Biomedical subjects

K K Chan

Publications and source records attributed to K K Chan.

At least 109 records · Page 6Linked to original sources

PubMed1995

Assessment of pacing maneuvers used to validate anterograde accessory pathway potentials.

Four pacing maneuvers have been proposed to validate an anterograde accessory pathway potential (APP): (1) atrial pacing to induce complete block between the atrial electrogram and the APP; (2) ventricular pacing to advance the APP without altering the timing of the atrial electrogram; (3) atrial pacing to induce complete block between the APP and the ventricular electrogram; and (4) ventricular pacing to advance the ventricular electrogram without altering the timing of the APP. The purpose of this study was to assess these validation techniques by applying them to electrograms that simulated APPs but which were known to be atrial in origin. In 32 patients undergoing an electrophysiology procedure, a split atrial electrogram containing two components separated by at least 30 msec (mean 54 +/- 15 msec) was recorded. Using an atrial extrastimulus technique, complete block between the two components of the atrial electrogram (criterion 1) could never be induced, but complete block between the second component of the atrial electrogram and the ventricular electrogram (criterion 3) consistently was induced. Using a ventricular extrastimulus technique, the second component of the atrial electrogram consistently could be advanced by 10 to 40 msec without altering the timing of the first component (criterion 2). In addition, with ventricular pacing, the ventricular electrogram consistently was advanced without altering the timing of the two components of the atrial electrogram (criterion 4). In conclusion, among the four pacing maneuvers used to validate an anterograde APP, the only one that may be specific for an APP is the ability to induce complete block between the atrial electrogram and the APP.

Adult↗

PubMed1995

Ultrasound-guided percutaneous transhepatic gallbladder drainage followed by laparoscopic cholecystectomy: a new trial in the treatment of severe acute suppurative cholecystitis.

Seven cases of acute suppurative cholecystitis underwent percutaneous transhepatic gallbladder drainage followed by laparoscopic cholecystectomy at the Tainan Municipal Hospital. All the patients had frank septic phenomena clinically, including fever, jaundice, leukocytosis and unstable blood pressure. Organisms were cultured from both blood and bile specimens. Ultrasound-guided transhepatic puncture of the gallbladder was performed for bile drainage, and laparoscopic cholecystectomy was subsequently performed two to five days later after the patients had stabilized. No procedure-related complications from either percutaneous transhepatic gallbladder drainage or laparoscopic cholecystectomy were observed. All patients had early recovery, shortened hospital stay and good cosmetic results. These preliminary results show that laparoscopic cholecystectomy is a safe method and can be employed in those patients with symptomatic gallstone associated with suppurative cholecystitis after preoperative biliary drainage.

Acute Disease↗

PubMed1995

Glutathione S-transferase M1 genotype affects aminobiphenyl-hemoglobin adduct levels in white, black and Asian smokers and nonsmokers.

Cigarette smoking is the major cause of bladder cancer in men in the United States, and the arylamines contained in cigarettes smoke, including 4-amino-biphenyl (4-ABP), are believed to play an important role in the induction of bladder cancer among smokers. N-acetylation, which is catalyzed by the genetically controlled hepatic N-acetyltransferase enzyme displaying two phenotypes (slow versus rapid), is a detoxification pathway for arylamines with regard to bladder carcinogenesis. In Los Angeles, CA, non-Hispanic white (white), black, and Asian males have comparable smoking habits and yet dramatically different risks of bladder cancer (31 of 100,000 in whites, 16 of 100,000 in blacks, and 13 of 100,000 in Chinese and Japanese). Previously, we have demonstrated that the prevalence of slow acetylators (the high-risk phenotype) was highest in whites (54%), intermediate in blacks (34%), and lowest in Asians (14%). We also showed that mean 3- and 4-ABP hemoglobin adduct levels were significantly higher in cigarette smokers relative to nonsmokers, and that the level increased with increasing number of cigarettes smoke/day. Most importantly, slow acetylators consistently exhibited higher mean levels of ABP hemoglobin adducts relative to rapid acetylators, regardless of race and level of cigarette smoking. We assessed 151 residents of Los Angeles County (CA) who were either white, black, or Asian (Chinese or Japanese) and over the age of 30 years for their glutathione S-transferase M1 (GSTM1) genotype (null versus non-null), acetylator phenotype (slow versus rapid), levels of 3- and 4-ABP hemoglobin adducts, and current use of tobacco products. Whites (27%) had the highest prevalence of the highest risk profile (slow acetylator, GSTM1 null), followed by blacks (15%) and Asians (2.7%), and the difference was statistically significant (P = 0.006). Whites also had less than one-half the prevalence of the "protective" profile (rapid acetylator, GSTM1 non-null) relative to blacks and Asians (23 versus 57%; P = 0.0001). Regardless of race and level of cigarette smoking, mean levels of 3- and 4-ABP hemoglobin adducts were higher in subjects possessing the higher risk (GSTM1/acetylator profile. Mean level of 4-ABP hemoglobin adduct (adjusting for race, cigarette smoking, and acetylator phenotype) was significantly higher in subjects possessing the GSTM1-null versus GSTM1-non-null genotype (46.5 versus 36.0 pg/g Hb; P = 0.037). The comparable difference in mean levels of 3-ABP hemoglobin adduct was borderline significant (1.6 versus 1.1 pg/g Hb; P = 0.07). Thus, our results suggest that GSTM1 is involved in the detoxification of 3- and 4-ABP and may contribute to the racial variation in bladder cancer incidence among white, black, and Asian males in Los Angeles, CA.

