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Biomedical subjects

D H Ho

Publications and source records attributed to D H Ho.

At least 73 records · Page 4Linked to original sources
PubMed1985

Radioimmunoassay for etoposide and teniposide.

A radioimmunoassay for VP-16 or VM-26 was developed by using tritiated ligand and antisera produced from rabbits immunized with succinyl-VP-16 bovine serum albumin conjugates. Separate determinations of VP-16 and its hydroxy acid, a metabolite which cross-reacted with the VP-16 antisera, could be accomplished by extracting samples with chloroform in which the metabolite was insoluble. The assay was reproducible and sensitive. Extracted standard curves were linear from 0.025 to 5 micrograms for VP-16 and 0.1 to 10 micrograms for the hydroxy acid per 0.5 ml assay mixture. Fifty percent inhibition of binding was achieved at 0.066 and 0.55 microgram for VP-16 or VM-26 and the metabolite, respectively. Preliminary disposition studies in mice and dog, and human urinary excretion support the application of the assay in pharmacologic studies.

Animals↗
PubMed1985

Clinical pharmacology of timentin (ticarcillin and clavulanic acid).

Ticarcillin (4 gm) and clavulanic acid (0.1 gm) were simultaneously administered as timentin to patients with cancer as therapy for infections. The pharmacokinetics of both ticarcillin and clavulanic acid were studied in 15 patients after 30-minute and 2-hour intravenous infusions. The mean (+/- SD) ticarcillin plasma peak concentrations after the two infusions were 341 +/- 76 and 210 +/- 60 micrograms/ml. The plasma terminal t1/2 values of ticarcillin were 80 +/- 32 and 56 +/- 12 minutes. The AUCs were 631 +/- 189 and 601 +/- 230 mg/L X hr. The volumes of distribution of the area were 15 +/- 5 and 21 +/- 7 L and total clearances were 115 +/- 36 and 127 +/- 54 ml/min. The corresponding values for clavulanic acid after the infusions are as follows: mean peak concentrations, 5 +/- 1 and 4 +/- 1 micrograms/ml; plasma terminal t1/2 values, 84 +/- 24 and 74 +/- 36 minutes; AUCs, 11 +/- 3 and 11 +/- 6 mg/L X hr; volumes of distribution of the area, 22 +/- 3 and 32 +/- 6 L; and total clearances, 170 +/- 58 and 175 +/- 68 ml/min.

Adult↗
PubMed1985

In vitro studies of BMY-28142, a new broad-spectrum cephalosporin.

BMY-28142 was compared with other broad-spectrum antibiotics against gram-positive cocci and gram-negative bacilli. BMY-28142 was highly active against all gram-negative bacilli and especially against Enterobacter cloacae, Serratia marcescens, and Morganella morganii. Its in vitro activity suggests that BMY-28142 should prove to be useful for the treatment of gram-negative bacillary infections.

Anti-Bacterial Agents↗
PubMed1984

Central nervous system pharmacology of Baker's antifolate (NSC139105) in man.

Radiolabelled Baker's Antifolate (BAF) was administered to 6 patients undergoing surgical resection of intracerebral tumors. Levels of radioactivity in resected tumor and edematous brain adjacent to tumor were generally higher than levels in concurrent plasma samples and were generally comparable to levels in temporalis muscle. Levels in tumor cyst fluid were far lower than concurrent plasma levels and levels in surrounding tumor. Chromatography was performed on tumor from 2 patients and revealed that only a small proportion of the radioactivity represented unchanged BAF. The major metabolite present in tissues was 1 000 times less potent as an inhibitor of dihydrofolate reductase than was BAF. Five patients had cerebrospinal fluid (CSF) sampled following administration of tracer doses of radiolabelled BAF. Radioactivity levels were far lower in CSF than in plasma. Levels of radioactivity in the CSF were also far lower than levels in tumor and brain samples from other patients and were slightly lower than tumor cyst fluid levels. Two patients had CSF collected after they received therapeutic doses of BAF. In these patients, both CSF and plasma were assayed using a dihydrofolate reductase inhibition assay. As with tracer dose studies, CSF concentrations of BAF were substantially lower than were concurrent plasma concentrations. Thus it appears that only very low concentrations of BAF are attainable in human CSF and intracerebral tumor, although a metabolite which is a very weak inhibitor of dihydrofolate reductase attains high concentrations in tumor.

