), aged 1-3 years, body weight 19-25 kg, were each given a single 30 mg dose of DTZ as a solution by i.v injection, the same dose orally from an immediate release tablet (Cardizem, Aventis Pharma, Canada, QC), and also t.i.d. for 10 doses. A 3-4 week washout period was allowed between each treatment. Blood samples (4 ml each) were obtained after each treatment from each animal via a cephalic vein at 0 (just before dosing), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, and 12.0 h post dose. Urine samples were collected for 24 h. The plasma samples were immediately separated by centrifugation and stored at -20 degrees C until analysis. The results showed that the bioavailability after a single p.o. dose of DTZ was 26+/-24%. Following a single i.v. dose, DTZ declined bi-exponentially with a terminal half-life (t1/2) of 4.2+/-1.7 h. N-Monodesmethyl DTZ (M(A)), deacetyl DTZ (M1), and deacetyl N-monodesmethyl DTZ (M2) were the major metabolites. Contrary to the results observed in clinical studies, there were no increase of plasma concentrations of DTZ after repeated doses (accumulation factor R = 0.94+/-0.51). Plasma concentrations of M1 decreased following repeated oral doses, accompanying by an increase of plasma concentrations of M2, although these changes were not statistically significant (p >0.05). This study cautions the use of mongrel dogs for direct extrapolation to humans, particularly for chronic pharmacokinetics studies of DTZ.

Administration, Oral↗
PubMed2001

VEGF-2 (St Elizabeth's Medical Center).

St Elizabeth's Medical Center of Boston is developing VEGF gene therapy for the potential treatment of angina and diabetic neuropathy. The center is studying three isoforms of VEGF, although the expression of phVEGF165 has yielded the most positive results [312563]. VEGF-2 gene therapy augments perfusion of ischemic myocardium that contributes to improved clinical outcomes in patients with chronic myocardial ischemia as assessed by NOGA electromechanical mapping [390786]. Phase I trials demonstrated that gene transfer directly into the heart of the patient facilitates blood flow to the primary muscles of the heart, providing relief of angina [348564]. Reduced angina was reported by 28 out of 30 patients and tolerance of exercise increased from 240 to 410 s up to 180 days post-therapy [348632].

Animals↗
PubMed2000

Determination of plasma concentrations of losartan in patients by HPLC using solid phase extraction and UV detection.

PURPOSE: To establish a HPLC assay for plasma losartan and its active metabolite EXP3174 to facilitate clinical pharmacokinetic studies. METHODS: the HPLC system consisted of a 250 x 2 mm i.d. C18 reversed phase column preceded by a 4 x 4 mm guard column, a UV detector set at 254 nm, and an integrator. The mobile phase was a mixture of 0.01 M ammonium phosphate: acetonitrile: methanol (6:3:1) containing 0.02 % sodium azide and 0.04% TEA, with pH adjusted to 3.2. The system was operated isocratically at ambient temperature at a flow rate of 0.3 ml/min. Losartan and its active metabolite EXP3174 were extracted from plasma using C2 bonded silica gel standard solid phase extraction. RESULTS: recoveries of losartan and EXP3174 from plasma were greater than 70%. Using 0.5 ml of plasma sample, standard curves were linear from 10 to 300 ng/ml (r2 = 0.996 and 0.997 for losartan and EXP 3174, respectively). Sensitivity of the assay was < 10 ng/ml. Intra-and inter-assay variations were < 10 and 15%. respectively. The assay has been successfully applied to measuring plasma concentrations of losartan and EXP3174 in patients receiving a daily dose of losartan (50-100 mg). CONCLUSION: The HPLC assay has adequate sensitivity, reproducibility, and specificity for clinical pharmacokinetic studies.

Antihypertensive Agents↗
PubMed2000

The spindle checkpoint in the dinoflagellate Crypthecodinium cohnii.

