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Biomedical subjects

W E Wung

Publications and source records attributed to W E Wung.

15 recordsLinked to original sources
PubMed1987

Molecular modification of anticholinergics as probes for muscarinic receptors. 1. Amino esters of alpha-substituted phenylacetic acid and related analogues.

Two series of compounds having the general structure of C6H5CRR'COOCH2CH2NEt2 were synthesized and examined for their antispasmodic activities. These compounds were selected as structural probes for exploring the nature of muscarinic cholinergic receptor binding sites that interact with atropine-like anticholinergics. These studies indicate a rather strict size limitation for the hydrophobic region of the receptor and suggest intramolecular hydrogen bonding as a possible means to explain the observed stereoselectivity.

Alkylation↗
PubMed1984

A high-performance liquid chromatographic assay with improved selectivity for cisplatin and active platinum (II) complexes in plasma ultrafiltrate.

cis-Diamminedichloroplatinum(II) (DDP) was measured in plasma ultrafiltrate following derivatization with sodium diethyldithiocarbamate (DDTC) by quantitation against a nickel chloride internal standard. A chloroform extract containing the Pt(DDTC)2 and Ni(DDTC)2 complexes was separated by reversed-phase high-performance liquid chromatography on a C18 radial compression column. The complex was eluted with methanol/water, 4/1, at a flow rate of 1.5 ml/min, and was detected at 254 nm. The limit of sensitivity was 0.1 microgram/ml DDP in the ultrafiltrate. This analytical approach was validated by comparison to graphite furnace atomic absorption spectrophotometric determinations of duplicate samples. There was clearly a component of the ultrafiltrable platinum present that was resistant to derivatization by DDTC. Evidence is presented that this component, presumably Pt(II) complexed with endogenous small molecules, is non cytotoxic and, hence, that this method may be selective for "active Pt(II)." This method offers an advantage over atomic absorption determination of total platinum in ultrafiltrate which does not discriminate between active and inactive forms, and over off-line FAA detection of parent DDP in HPLC eluates which ignores other active forms. Using this technique we have measured the pharmacokinetics of DDTC-reactive Pt(II) in humans after either i.v. infusion or infusion of DDP into the peritoneal cavity of patients with ovarian carcinoma.

Chromatography, High Pressure Liquid↗
PubMed1984

Hypoxanthine concentrations in normal subjects and patients with solid tumors and leukemia.

Mean plasma hypoxanthine (Hyp) concentrations determined by high-pressure liquid chromatography were 0.56 microM (range, 0.2 to 1.9 microM) in 16 normal subjects, 0.68 microM (range, 0.1 to 1.1 microM) in 10 untreated acute leukemic subjects, and 0.89 microM (range, 0.3 to 2.6 microM) in 14 solid tumor patients. Despite large differences in Hyp concentration between patients, every 4-hr sampling, indicated that diurnal variation in individual patients was small (maximum, 2.3-fold). While the mean plasma and malignant effusion Hyp concentrations did not differ significantly, bone marrow plasma Hyp concentration averaged 4.0-fold greater than that of simultaneously drawn venous plasma. Allopurinol 300 mg p.o. caused a mean 1.5-fold increase in plasma Hyp within 3 hr. In 17 patients with acute leukemia, treatment with allopurinol at 300 mg daily plus initiation of chemotherapy caused a mean 7-fold increase in plasma Hyp to 4.6 microM (range, 1 to 12 microM). The ability of Hyp to modulate the toxicity of antimetabolites affecting purine synthesis (6- diazao -5- oxonorleucine , 6-methylmercaptopurine riboside, 6-mercaptopurine, and 6-thioguanine) was determined in vitro using human B-lymphoblast (WI-L2) and promyelocytic leukemia (HL-60) cell lines. Hyp permitted growth of both cell lines in the presence of clinically achievable concentrations of all 4 drugs, but the initial culture concentrations of Hyp required were above those found in patients. Since Hyp was consumed rapidly during the culture period, the average Hyp concentrations required for the protection of cells were actually much lower. We conclude that, in patients with acute leukemia receiving allopurinol during chemotherapy, plasma Hyp concentrations are significantly elevated; the potential for antagonism of antimetabolite activity is uncertain.

Acute Disease↗
PubMed1983

Effect of allopurinol on the toxicity of high-dose 5-fluorouracil administered by intermittent bolus injection.