Adult↗

PubMed1995

Bilateral root-resorption of upper first permanent molars.

Root-resorption of first permanent molars by impacted premolars is generally considered to be rare, although a few cases have been reported. A case is presented, of bilateral root-resorption of upper first permanent molars by unerupted second premolars, and a number of clinical conclusions are discussed.

Bicuspid↗

PubMed1994

Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508.

The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P < 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.

Cyclophosphamide↗

PubMed1994

Acetylator phenotype, aminobiphenyl-hemoglobin adduct levels, and bladder cancer risk in white, black, and Asian men in Los Angeles, California.

BACKGROUND: There is a large body of epidemiologic and experimental data that have identified a number of arylamines as human bladder carcinogens. Metabolic activation is required to biotransform these arylamines into their carcinogenic forms, and N-hydroxylation, which is catalyzed by the hepatic cytochrome P4501A2 isoenzyme, is generally viewed as the first critical step. On the other hand, the N-acetylation reaction, catalyzed by the hepatic N-acetyltransferase enzyme, represents a detoxification pathway for such compounds. The N-acetyltransferase enzyme is coded by a single gene displaying two phenotypes, slow and rapid acetylators. In the United States, cigarette smoking is a major cause of bladder cancer in men, and carcinogenic arylamines present in cigarette smoke are believed to be responsible for inducing bladder cancer in smokers. PURPOSE: Our purpose was to test the differences in three ethnic/racial groups for the prevalence of acetylator phenotypes and to ascertain whether slow acetylators actually have higher levels of activated arylamines in comparison with rapid acetylators. METHODS: One hundred thirty-three male residents of Los Angeles County who were either white, black, or Asian (Chinese or Japanese) and over the age of 35 years were assessed for their acetylator phenotype and levels of 3- and 4-aminobiphenyl (ABP) hemoglobin adducts. Subjects were either lifetime nonsmokers (n = 72) or current cigarette smokers of varying intensity (n = 61). RESULTS: The proportion of slow acetylators was highest among whites (54%), intermediate among blacks (34%), and lowest among Asians (14%). Similarly, geometric mean levels of both 3- and 4-ABP-hemoglobin adducts were highest in whites (1.80 and 49.2 pg/g hemoglobin [Hb], respectively), intermediate in blacks (1.54 and 38.5 pg/g Hb), and lowest in Asians (0.73 and 36.0 pg/g Hb). As expected, cigarette smokers had significantly higher mean levels of both 3- and 4-ABP-hemoglobin adducts relative to nonsmokers, and the levels increased with the number of cigarettes smoked per day (P < .0005 for both adducts). Slow acetylators consistently exhibited higher mean levels of ABP-hemoglobin adducts relative to rapid acetylators, independent of race and level of smoking. CONCLUSION: The present cross-sectional survey supports acetylation phenotype as an important determinant of bladder cancer risk and a possible major factor in the varying bladder cancer risk among whites, blacks, and Asians.

Acetylation↗

PubMed1994

Preclinical pharmacokinetics and stability of isophosphoramide mustard.