Dinoflagellates are a major group of organisms with an extranuclear spindle. As the purpose of the spindle checkpoint is to ensure proper alignment of the chromosomes on the spindle, dinoflagellate cell cycle control may be compromised to accomodate the extranuclear spindle. In the present study, we demonstrated that nocodazole reversibly prolonged the G2 + M phase of the dinoflagellate cell cycle, in both metaphase and anaphase. The regulation of the spindle checkpoint involves the activation and inhibition of the anaphase promoting complex (APC), which in turn degrades specific cell cycle regulators in the metaphase to anaphase transition. In Crypthecodinium cohnii, nocodazole was also able to induce a prolongation of the degradation of mitotic cyclins and a delay in the inactivation of p13(suc1)-associated histone kinase activities. In addition, cell extracts prepared from C. cohnii in G1 phase and G2/M phase (or nocodazole treated) were able to activate and inhibit, respectively, the degradation of exogenous human cyclin B1 in vitro. The present study thus demonstrated the presence of the spindle checkpoint and APC-mediated cyclin degradation in dinoflagellates. This is discussed in relation to a possible role of the nuclear membrane in mitosis in dinoflagellates.

Anaphase↗
PubMed2000

A simple high-performance liquid chromatography assay for simultaneous measurement of adenosine, guanosine, and the oxypurine metabolites in plasma.

To study the effect of pharmacologic agents on the biologic fate of adenosine, a reversed-phase high-performance liquid chromatography (HPLC) assay coupled with a solid-phase extraction (SPE) method was developed for simultaneous determination of plasma adenosine, hypoxanthine, xanthine, inosine, guanosine, and uric acid. The HPLC system consisted of a reversed phase C18 column, UV detector set at 254 nm, and a mobile phase composed of 0.01 M ammonium phosphate: methanol (9.5 : 0.5) vol/vol with the final pH adjusted to 3.9. The standard curves were linear between 0.1-2 microg/mL for all the analytes (except uric acid 50-400 microg/mL), with r2 > 0.99. The absolute recoveries were >60% and accuracy >85% in almost all cases. The limit of detection was <1 ng based on absolute injection of the analytes. The intraassay variations were <10% and interassay variations <15%. The presence of a wide range of medications in plasma samples did not interfere with the assay. The assay was applied successfully to measure plasma adenosine and the oxypurine metabolites in humans and rats. It was noted that plasma concentrations of adenosine and the oxypurine metabolites can vary considerably depending on the method of blood sample collection, and that species differences are apparent.

Adenosine↗
PubMed2000

Technology evaluation: transgenic antithrombin III (rhAT-III), Genzyme Transgenics.

AT-III LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery such as cardiopulmonary bypass.

Adolescent↗
PubMed2000

Transgenic antithrombin III (Genzyme).

ATIII LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB). GTC has a license from Behringwerke (Hoechst Marion Roussel; now Aventis Pharma) to develop transgenic AT-III. Behringwerke retains exclusive worldwide marketing rights to the product, but has to purchase its entire supply of transgenic AT-III from GTC [156364]. In March 1997, GTC signed an agreement with SMIG, a joint venture formed by GTC and Sumitomo Metals, under which SMIG has the rights to develop rhAT-III in Asia in return for US dollar 4.4 million in additional funding for the continued transgenic development of rhAT-III. The dollar 4.4 million will be paid upon reaching certain milestones, which GTC expected to complete in 1997 [240202]. In December 1998, US-05843705 was issued covering rhAT-III production in transgenic goats [302263]. In January 2000, the results of the European phase III trial, which were significant in meeting the trial's primary endpoint of reduction in the use of fresh frozen plasma were reported. The trial was also significant in two of three secondary endpoints, maintenance of normal AT-III levels and changes in D-dimer and fibrin monomer [352041,353372]. Three phase III trials were initiated in the second quarter of 1998. Two identical trials, one in Europe and one in the US, evaluated the safety and efficacy of rhAT-III compared to placebo in restoring heparin sensitivity to heparin-resistant patients scheduled for elective cardiac surgery requiring CPB. The third trial, in both the US and Europe, will determine whether rhAT-III matches, at equivalent doses, the ability of plasma-derived AT-III to restore heparin sensitivity among heparin-resistant patients undergoing CPB [292235,292861]. Full enrollment onto the US trial was complete by the end of first quarter 2000 [363589], and the companies aim to complete trials and submit a filing by the end of 2000 [353372]. Clinical trials of the proteins in Japan were expected to begin in 1998 [286086].

Journal Article↗
PubMed1999

A simple high-performance liquid chromatography assay for simultaneous determination of plasma norepinephrine, epinephrine, dopamine and 3,4-dihydroxyphenyl acetic acid.