Antineoplastic Agents↗
PubMed1984

In vitro activity of WIN 49375 compared with those of other antibiotics in isolates from cancer patients.

The activity of WIN 49375 [6-fluoro-1, 4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid], a new synthetic quinolone, was tested in vitro against 587 clinical isolates. The MICs for 90% of isolates of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae were 0.20, 1.56, and 0.39 microgram/ml, respectively. The MICs for 90% of isolates of Pseudomonas aeruginosa and Serratia marcescens were both 3.12 micrograms/ml. WIN 49375 was minimally active against gram-positive cocci. Its in vitro activity suggests that it may be useful for the treatment of gram-negative bacillary infections.

Anti-Bacterial Agents↗
PubMed1984

Clinical pharmacokinetics of aztreonam in cancer patients.

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.

Adolescent↗
PubMed1983

Effects of hepatic function on vancomycin clinical pharmacology.

Using a recently developed radioimmunoassay, we performed 15 vancomycin pharmacology studies in cancer patients with infections. Vancomycin (500 mg) was infused intravenously for 30 min every 6 h for up to 7 days. The plasma disappearance curve was biphasic, with an initial half-life of less than 30 min. The second half-life (t1/2 beta), not dose related, varied from 1.4 to 231 h among the patients. In six studies of patients with normal hepatic functions, the t1/2 beta was 2.6 h; the rate of total clearance was 162 ml/min. In contrast, nine studies of patients with impaired liver function had a much longer t1/2 beta (37 h) and a decrease in the rate of total clearance to 48 ml/min. These factors resulted in an increase in the value of area under the concentration-time curve from 59 to 3,434 micrograms X h/ml. These results have demonstrated the importance of the effects of liver function on vancomycin disposition. The vancomycin dose and schedule should be adjusted for patients with liver impairment.

Adult↗
PubMed1982

Clinical pharmacology of bruceantin by radioimmunoassay.

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

Antineoplastic Agents, Phytogenic↗
PubMed1982

Effect of malnutrition on methotrexate toxicity and tissue levels of dihydrofolate reductase in the rat.

The effect of malnutrition on the toxicity of methotrexate (MTX) and the dihydrofolate reductase (DHFR) content of the liver, small intestinal mucosa, kidney, and bone marrow of male Sprague-Dawley rats was studied. Malnutrition was induced by reducing the daily intake of chow to one third for 14 days. A single ip treatment with MTX was lethal to three of nine rats at a dose of 37.5 mg/kg and to three of five rats at a dose of 50.0 mg/kg but caused only transient weight loss to similarly treated full-fed, age-matched controls. Although the body weights and absolute tissue weights were reduced in malnourished rats, only the liver and small intestinal mucosa were smaller relative to their respective body weights. The cellular DHFR content of liver and bone marrow from malnourished rats was lower than that from the controls, although in terms of the content per gram of tissue, there was no significant change. While the total DHFR in malnourished rat tissues was significantly lower than that for the controls, only the total-liver DHFR was lower relative to the body weight. The increased toxicity of MTX to malnourished rats may be related to the DHFR levels in the liver and bone marrow.

Animals↗
PubMed1981

Sensitive radioimmunoassay for vancomycin.

A radioimmunoassay for vancomycin has been developed which uses rabbit antiserum induced by vancomycin-bovine serum albumin conjugates and vancomycin labeled with 3H or 125I. Using either isotope, the method is simple and reproducible and has a sensitivity of 4 or 0.04 ng/ml, depending on the tracer used. This is 200- to 20,000-fold improvement in sensitivity compared with the most sensitive bioassay. Drug levels in serum or urine samples from patients receiving vancomycin can be determined by this assay procedure without processing. The data obtained with 3H and 125I labels were in good agreement. Patients' plasma vancomycin concentrations determined by radioimmunoassay correlated well with those determined by bioassay when the drug was administered intravenously. However, after oral administration the drug could be detected only by radioimmunoassay. The antiserum was evaluated for cross-reactivity with a wide variety of antibiotics and cancer chemotherapeutic agents, and no significant interference was found.

Animals↗
PubMed1981

Clinical pharmacology of moxalactam in patients with malignant disease.

