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Biomedical subjects

M N Chang

Publications and source records attributed to M N Chang.

At least 37 records · Page 2Linked to original sources
PubMed1989

Confidence intervals for a normal mean following a group sequential test.

This paper presents methodology based on the likelihood-ratio test, developed for construction of confidence intervals for a normal mean, following a group sequential test. Examples show that the confidence intervals produced by this method have accurate nominal probability of coverage and have generally shorter average length than that produced by Tsiatis, Rosner, and Mehta (1984, Biometrics 40, 797-803).

Clinical Trials as Topic↗
PubMed1987

L-652,469--a dual receptor antagonist of platelet activating factor and dihydropyridines from Tussilago farfara L.

L-652,469, 14-acetoxy-7 beta-(3'-ethylcrotonoyloxy)-notonipetranone, isolated from the methylene chloride extracts of the buds of Tussilago farfara L, was found to inhibit both platelet activating factor (PAF) and Ca2+ entry blocker binding to membrane vesicles. It inhibits the [3H]PAF specific binding to rabbit platelet membranes with equilibrium inhibition constants (Ki) of 3.2 and 4.0 microM in the presence of 150 mM NaCl and 10 mM MgCl2 respectively. It is a competitive PAF receptor antagonist with an equilibrium dissociation constant (KB) of 5.16 microM. It also competitively inhibits the specific binding of Ca2+ channel blockers (e.g. [3H]nitrendipine; Ki = 1.2 microM) in cardiac sarcolemmal vesicles. At 10(-5) M, L-652,469 causes a 60% relaxation of Ca2+-induced contraction of rat thoracic aorta strips. Due to its dual antagonistic activities, L-652,469 potently inhibits the gel-filtered rabbit platelet aggregation with a pA2 of 5.79. It was also found to be orally active with a beneficial effect to inhibit the PAF-induced rat foot edema and the first phase of carrageenan-induced rat hindpaw edema.

Animals↗
PubMed1987

Three consecutive phase II studies of recombinant interferon alfa-2a in advanced malignant melanoma. Updated analyses.

In three consecutive Phase II trials of recombinant interferon alfa-2a (rIFN alfa-2a; Roferon-A Hoffmann-La Roche, Nutley, NJ) involving 96 patients with advanced malignant melanoma, an overall response rate of 22% was observed. For all study participants, the median time to disease progression was 1.7 months, and the median survival was six months. Most regressions occurred within one month of commencing therapy, were usually limited to soft tissue metastases, and were transient. However, responses in three patients were long term, lasting 32+, 36+, and 41+ months. A thrice weekly intramuscular dose of 50 x 10(6) U/m2 produced an intolerable flulike illness concomitant with a median weight loss of 5.6 kg. The addition of cimetidine to the same dose in 35 patients was of no therapeutic value. A dose of 12 x 10(6) U/m2 produced clinically acceptable toxicities, and a median weight loss of 2.1 kg. There was no apparent dose response relationship, nor were there any obvious sequelae from antibody formation to interferon alfa-2a. As single agent therapy in malignant melanoma, interferon alfa-2a was only marginally useful in most patients. Nevertheless, combination regimens of this agent with cytotoxic agents, alternative molecular species of interferon, and lymphokines, notably tumor necrosis factor, offer a conceptually intriguing dimension in the design of future clinical trials.

Adjuvants, Immunologic↗
PubMed1987

Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699.

A beta-lactone isolated from Fusarium sp. has been shown to be a potent specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase [(S)-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase (CoA-acetylating), EC, 4.1.3.5] from rat liver. The structure of this beta-lactone, termed L-659,699, is (E,E)-11-[3-(hydroxy-methyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2,4 - undecadienenoic acid. A partially purified preparation of cytoplasmic HMG-CoA synthase from rat liver was inhibited by L-659,699 with an IC50 of 0.12 microM. The enzyme HMG-CoA reductase, beta-ketoacyl-CoA thiolase, acetoacetyl-CoA synthetase, and fatty acid synthase were not inhibited to any extent by this compound. In cultured Hep G2 cells, the compound inhibited the incorporation of [14C]acetate into sterols with an IC50 of 6 microM, while incorporation of [3H]mevalonate into sterols in these cells was not affected. The activity of HMG-CoA reductase in the cultured Hep G2 cells was induced in a dose-dependent manner by incubation with L-659,699. A 37-fold increase in reductase was observed after a 24-hr incubation with 62 microM L-659,699. The effect of a number of analogs of L-659,699 on HMG-CoA synthase is also discussed.

Animals↗
PubMed1987

Phase II study of recombinant interferon-gamma in patients with disseminated malignant melanoma.

Twenty-eight patients with disseminated malignant melanoma received daily im therapy with recombinant interferon-gamma. The dose was 0.25 mg/m2 on Days 1-7 followed by a daily dose of 0.5 mg/m2 if tolerated. Among 27 patients, we observed three objective partial regressions (8.3, 3.7, and 3.9+ months). The median leukocyte count nadir was 2.5 X 10(3)/mm3 (range, 1.4-5.1). Constitutional symptoms included moderate to severe fever greater than 37 degrees C (100%), fatigue (59%), chills (37%), and mild to moderate myalgias (64%). Recombinant interferon-gamma produces manageable side effects but limited efficacy as employed in this study.

Adult↗
PubMed1987

Designs for group sequential phase II clinical trials.