Stability and preclinical pharmacokinetics of isophosphoramide mustard (IPM), an active metabolite of ifosphamide, were investigated using analytical methods developed in this laboratory. For stability evaluation of IPM we used a rapid, high-pressure liquid chromatographic (HPLC) method by which IPM is analyzed directly from aqueous solutions without derivatization on a 10-microns C-18 reversed-phase column with theophylline as the internal standard. IPM in sodium phosphate buffers was found to undergo pH-dependent first-order degradations. At pH 7.4 and 38 degrees C, the IPM solution showed a half-life of 45 min. A gas chromatographic-mass spectrometry (GC/MS) method for the analysis of IPM in plasma was also developed. This method utilized solid-phase extraction with deuterium-labeled IPM as the internal standard. The routine detection limit for the assay was 50 ng/ml with within-run and between-run coefficients of variation of 6% and 11%, respectively. By this method, stability of IPM in plasma and in RPMI 1640 tissue culture medium was evaluated, and its pharmacokinetics in the Sprague-Dawley rat following i.v. administration at 40 mg/kg were investigated. IPM was found to be more stable in these media, with half-lives in the range of 100 min. IPM plasma pharmacokinetics were found to decline monoexponentially with terminal half-lives ranging from 6.8 to 18.7 min and total clearance between 6.0 and 18.3 ml/min. Plasma protein binding of IPM was found to be 55%, and the partition ratio between plasma and red blood cells of 4.9 to 1, respectively. Cytotoxicity of IPM to L1210 cells was evaluated, and the results indicated that the IC50 with 1-h and 4-h exposure was 33 and 15 microM, respectively. Based on these data, IPM plasma levels in the rat declined below the IC50 in about 1 h at this dose. More frequent dosing or infusion may be necessary to maintain adequate drug levels for antitumor activity when IPM is administered directly.

Animals↗

PubMed1994

Intraperitoneal 5-fluoro-2'-deoxyuridine with escalating doses of leucovorin: pharmacology and clinical tolerance.

In a preceding study, we established the tolerance and pharmacokinetic behavior of 5-fluoro-2'-deoxyuridine (FdUrd) given by the intraperitoneal (IP) route. A dose of 3 g daily x 3 days was found satisfactory for Phase II study and exploration of biochemical modulation. Therefore, the current study was conducted to study the tolerance and pharmacokinetics of such a dose-schedule and route of FdUrd combined with escalating doses of leucovorin (LV). Fourteen patients were entered and 13 were evaluable for tolerance determination. Pharmacologic determinations of IP FdUrd and 5-Fluorouracil (FUra) derived from it and LV were obtained by HPLC methods on 11 occasions. Findings were compared with the preceding study of FdUrd alone. LV did not appear to alter the tolerance of IP FdUrd even in the four patients receiving the highest dose of LV (640 mg). Toxicities included nausea, vomiting, and rarely neutropenia and diarrhea. Pharmacokinetic parameters indicate a parallel rate of egress of FdUrd and LV from the peritoneal cavity. The pharmacologic advantage for FdUrd is at least 3 logs as previously reported and one log for LV. Evidence of antitumor effect was noted particularly among untreated patients with gastrointestinal primaries. We conclude that IP FdUrd 3 g and LV in doses of up to 640 mg x 3 days are well tolerated. Since FdUrd is more potent, has an even greater hepatic clearance and shows greater potential for modulation with LV than FUra, it may be the preferred fluoropyrimidine for subsequent studies via the IP route in the treatment of carcinomas with prominent peritoneal spread. The pharmacologic advantage for leucovorin is limited but it is a good marker for peritoneal clearance since it parallels FdUrd clearance.

Abdominal Neoplasms↗

PubMed1994

A rapid method for the separation and analysis of leaked and liposomal entrapped phosphoramide mustard in plasma.