A reversed-phase HPLC assay coupled with electrochemical detection for simultaneously measuring plasma levels of norepinephrine, epinephrine, dopamine, and 3,4-dihydroxyphenylacetic acid (DOPAC) was developed. Separation of the catecholamines and the internal standard isoproterenol was obtained by a mobile phase consisting of 7% methanol in 0.1 M citrate buffer containing 0.3 mM sodium ethylenediaminetetraacetic acid (EDTA), and 0.5 mM 1-octanesulfonic acid, operated under isocratic condition at a flow rate of 1.2 ml/min. The potential of the guard cell was set at +650 mV, the first electrode of the analytical cell at +100 mV and the second at + 350 mV. Using a signal-to-noise ratio of > 3, the minimum detection limit assessed by direct on column injection was < 10 pg for analyte. The assays were linear from basal concentrations to 400 ng/ml. The intra- and inter-assay variations were < 10 and 15%, respectively. The assay has been applied successfully to measure plasma concentrations of these catecholamines in humans, rabbits and rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Pharmacokinetics and hemodynamic effects of diltiazem in healthy volunteers: comparing resting with the effect of exercise.

PURPOSE: To determine the steady-state plasma concentrations of diltiazem (DTZ) and hemodynamic effect in humans at rest and during exercise. METHODS: Healthy volunteers (10 F, mean age 22, and 11 M, mean age 24) were recruited. Prior to receiving DTZ, each volunteer performed two 3-minute stages of treadmill exercise according to the Bruce protocol. Intra-arterial BP and ECG recordings were obtained before, during and immediately post exercise. Each volunteer then received DTZ 60 mg qid for one week. The same exercise protocol was repeated 1 h after the last dose. Steady-state plasma concentrations of DTZ were determined by a previously reported HPLC. RESULTS: DTZ decreased resting DBP from 84 +/- 13 to 79 +/- 10 mmHg (p > 0.05), and HR from 89 +/- 11 to 82 +/- 13 bpm (p < 0.05). During exercise, an average of 32 and 10% increase in SBP and DBP, respectively, and a 47% increase of HR was found (p < 0.05). DTZ limited these increases to 21% for SBP, 5% for DBP, and 44% for HR (p < 0.05 for drug effect). Steady-state plasma DTZ concentrations were 141 +/- 56 ng/ml. CONCLUSION: DTZ significantly decreased resting HR but not BP in health volunteers. It decreased both hemodynamic variables during exercise. Thus, the hemodynamic effects of diltiazem are more profound during exercise, and may be more useful surrogate markers for calcium antagonists and other cardiovascular agents in healthy volunteer studies.

Adult↗
PubMed1998

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration.

Deacetyl diltiazem (M1) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M1 was administered as a single 5 mg kg-1 dose intravenously (i.v.) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M1 and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M2). The t1/2 and AUC of M1 and M2 were 2.1 +/- 0.5 and 3.0 +/- 1.1 h, and 1300 +/- 200 and 240 +/- 37 ng h mL-1, respectively. The Cl and Clr of M1 were 60 +/- 10 and 0.81 +/- 0.63 mL min-1 kg-1, respectively. M1 significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p < 0.05), but had no significant effect on the heart rate (P > 0.05). The Emax and EC50 as estimated by the inhibitory sigmoidal Emax model were 20 +/- 18% 620 +/- 310 ng mL-1, respectively for SBP; 20 +/- 8.3% and 420 +/- 160 ng mL-1 for DBP.

Animals↗
PubMed1998

A simple high performance liquid chromatography assay for simultaneous determination of omeprazole and metronidazole in human plasma and gastric fluid.