The effect of allopurinol pretreatment on the toxicity of 5-fluorouracil (5-FU) was examined in a clinical trial. Twenty-three patients were given bolus infusions of 5-FU every two weeks in doses that produced mild toxicity (0.8-1.9 g/m2). On alternate courses patients were pretreated with allopurinol either 300 mg two hours prior to and 10 hours after 5-FU, or 300 mg every 8 hours for 4 doses starting 24 hours before 5-FU. Seventeen and 20 pairs of courses were evaluable from the 2- and 24-hour pretreatment groups, respectively. Allopurinol did not produce a significant degree of protection against 5-FU-induced myelosuppression or mucositis on either dose schedule. Neurotoxicity manifesting as both cerebellar and encephalopathic signs and symptoms was the most important toxicity encountered and was dose-limiting for 5-FU on this schedule. Mean oxipurinol serum concentrations at the time of 5-FU administration were 24 microM and 104 microM for the 2- and 24-hour allopurinol pretreatment schedules respectively. Allopurinol increased the T 1/2 of 5-FU by a mean of 67% in three of the four patients studied. Pretreatment with allopurinol did not reduce the toxicity of 5-FU administered as an intravenous bolus.

Allopurinol↗
PubMed1983

Modulation of plasma cyst(e)ine by cisplatin.

Some types of human malignant cells are cyst(e)ine auxotrophs. In 8 cancer patients given 10 courses of treatment cisplatin caused a mean (+/- S.D.) 83 +/- 17% decrease in plasma cyst(e)ine when measured before and 6 hr after drug infusion. The magnitude of the decrease correlated with peak plasma cisplatin concentration, and serial measurements demonstrated that in some patients plasma cyst(e)ine was still decreasing at 6 hr. The mean 6-hr plasma cyst(e)ine was low enough (9 +/- 9 microM) to prevent the proliferation of human promyelocytic (HL-60) cells in culture.

Cell Division↗
PubMed1983

Clinical pharmacokinetics of intraarterial cisplatin in humans.

The pharmacokinetics of intraarterially administered cisplatin (DDP) were studied in three patients with large hepatic tumors, and one patient with a fibrous histiocytoma in the thigh, using an assay sensitive to only those forms of non-protein bound DDP capable of reacting with the nucleophilic ligand diethyldithiocarbamate. Each patient received continuous intravenous and intraarterial infusions at various dose rates, with and without concurrent infusion of the neutralizing agent sodium thiosulfate. Steady-state DDP concentrations were achieved within two hours, and the mean (+/- SEM) plasma clearance at infusion rates of 5-15 mg/m2 per hour was 345 +/- 45 mL/m2 per minute. Apparent plasma clearance did not vary significantly with route of infusion. Based on the plasma clearance, predicted values for the relative advantage of an intraarterial infusion (Rt) were less than two for hepatic infusion; observed values averaged 1.9 +/- 0.5 (+/- SEM). The infusion of thiosulfate did not significantly increase plasma clearance. The mean (+/- SEM) extraction ratio for hepatic infusions was 0.24 +/- 0.09, and for infusion of the peripheral soft tissue sarcoma it was 0.27 +/- 0.03. These data indicate that from the point of view of both the tumor and the systemic circulation there is only a limited pharmacologic advantage for intraarterial infusion of DDP into organs with plasma flows of greater than 350 mL/m2 per minute.

Adult↗
PubMed1983

Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection.

The toxicity and pharmacokinetics of cis-diamminedichloroplatinum (cisplatin) (90 mg/sq m) administered as a single 4-hr peritoneal dialysis, with or without concurrent i.v. infusion of sodium thiosulfate, 0.43 or 2.13 g/sq m/hr for 12 hr, were studied on 20 courses of treatment. When given without thiosulfate, the toxicity of cisplatin was systemic rather than local, and the peritoneal cavity/plasma ratio of the area under the curve was 12. Addition of i.v. thiosulfate significantly reduced the nephrotoxicity. The concentration of cisplatin in the peritoneal cavity was sufficiently greater than that in the plasma to prevent thiosulfate, which equilibrated into the cavity, from interfering with the antitumor activity of cisplatin in the peritoneum. This study demonstrates a pharmacokinetic advantage of i.p. chemotherapy with cisplatin.

Adult↗
PubMed1982

Intraperitoneal cisplatin with systemic thiosulfate protection.