Pharmacokinetic studies of liposomal drugs should include simultaneous determination of leaked and entrapped drug in biological specimens. Due to the limited stability of many liposomal preparations in biological samples, a rapid analytical procedure is often necessary. Phosphoramide mustard (PM), a key cytotoxic metabolite of a widely used alkylating drug cyclophosphamide, has recently been entrapped into a liposomal formulation and the preparation has been found to be rather unstable in plasma. We have, therefore, developed a rapid method for the separation of liposome-associated PM from the unassociated drug and a method for their quantitation in plasma. This method involves the use of size exclusion mini-gel column and requires minutes to process. Due to the use of internal standards, this method tolerates low recovery and requires the collection of a single fraction of each of liposome-associated PM and the unassociated drug. The recovery of liposomal PM from the first fraction of the gel column was found to be 82.4 +/- 7.9% (SD, n = 8), whereas that of liposome-unassociated PM from the major fraction was 16.8 +/- 2.8% (SD, n = 8). However, the low recovery problem of liposome-unassociated PM was circumvented by adding the internal standard [alpha, beta-2H8] PM prior to separation, thus compensating for the loss of liposome-unassociated PM due to incomplete collection. Two types of standard curve were constructed for quantitation of liposome-associated PM and unassociated PM and the linearity for both was excellent. Assay validation indicated that within-run RSD values at 213 ng, 426 ng and 1065 ng for liposomal PM were 4.2, 4.3 and 3.0%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Risk factors for acute myocardial infarction in a southern Chinese population.

Although the mortality rate from coronary artery disease in Hong Kong is only one-fourth of that of northern Europe and the United States, the disease has been and remains the second major cause of death (after all cancers combined). Beginning in 1987, we have conducted a case-control study of acute myocardial infarction in four Hong Kong hospitals. This study, one of the biggest case-control studies conducted in the Chinese population of both men and women, confirms the importance of several risk factors--cigarette smoking, history of hypertension, history of diabetes, body fatness, and lack of physical activity--previously described in data collected in western populations. In addition, more adverse childhood experience was also found to be an important risk factor of acute myocardial infarction. Further research in appropriate intervention measures in education in the prevention and cessation of smoking, the control of blood pressure, diabetes, and overweight, and adequate exercise could significantly help reduce the risk of acute myocardial infarction in the Hong Kong Chinese population.

Aged↗

PubMed1994

Site-differential gastrointestinal absorption of benazepril hydrochloride in healthy volunteers.

The absorption of benazepril-HCl (BZPH), an orally active angiotensin-converting enzyme (ACE) inhibitor, in various regions of the gastrointestinal (GI) tract was investigated using an intestinal intubation technique. Thirteen subjects completed this single-dose, three-phase sequential crossover study. The drug (20 mg) was administered either as a 4-hr colonic infusion (COLON) or as a small intestinal infusion (SI) in the first two phases and as an oral bolus solution (ORAL) in the third phase, with a 2-week washout between each treatment. Serial plasma and urine samples were collected for up to 4 days after dosing. BZPH and its active metabolite benazeprilat (BZPL) were determined using a gas chromatography/mass spectrometry method. BZPH was absorbed rapidly into the bloodstream (Tmax = 0.5 hr after ORAL). Absorption was also rapid for SI, with a postinfusion half-life (0.57 hr) nearly identical to that for ORAL (0.59 hr). The absorption rate after COLON was much slower (lower Cmax and longer Tmax) compared to that after SI, and the apparent half-life (1.7 hr) was prolonged. SI delivered 90%, whereas COLON delivered 23%, of the drug into the systematic circulation as compared to ORAL. BZPL was rapidly formed upon drug absorption. The metabolite-to-drug AUC ratios were comparable for SI and ORAL (8.9 vs 9.7), indicating that first-pass metabolism of BZPH was neither saturable nor input rate dependent. The metabolite-to-drug AUC ratio was reduced for COLON (5.0), indicating that the mechanism of absorption of BZPH in the colon may be different than that after SI and ORAL. Urinary recovery data were consistent with plasma data.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Pharmacokinetics and metabolism of diclofenac sodium in Yucatan miniature pigs.

The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 +/- 17 vs 252 +/- 54 mL/hr/kg). The plasma levels of the metabolites 4'-hydroxy, 5-hydroxy, 3'-hydroxy, 4',5-dihydroxy, and 3'-hydroxy-4'-methoxy diclofenac were considerably lower in minipigs than in man after both i.v. and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (Ka = 0.52 +/- 0.11, 0.59 +/- 0.13, and 1.2 +/- 0.7 hr-1, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Transsynovial drug distribution: synovial mean transit time of diclofenac and other nonsteroidal antiinflammatory drugs.