Antibiotics which are actively secreted into gastric fluid may be more efficacious in the eradication of Helicobacter pylori in peptic ulcer disease. Other agents used in the treatment of this disease such as omeprazole or other anti-secretory agents may alter the secretion and/or distribution characteristics of antibiotics. In order to test the applicability of these concepts to metronidazole, a sensitive and specific high performance liquid chromatography (HPLC) assay was developed to quantitate omeprazole in plasma, and metronidazole in plasma and gastric fluid. The HPLC system consisted of a multi-phase column combining anion exchange and reversed phase separation (OmniPac Pax-500, Dionex), and a variable wavelength UV detector set at 254 nm. The mobile phase was a mixture of 0.1 M sodium phosphate buffer:methanol:acetonitrile (60:20:20) with final pH adjusted to approximately 7.0. Metronidazole and omeprazole were extracted by adsorption onto a C2-bonded silica gel solid phase extraction column, and eluted with methanol. The extract was dried, reconstituted in a solution of acetyl salicylic acid (ASA), and then injected into the HPLC system. Under these conditions, metronidazole, omeprazole and ASA were well separated and recoveries in plasma were greater than 80%. Omeprazole could not be measured in gastric fluid because of rapid decomposition. Using 0.3 ml of sample, the assay sensitivity was less than 0.1 microgram ml-1 and linear up to 10 micrograms ml-1. Both intra- and inter-assay CV were greater than 15%. It was applied successfully in determining metronidazole concentrations in clinical samples of plasma and gastric fluid.

Anti-Infective Agents↗
PubMed1998

Pharmacokinetics and hypotensive effect of diltiazem in rabbits: comparison of diltiazem with its major metabolites.

To assess the contribution of its metabolites to the antihypertensive effects of diltiazem, a previously established rabbit model has been used to compare the pharmacokinetics and haemodynamic effects of the drug with those of its major metabolites deacetyldiltiazem (M1) and deacetyl-N-monodemethyldiltiazem (M2). Diltiazem, M1 and M2 were administered separately to each animal (n = 5 or 6 per study group) as a single 5 mg kg(-1) intravenous dose. Blood samples, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to 8 h, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites were determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vdss) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SBP and DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P > 0.05). These results indicate that diltiazem is a more potent hypotensive agent than M1 or M2, possibly because of the higher plasma concentrations secondary to the smaller CL and Vdss of diltiazem compared with the metabolites. The effects of the metabolites might, however, be more sustained.

Animals↗
PubMed1998

Pharmacokinetics and haemodynamic effect of diltiazem in rats: effect of route of administration.

Diltiazem is a calcium antagonist widely used for the treatment of angina and hypertension. Previous studies in patients have shown that the haemodynamic effects of diltiazem are greater after parenteral rather than oral administration. The rat has been used as an animal model to determine the effect of the route of administration on the pharmacokinetic and haemodynamic effects of diltiazem. The results showed that plasma concentrations of diltiazem were more than 10 times higher after the intra-arterial dose. The plasma concentrations of the major metabolites were also higher after intra-arterial administration, although only for deacetyl diltiazem (M1) did the difference reach statistical significance (P < 0.05). The haemodynamic effects (on blood pressure and heart rate) of diltiazem were considerably greater after intra-arterial administration; this was attributed mainly to the much higher plasma concentrations of diltiazem. The hypotensive and chronotropic effects of diltiazem were similar; Emax and EC50 for diastolic blood pressure were 72+/-19% and 4.4+/-5.9 microg mL(-1); for heart rate they were 77+/-32% and 10.0+/-11.7 microg mL(-1), respectively. The haemodynamic effects of diltiazem are much greater after intra-arterial administration, mainly because of the much higher plasma concentrations of the drug. The contribution by the metabolites would be minimal after this route of administration.

Administration, Oral↗
PubMed1998

Pharmacokinetics and hypotensive effect of diltiazem in rabbits after a single intravenous administration: effect of phenobarbital.

Metabolism of the widely used calcium antagonist diltiazem (DTZ) is an important contributing factor to its therapeutic effects. In order to study the effects of CYP3A induction on the pharmacokinetics and haemodynamic effect of DTZ, it was administered as a single 5 mg/kg dose i.v. to two groups of New Zealand white rabbits (n = 6 in each group). Prior to the injection, one of the groups received phenobarbital 20 mg/kg s.c. two times a day for 3 days to ensure CYP3A induction, and the other received normal saline. A third group of animals (n = 6) received neither phenobarbital nor DTZ, and served as the control. Blood samples, systolic and diastolic blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 7 h, and urine samples for 48 h post-dose. Plasma concentrations of DTZ and its metabolites were determined by HPLC. The results showed that phenobarbital increased the Cl and Vdss of DTZ from 24 +/- 14 to 51 +/- 4.9 ml/min/kg and from 1.9 +/- 1.2 to 3.8 +/- 0.7 l/kg, respectively (p < 0.05). It also decreased the plasma concentrations of DTZ and all the measured metabolites in this study. Both phenobarbital and DTZ decreased SBP and DBP significantly without affecting the HR.