Pharmacological studies of moxalactam were conducted with 37 cancer patients. Intramuscular administration of 500 mg of moxalactam to 10 patients produced a mean peak serum concentration of 12.4 micrograms/ml. The serum terminal-phase half-life was 3.9 h. Intravenous administration of 500 mg of moxalactam over 5 min to the same 10 patients produced a mean serum concentration of 42.0 micrograms/ml at 15 min, which decreased to 3.3 micrograms/ml at 6 h. A dose of 1 g of moxalactam was given in an identical manner to the same 10 patients. The mean serum concentration was 69.7 micrograms/ml at 15 min and 7.4 micrograms/ml at 6 h. The mean proportions of a drug recovered in the urine by 12 h after administration were 59% after the intramuscular dose and 61 and 55% after the single intravenous doses. Multiple-dose intravenous studies were also conducted. The serum terminal-phase half-life varied from 2.0 to 3.2 h. Continuous infusion studies were performed by up to 9 days by using a loading dose of 1 g over 0.5 h, followed by 2 g every 6 h. Serum concentrations were maintained at about 30.0 micrograms/ml during the study period.

Adult↗
PubMed1981

Pharmacokinetics of cefoperazone in patients with neoplastic disease.

The pharmacokinetics of cefoperazone, a new semisynthetic cephalosporin, were studied in 34 patients with neoplastic disease. This compound was administered in a variety of doses and schedules without observable toxicity in any patient. The mean peak serum concentration after a 15-min intravenous infusion of 2 g was 264 microgram/ml after the first dose; the serum half-life was 2.1 h. There was no significant change in half-life or serum concentrations after 4 or 7 days of therapy. The mean peak serum concentration after infusion of 1 g over 15 min was 133 microgram/ml, with a mean of 10.7 microgram/ml at 6 h. The serum half-life was 2 h. The mean peak serum concentration after infusion of 1 g over 0.5 h was 101 microgram/ml. When 8 g was subsequently administered daily by a continuous infusion schedule, levels were maintained at 80 microgram/ml. When the dose was increased to 16 g daily, serum concentrations were maintained at an average of 153 microgram/ml. Only 37% of cefoperazone was recovered in the urine in a 12-h period after the initial dose, suggesting the importance of other mechanisms of excretion; however, serum concentrations in one patient with renal insufficiency were significantly higher than serum concentrations in patients with normal renal function.

Adolescent↗
PubMed1981

Comparison of vancomycin disposition in rats with normal and abnormal renal functions.

Vancomycin levels in the tissues and urine of rats with renal damage were compared with those of control rats. Renal damage was induced by a single intravenous injection of uranyl nitrate. After 5 days, when the plasma urea nitrogen levels had increased 7- to 22-fold, a single intraperitoneal vancomycin injection of 10 mg/kg yielded significantly higher plasma and tissue levels in these rats than in the control rats that did not receive uranyl nitrate. At 73 h after the vancomycin injection, the plasma vancomycin concentration in the rats with renal damage was 1.8 +/- 1.1 microgram/ml (mean +/- standard deviation), whereas in control rats the level had fallen to 0.004 +/- 0.002 microgram/ml. Control rats excreted 50.5% of a single dose in the urine within the 3 days, whereas rats with renal damage excreted only 35.6%. These results indicate that vancomycin pharmacokinetics is affected by renal function in rats. Therefore, the drug should be used very cautiously in patients with impaired renal function. The serum levels must be monitored, and the frequency and size of doses may have to be reduced.

Acute Kidney Injury↗
PubMed1981

A radioimmunoassay for 5-methyltetrahydrohomofolate.

A radioimmunoassay for 5-methyltetrahydrohomofolate has been developed by using antibody induced in rabbits by 5-methyltetrahydrohomofolate-bovine serum albumin conjugates. The labeled drug was prepared by condensing it with [3H]histamine or [125I]histamine. The assay employing either isotope was simple and reproducible and had identical sensitivities. The specificity of the antibody was characterized by comparing the effectiveness of various related compounds in displacing labeled 5-methyltetrahydrohomofolate from the binding site of the antisera. At concentrations up to 1000 microgram/ml, homofolate acid, tetrahydrohomofolic acid, folic acid and methotrexate showed no competition for the binding. 5-methyltetrahydrofolic acid and 5-formyltetrahydrofolic acid cross-reacted with the antisera; the concentrations producing 50% binding inhibition were 2.8 and 24 microgram, respectively, as compared to 0.01 microgram for 5-methyltetrahydrohomofolate. The assay can be used for measuring the drug in plasma and tissues. This study supports its usability for clinical pharmacologic studies.