The synovial mean transit time of diclofenac was determined by two methods from existing plasma and synovial fluid concentration-time data. These data were obtained from single- and multiple-dosing regimens of diclofenac in patients with osteoarthritis and rheumatoid arthritis. Plasma and synovial fluid concentration-time data taken from the literature for four other nonsteroidal antiinflammatory drugs (etodolac, ibuprofen, indomethacin, and tenoxicam) were also analyzed. The two methods of data analysis rely on the determination of the ratio of the area under the synovial fluid concentration-time curve to the area under the plasma concentration-time curve. Both methods can be considered noncompartmental because in determining the first-order exit rate constant for the synovial fluid (the inverse of the synovial mean transit time), an analysis of the overall distribution and elimination characteristics of the drug is unnecessary. Method 1 makes use of the information contained in the postdistributional synovial fluid to plasma concentration ratio whereas method 2 is a linear pharmacokinetic model using a partial-areas analysis. The single dose mean +/- S.D. synovial fluid exit rate constant for diclofenac was 0.39 +/- 0.33 hr-1 (n = 6), which was not significantly different from that determined by method 2; which was 0.49 +/- 0.52 hr-1. The steady state mean +/- S.D. diclofenac synovial fluid exit rate constants for methods 1 and 2 were 0.43 +/- 0.18 and 0.54 +/- 0.71 hr-1 (n = 8), respectively, which were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Effect of allatostatin and proctolin on antennal pulsatile organ and hindgut muscle in the cockroach, Diploptera punctata.

Diploptera punctata allatostatins are brain neuropeptides that inhibit juvenile hormone synthesis by corpora allata. They also occur in nerves of many organs other than corpora allata. The distribution of allatostatins in, and the effect of allatostatins on two other organs, antennal pulsatile organ and hindgut, are demonstrated here. Allatostatin I-like immunoreactive material is present in cells of subesophageal and terminal abdominal ganglia; these ganglia are known to contain the cells that project to antennal heart nerve and proctodeal nerve, respectively. Electron micrographs of both organs show nerve terminals with allatostatic immunoreactive granules along with terminals containing nonimmunoreactive granules. Immunoreactive neurosecretory granules are about 200 nm in largest dimension. In the antennal pulsatile organ, profiles of the nerve terminals are larger in the ampullar wall than in the muscle; in hindgut the terminals with immunoreactive granules are associated with the muscle net below the circular muscle. Hindgut responded to allatostatins I and IV with a dose-dependent decrease in amplitude and frequency of contraction that was reversible, with the threshold concentration for response between 10(-8) and 10(-7) M. In contrast, pulsatile organ muscle showed no such change with either allatostatin at 10(-7)-10(-4) M. However, both organs responded to proctolin with increased amplitude and frequency of contractions. Allatostatins I and IV inhibited the proctolin-induced increase of hindgut contraction, whereas no such effect was seen in antennal pulsatile organ muscle. Extract of antennal pulsatile organ muscle showed proctolin-like bioactivity that comigrated with authentic proctolin on three sequential HPLC systems.

Animals↗

PubMed1993

Structure-activity relationships in corpora allata of the cockroach Diploptera punctata: roles of mating and the ovary.

Morphometric studies were made on corpora allata of the cockroach Diploptera punctata from animals in which increasing gland size is not coupled to hormone synthesis (ovariectomized mated females; last-instar larvae) and in which gland size is coupled to hormone synthesis (normal mated and virgin females; penultimate-instar larvae). Cell number, gland volume, and juvenile hormone synthesis were measured. From electron micrographs, nuclear, cytoplasmic, and extracellular volumes; and cell membrane area were calculated; and fine structure described. Low-activity glands of ovariectomized mated females resembled high-activity glands from mated females in high cell number, large overall and cytoplasmic volume, and low nuclear-cytoplasmic ratio; they differed in having organelles typical of low-activity glands, mitochondria with dense matrices and large whorls of smooth endoplasmic reticulum. Inactive last-instar larval glands resembled mated ovariectomized female glands in increased cell number and organelles characteristic of inactive glands; however, their nuclear-cytoplasmic volume ratio was much higher. Penultimate larval glands with high activity per cell resembled active glands of normal mated females. Ovariectomy did not change morphometric parameters of virgin female glands; thus mating results in increase in size of adult female glands whereas the growing ovary is needed for changes in mitochondria and endoplasmic reticulum associated with high juvenile hormone synthesis.

Animals↗

PubMed1993

Preclinical pharmacology of the antitumor agent O-6-methylguanine in CDF1 mice.