Animals↗
PubMed1997

Effect of diltiazem on intraarterial blood pressure and heart rate during stress testing in patients with angina: a gender comparison study.

The purpose of this study was to measure the blood pressure and electrocardiographic responses of a small, matched group of women (n = 8) and men (n = 9) who experienced typical, effort angina during an exercise on the treadmill (up to the second stage of a Bruce protocol). These responses were measured before and after therapy with diltiazem (60 mg four times daily for 1 week). Reports of previous studies have described significant gender differences in blood pressure responses to diltiazem in healthy volunteers tested with the same protocol. In contrast to the data in healthy individuals, gender differences in blood pressure responses to exercise before and after diltiazem administration were not observed. Results of analysis of pulse pressure responses to exercise were also similar in male and female patients with angina. A significant postexercise drop in blood pressure was observed, which was augmented by diltiazem. These data suggest that gender differences in drug action may be difficult to demonstrate in patients with vascular disease.

Angina Pectoris↗
PubMed1997

Effect of diltiazem on plasma concentrations of oxypurines and uric acid.

To determine the clinical effect of diltiazem on the metabolism of adenosine, and its importance in ischemic heart disease, arterial plasma concentrations of the purine metabolites were determined in 21 healthy volunteers (10 female and 11 male) and 19 patients with effort angina (8 female and 11 male) before, during, and immediately after standard treadmill exercise tests conducted before and after they had taken 60 mg diltiazem (Cardizem; Hoechst Marion Roussel, Laval, QC, Canada) four times a day for 1 week. The results showed that the cardiac patients had significantly lower mean plasma concentrations of uric acid (46.82 +/- 25.51 versus 95.47 +/- 35.41 micrograms/ml, p 0.05), inosine (0.25 +/- 0.19 versus 0.84 +/- 0.17 microgram/ml, p < 0.05), and hypoxanthine (0.28 +/- 0.35 versus 0.50 +/- 0.27 microgram/ml, p < 0.05). Diltiazem decreased the mean resting plasma concentrations of uric acid in patients (uric acid 43.47 +/- 22.26 versus 46.82 +/- 25.51 micrograms/ml, p < 0.05) and healthy volunteers (uric acid 85.68 +/- 26.71 versus 95.47 +/- 35.41 micrograms/ml, p < 0.05). There was no statistically significant change in the plasma concentrations of the purine metabolites during exercise (p < 0.05). Female subjects had significantly lower plasma concentrations of uric acid than males (patients, 34.87 +/- 26.93 versus 55.78 +/- 21.25 micrograms/ml; healthy volunteers, 84.79 +/- 32.07 versus 104.22 +/- 37.05 micrograms/ml; p < 0.05 for both). Results of the study suggest that normal therapeutic doses of diltiazem may modulate the metabolism of adenosine and that some of the purine metabolites may be useful markers for specific types of ischemic heart disease.

Adenosine↗
PubMed1996

Effect of omeprazole on movement of intravenously administered metronidazole into gastric juice and its significance in treatment of Helicobacter pylori.

Four healthy, Helicobacter-negative volunteers were studied to determine the effect of omeprazole on the movement of metronidazole across the gastric mucosa into the gastric lumen. Each received a 500-mg intravenous infusion of metronidazole and repeated serum, and gastric juice samples were obtained concomitantly over an 8-hr study via indwelling intravenous catheter and nasogastric tube. The same protocol was repeated following one week of oral omeprazole 20 mg twice daily. Metronidazole concentrations were measured by high-performance liquid chromatography. The results demonstrated that: metronidazole moves rapidly from serum into gastric juice; omeprazole causes a marked reduction in total metronidazole concentrations in gastric juice, completely accounted for by pH-related shifts in the proportion of ionized metronidazole, but does not alter concentrations of nonionized metronidazole, which remain above the MIC level against H. pylori; and even under conditions where no pH-related drug trapping occurs (pH > 4), concentrations of metronidazole were higher in gastric juice than in serum during most of the study, indicating that a special transport mechanism may be operational. The practical implication of this effect of omeprazole in combination therapy with metronidazole remains to be established.

Adult↗