Animals↗
PubMed1981

Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-beta-D-arabinofuranosylcytosine.

cis-Dichlorodiammineplatinum(II) and 1-beta-D-arabinofuranosylcytosine display a dramatic synergistic effect when tested in simultaneous combination on LoVo cells, a human colon carcinoma cell line. 1-beta-D-Arabinofuranosylcytosine alone does not induce any cytotoxicity on LoVo cells even at high concentrations but is able to increase up to 1000 times the lethal effects of cis-dichlorodiammineplatinum(II). DNA elution experiments show that 1-beta-D-arabinofuranosylcytosine increases the amount of cis-dichlorodiammineplatinum(II)-induced DNA cross-links. The possible mechanisms of this effect are discussed, and some explanations are proposed.

Carcinoma↗
PubMed1981

Ceforanide kinetics.

Pharmacologic studies of the semisynthetic cephalosporin ceforanide were conducted in 29 cancer patients. Intravenous doses of 500 mg over 30 min every 6 hr to 10 patients induced mean peak serum concentrations between 44.7 and 51.5 micrograms/ml, while in 10 patients receiving 1 gm over 30 min every 12 hr mean peak serum concentrations varied from 73.4 to 91.8 micrograms/ml. Twelve hours after 1 gm of drug, mean serum concentrations varied between 5.6 and 6.5 micrograms/ml. After a 500-mg loading dose, continuous infusion of 500 mg every 4 hr, 10 patients maintained serum concentrations above 34.2 micrograms/ml for 7 or 8 days. Most of the drug was excreted in the urine in the initial 6 hr after administration and mean urinary concentration of 1,315 micrograms/ml were obtained during this time. Serum half-life ranged between 2.2 and 2.9 hr on all schedules and therefore wa longer than that of other cephalosporins. No serious toxicity was noted. The relatively broad spectrum of activity in addition to the long half-life suggests clinical utility for this drug.

Adolescent↗
PubMed1980

Treatment of cultured human colon carcinoma cells with fluorinated pyrimidines.

The shape of the initial part of the dose-dependent response curve of LoVo cells, an established human colon carcinoma cell line, exposed for 1 hr to graded concentrations of 5-FU depended on the medium supplement, i.e., fetal calf serum (FCS), in which the cells were treated and subsequently incubated for colony-formation. At concentrations of 50--100 micrograms/ml (equivalent to peak plasma levels following an in vivo bolus dose of 15 mg/kg) cell kill was completely prevented by FCS. The serum did not contain thymidine (TdR) but had significant amounts of uridine (UR). When 5-FU was delivered in dialyzed FCS, concentrations of 50--100 micrograms/ml achieved only a modest 15% cell kill after 1 hour treatment. Regardless of medium supplement, the killing effect of 5-FU did not increase beyond concentrations greater than 2,000 micrograms/ml. Increasing the exposure interval dramatically increased the killing of LoVo cells by 5-FU, although the effects of medium supplement on the degree of cell survival persisted for about 12 hours. Virtually all of the incorporated 5-FU was transformed into 5-FUR, and a very small proportion eventually was incorporated into nucleic acids, suggesting that the killing effect of 5-FU on LoVo cells is mediated mostly by ribosidation and not by conversion into the deoxyribonucleoside. This conclusion is supported by the failure of 5-FUdR to kill LoVo cells after a treatment interval of one hour, even at concentrations of 5000 micrograms/ml; yet after the same exposure interval, 5-FUR effectively killed cells at concentrations of 50--100 micrograms/ml. TdR afforded no protection from cell kill by 5-FU. In contrast, UR was capable of protecting LoVo cells from the lethal effects of both 5-FU and 5-FUR even at concentrations as low as 10 micrograms/ml. Ftorafur exposed to LoVo cells for 1 hour had a slight killing effect (about 20--25%) at concentrations ranging up to 2000 micrograms/ml. Although the lethal effect of ftorafur was slightly increased after longer periods of incubation, it failed to reach 90% even after intervals of 48 hours. The results on cellular sensitivity that we obtained for LoVo cells treated with various fluorinated pyrimidines differ substantially from those of other investigators who used different methods to assess cell killing on nonhuman and noncolonic cell systems. The predictive relevance of these data as compared to those obtained in other systems is justified by the suboptimal results with these agents in clinical practice.

Cell Line↗