Seventeen patients with intraperitoneal tumors were treated by 4-hour intraperitoneal dialysis with cisplatin alone, or in combination with an intravenous neutralizing agent, sodium thiosulfate. Cisplatin alone, 90 mg/m2 body surface area intraperitoneally, produced nephrotoxicity. When intraperitoneal cisplatin therapy was combined with intravenous thiosulfate treatment, the dose of cisplatin could be escalated to 270 mg/m2 body surface area without causing an increase in serum creatinine levels or undue myelosuppression. Even at doses up to 270 mg/m2, no local toxicity occurred. The peak peritoneal concentration of free reactive cisplatin averaged 21-fold higher than the plasma level, and the area under the peritoneal cisplatin elimination curve averaged 12-fold more than the area under the plasma curve. Neither of these ratios varied significantly with cisplatin dose. Regression of intraperitoneal tumor masses was observed in patients with far-advanced ovarian carcinoma, mesothelioma, and malignant carcinoid.

Adult↗
PubMed1981

Modulation of 5-fluorouracil toxicity by allopurinol in man.

Oxipurinol, the major metabolite of allopurinol, decreased the toxicity of 5-fluorouracil (5-FU) to human granulocyte colony-forming units in vitro by a factor of four. The ability of allopurinol to reduce 5-FU toxicity in vivo was studied in 23 advanced cancer patients during 42 courses of treatment. 5-FU was administered by continuous intravenous infusion for five days; allopurinol, 300 mg, po, every 8 hours was started 2 hours before and continued during and for 24 hours after 5-FU infusion. 5-FU was escalated from 1.5 to 2.25 g/m2/day on separate courses; the dose-limiting toxicity was mucositis which occurred at a level of 2.0 g/m2/day. At a 5-FU dose rate of greater than 2.0 g/m2/day 5-FU pharmacokinetics were nonlinear, reflecting saturation of catabolic pathways, and the steady-state 5-FU serum concentration was approximately 4 times that which was tolerable without allopurinol. At these concentrations of 5-FU oxipurinol significantly influenced the clearance of 5-FU. Thus concurrent allopurinol therapy permitted a doubling of the maximum tolerated dose of 5-FU and a four-fold increase in the tolerated concentration x time exposure to 5-FU.

Adenocarcinoma↗
PubMed1981

Long-duration intracavitary infusion of methotrexate with systemic leucovorin protection in patients with malignant effusions.

18 patients with malignant effusions were treated with continuous intraperitoneal, intrapleural, or intrapericardial infusion of methotrexate (MTX) 30 mg/m2 per d combined with simultaneous intravenous administration of leucovorin at a dose rate calculated to yield an equimolar concentration in the serum. In the serum the geometric mean steady-state MTX concentration was 0.95 microM, whereas it was 24 microM in the peritoneal, 213 microM in the pleural, and 434 microM in the pericardial cavities. Mean clearance was 6.6 ml/min from the peritoneal cavity, 2.6 ml/min from the pleural cavity, and 0.14 ml/min from the pericardial cavity. Leucovorin provided sufficient protection to allow the duration of infusion to be escalated from 24 to 120 h before myelosuppression was encountered. Marrow thymidylate synthetase activity was inhibited by an average of 46% compared to 86% inhibition in malignant cells in the effusions. Flow cytometric analysis showed no perturbation of the cell cycle phase distribution of marrow cells. All eight of the evaluable patients have responded: three received no other form of therapy, five also received systemic hormonal or chemotherapy. This study demonstrated that tumors confined to third space body fluids can be given very high concentration x time exposures to MTX with minimal systemic toxicity.

Drug Therapy, Combination↗
PubMed1980

Simultaneous liquid chromatography of 5-fluorouracil, uridine, hypoxanthine, xanthine, uric acid, allopurinol, and oxipurinol in plasma.

A reversed-phase "high-pressure" liquid-chromatographic method is described for simultaneous analysis for 5-fluorouracil, uridine, hypoxanthine, xanthine, uric acid, allopurinol, and oxipurinol. Separation was optimal with phosphate buffer (50 mmol/L, pH 4.60) as eluent. A simple acid extraction procedure yielded quantitative recoveries and permitted adequate separation for interfering peaks. Compounds were identified by their retention times, absorbance ratios, co-elution with standards, and enzymatic shifts. With a computerized integrator we quantitated these compounds in widely varying concentrations with a single injection. The limit of sensitivity was 0.1 mumol/L for the compounds studied. This method was applied to determine mean values for those compounds in normal human plasma. They are (in mumol/L): uric acid 276 (SD 55), hypoxanthine 0.46 (SD 0.21), xanthine 0.40 (SD 0.27), and uridine 4.50 (SD 1.70). Erythrocytes and platelets can continue to release hypoxanthine and xanthine into plasma or serum after a blood specimen has been drawn. We believe this explains the higher values previously reported for hypoxanthine and xanthine in serum.