O-6-methylguanine (O6-mG), a guanine analog recently shown to be a potent inhibitor of alkylguanine-DNA alkyltransferase, has been found to potentiate the antitumor activity of nitrosoureas, in particular, carmustine (BCNU), in resistant cell lines (HT-29 mer+) and is targeted for development as a modulating agent with chloroethyl nitrosoureas. A high-performance liquid chromatography (HPLC) assay of O6-mG in plasma has been developed using a microC18 reverse-phase column. O6-mG and the internal standard deoxyguanosine (dGuo) were eluted with a linear gradient of from 15% to 35% methanol in 0.5 M ammonium acetate (pH 6.5) at a flow rate of 1 ml/min. The assay was linear over a 4-log concentration range with a detection limit of 0.1 microgram/ml. The within-run and between-run coefficients of variation (CV) were found to be 8.1% and 9.3%, respectively. The pharmacokinetics (PK) of O6-mG were investigated in healthy CDF1 mice following separate i.v. and i.p. administrations. At 20 mg/kg i.v., plasma O6-mG gave a biexponential profile with a terminal half-life (t1/2) of 24 min and a total clearance (CLT) of 23.7 ml min-1 kg-1. Higher doses (40-80 mg/kg) revealed a fluctuating third phase, probably due to enterohepatic cycling. Dose-dependent kinetics as measured by CLT and area under the plasma-concentration curve (AUC) values were also seen. Following i.p. dosing, O6-mG was completely absorbed and available to the circulation. No acute toxicity was observed in the animals, except for mild sedation, a possible side effect of the 10% ethanol used in the formulation. Studies on the cellular metabolism of highly purified [3H]-O6-mG have shown that the compound is not anabolized by a human lymphoblastoid cell line (CEM). Biochemistry studies have shown that the parent molecule is inactivating the alkylguanine-DNA alkyltransferase (AGT), thus exerting its pharmacological effect.

Animals↗

PubMed1993

Lipids, lipoproteins and other coronary risk factors in Chinese male survivors of myocardial infarction.

OBJECTIVE: To assess the importance of an abnormal lipid profile as a risk factor in relation to non-biochemical risk factors, and to define the risk levels for lipid, lipoprotein and apolipoprotein in a Chinese population. PATIENTS AND METHODS: Serum lipids, lipoproteins, apolipoproteins and other cardiovascular risk factors were studied in 89 Chinese men 3 months after acute myocardial infarction and 56 controls. RESULTS: Cases had higher mean total cholesterol (TC), LDL- and VLDL-cholesterol, triglycerides and apolipoprotein B (Apo B), and lower mean HDL-cholesterol and apolipoprotein AI (Apo AI). Mean BMI was also higher, as was the prevalence of smokers and subjects with a history of hypertension. In univariate analysis, the odds ratios for TG > or = 1.6 mmol/l, LDL-cholesterol > or = 4.1 mmol/l, VLDL-cholesterol > or = 0.73 mmol/l, Apo B > or = 104 mg/dl were of the same order of magnitude as being a current smoker, having a BMI > or = 24.3 kg/m2, and a history of hypertension. High HDL-cholesterol (> or = 1.39 mmol/l) and Apo AI (> or = 139 mg/dl) were protective factors. The odds ratios for successively higher quartile values of cholesterol were not statistically significant. Multiple logistic regression identified smoking habit, history of hypertension, obesity, high Apo B and low Apo AI concentrations as independent risk factors for myocardial infarction. CONCLUSIONS: In a Chinese population, low serum Apo AI and high Apo B are risk factors for myocardial infarction of a comparable magnitude to smoking, hypertension and obesity.

Apolipoprotein A-I↗

PubMed1993

The West Midlands epithelial ovarian cancer adjuvant therapy trial.

In a multicentre prospective randomized controlled trial, single agent cisplatinum was compared with whole abdomino-pelvic moving strip radiotherapy in the management of Stage IC-III epithelial ovarian cancer patients who had no macroscopic residual disease after primary surgery. Over a 6-year period 40 eligible patients were recruited, 15 of whom had Stage III disease. The overall 5-year survival was 60% with no significant survival difference between the treatment groups. Acute toxicity was common in both arms and six (11%) patients experienced significant long term disability.

Chemotherapy, Adjuvant↗