Allopurinol↗
PubMed1979

The specificity of antimorphine and antimeperidine antibodies and their reactivity with opioid peptides.

The specificity of antimorphine and antimeperidine antisera was measured by competitive displacement of immunizing radiolabeled haptens. Antimorphine antisera demonstrated a high degree of specificity for a conformation of the phenylpiperidine moiety contained within the structures of morphine and its congeners of the morphinan and benzomorphan series. Antimeperidine antisera demonstrated a high degree of specificity for a different conformation of the phenylpiperidine moiety represented within the structures of meperidine and its semisynthetic derivatives. The reactivity of methionine- and leucine-enkephalin, several synthetic enkephalin analogs, and alpha- and beta-endorphin with the antibodies was tested using purified immunoglobulin G in order to avoid serum-induced proteolysis. No significant cross-reactivity of antimorphine antibodies with any of the opioid peptides was detected. All of the opioid peptides tested exhibited weak but immunologically specific cross-reactivity with antimeperidine antibodies. These findings suggest that conformations analogous to the phenylpiperidine moiety in morphine as have been proposed for [Tyr1] in opioid peptides do not appear to be present as measured by immunochemical methods. A conformation with weak stereochemical similarity to the phenylpeperidine moiety in meperidine does appear to be present. The possible homologies between [Phe4] of opioid peptides, meperidine and hydrophobic side chains of certain oripavine derivatives are discussed.

Antibody Specificity↗
PubMed1976

The production and characterization of antibodies reactive with meperidine.

Meperidinic acid was converted to O-meperidinyl-glycollic acid and covalently attached to bovine serum albumin. Rabbits injected with this conjugate produced antibodies reactive with meperidine which were measured by the ammonium sulfate method. The specificities of these antisera were studied by competitive inhibition of the binding of 100 pmol/ml of 3H-meperidine to antibody by the prior addition of increasing concentrations of various unlabeled compounds. The concentrations in nanomoles per milliliter of various unlabeled opiods required to inhibit 3H-meperidine binding by 50% (I50) were: meperidine, 0.08; O-meperidinyl-glycollic acid, 1.7; methadone, 580; heroin, 1750; codeine, 2600; and morphine, 4200. Several psychopharmacologically active compounds were found to have I50 values comparable to the nonmeperidine opioids: hydroxyzine. HCl, 460; propoxyphene, 4,500; diazepam, 6,500; and cocaine, 10,800. The metabolites of meperidine exhibited the following I50 values: normeperidine, 0.7; meperidinic acid and normeperidinic acid, 210. A radioimmunoassay for meperidine which employs this antiserum was shown to be approximately 100 times more sensitive than the spectrophotometric method of Burns et al. (J. Pharmacol. Exp Ther. 114: 289-293, 1955). In this assay only normeperidine and some of the meperidine congeners might be expected to interfere with the measurement of meperidine. The degree of normeperidine interference was shown to be comparable to that present in the existing assay method.

Animals↗
PubMed1976

The production and characterization of antibodies reactive with meperidine.

Meperidinic acid was converted to O-meperidinyl-glycollic acid and covalently attached to bovine serum albumin. Rabbits injected with this conjugate produced antibodies reactive with meperidine which were measured by the ammonium sulfate method. The specificities of these antisera were studied by competitive inhibition of the binding of 100 pmol/ml of 3H-meperidine to antibody by the prior addition of increasing concentrations of various unlabeled compounds. The concentrations in nanomoles per milliliter of various unlabeled opiods required to inhibit 3H-meperidine binding by 50% (I50) were: meperidine, 0.08; O-meperidinyl-glycollic acid, 1.7; methadone, 580; heroin, 1750; codeine, 2600; and morphine, 4200. Several psychopharmacologically active compounds were found to have I50 values comparable to the nonmeperidine opioids: hydroxyzine-HC1, 460; propoxyphene, 4,500; diazepam, 6,500; and cocaine, 10,800. The metabolites of meperidine exhibited the following I50 values: normeperidine, 0.7; meperidinic acid and normeperidinic acid, 210. A radioimmunoassay for meperidine which employs this antiserum was shown to be approximately 100 times more sensitive than the spectrophotometric method of Burns et al. (J. Pharmacol. Exp. Ther. 114:289-293, 1955). In this assay only normeperidine and some of the meperidine congeners might be expected to interfere with the measurement of meperidine. The degree of normeperidine interference was shown to be comparable to that present in the existing assay method.

Animals↗