The main goal of Phase II cancer clinical trials is to identify the therapeutic efficacy of new treatments. For ethical reasons, group sequential procedures, which allow for early stopping when a treatment is either extremely effective or extremely ineffective, have been widely employed in these trials. Although several useful design methods have been discussed in the literature (Fleming, 1982, Biometrics 38, 143-152; Lee, 1979, Cancer Treatment Reports 63, No. 11-12), we are unaware of any results addressing the problem of finding an optimal rule easily by computer. In this paper, using an idea based on the Neyman-Pearson lemma, we propose a method to search over a restricted set of designs and to select the optimal one in this set according to optimality criteria. In all the combinations we have investigated (more than 100) the optimal design produced by our method is the true global optimum. Other applications are discussed.

Antineoplastic Agents↗
PubMed1986

Specific binding of [3H]dihydrokadsurenone to rabbit platelet membranes and its inhibition by the receptor agonists and antagonists of platelet-activating factor.

Kadsurenone inhibits specifically and competitively the specific binding of 3H-labeled platelet-activating factor ([3H]PAF) to rabbit platelet membranes. Since the 5-propyl analog of kadsurenone (dihydrokadsurenone) retains roughly the same potency as kadsurenone, [3H]dihydrokadsurenone was therefore synthesized through tritiation of kadsurenone. Specific binding of [3H]dihydrokadsurenone in rabbit platelet membranes is saturable. Scatchard analysis of binding data reveals the presence of a single class of binding sites with an equilibrium dissociation constant (KD) of 16.81 ( +/- 0.57) nM. The total number (Bmax) of detectable binding sites is 2.27 ( +/- 0.09) pmol/mg protein. Both C16- and C18-PAF fully displace the specific binding of (3H]dihydrokadsurenone (5 nM) with an identical ED50 of 3.6 X 10(-9) M. Dihydrokadsurenone and kadsurenone also displace the specific binding with roughly the same potency (ED50 = 4.4 X 10(-8) M). Several other PAF analogs and PAF receptor antagonists tested show relative potencies roughly similar to those found in the [3H]PAF-specific binding assay. Other pharmacological agents with no PAF antagonistic activities did not inhibit the specific binding of [3H]dihydrokadsurenone. These results agree with our previous conclusion that kadsurenone is a specific and competitive receptor antagonist and strongly suggest that PAF and the PAF receptor antagonists tested may interact at a common binding site in the PAF receptor.

Animals↗
PubMed1986

Confidence intervals following group sequential tests.

A procedure is proposed for obtaining confidence intervals for the probability of response following completion of a group sequential phase II trial. Numerical examples showed that, by ordering the sample space using the likelihood principle, we are able to shorten the length of the intervals and to obtain more accurate coverage of probability relative to previously proposed methods. The method may also be used for interval estimation following phase III trials.

Clinical Trials as Topic↗
PubMed1986

Evaluation of bisantrene administered by 72-hour infusion in women with metastatic breast cancer.

Bisantrene was administered by 72-h continuous infusion at a dosage level of 240 mg/m2 to 17 patients with metastatic breast cancer who had received only one prior chemotherapy regimen and no prior doxorubicin. Three patients (18%) achieved partial regressions lasting 51, 106, and 213 days. For all patients, the median time to disease progression was 83 days and median survival was 280 days. Eleven patients received doxorubicin after removal from protocol and were evaluable for response, and four (36%) achieved a partial regression. We conclude that bisantrene administered by the method we employed is not associated with substantial clinical benefit in this population of patients.

Adult↗
PubMed1986

Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of bilateral oophorectomy with that of tamoxifen at a dose of 10 mg twice daily in premenopausal women with metastatic breast cancer, and to examine the efficacy of each as a crossover treatment. Initial treatment responses were seen in ten of 27 patients (37%) treated with oophorectomy and seven of 26 patients (27%) treated with tamoxifen. The difference was not statistically significant. Crossover responses were seen in five of 15 patients (33%) treated with oophorectomy, including three responses in ten prior tamoxifen nonresponders; and two of 18 patients (11%) treated with tamoxifen. Time to progression distributions were not significantly different during initial treatment, and no significant differences in survival were noted. Thus, there was no overall disadvantage to the use of tamoxifen as opposed to oophorectomy as initial hormonal therapy, and a failure to respond to tamoxifen did not preclude a response to subsequent oophorectomy. Exploratory data analysis within subsets indicated consistent differential treatment effects in the visceral dominant patients. Of the 16 such patients treated with oophorectomy, eight (50%) experienced objective responses but there were no responses in the 14 patients treated with tamoxifen. In the nine visceral dominant crossover patients who had not responded to initial tamoxifen, three (33%) subsequently responded to oophorectomy. Time to progression distributions within the visceral dominant subset appeared to be better for the patients treated initially with oophorectomy. However, one must be very cautious in drawing conclusions from exploratory subset analyses, especially with the small sample size. Further studies would be required to test any hypothesis of differential organ site responsiveness.

Adult↗
PubMed1986

Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of tamoxifen (TAM) alone with that of TAM plus aminoglutethimide (AG) and hydrocortisone (HC). Patients failing TAM could receive AG and HC. Objective responses to therapy were seen in 21 of 49 TAM patients (43%) and 25 of 51 TAM, AG and HC patients (49%). Time to disease progression and survival distributions were not significantly different between the treatment arms. Toxicity was greater for patients treated with TAM, AG, and HC and the trial was discontinued early for this reason. Twenty-four patients received AG and HC after TAM therapy and three (12%) achieved a response. We conclude that the combination of TAM, AG, and HC is not recommended over TAM alone because toxicity appears to outweigh any potential therapeutic advantage.

Adult↗
PubMed1986

Phase II trials of recombinant leukocyte A interferon in disseminated malignant melanoma: results in 96 patients.

Ninety-six patients with advanced malignant melanoma received thrice weekly im recombinant leukocyte A interferon (Roferon-A) in three consecutive phase II trials utilizing doses of 12 X 10(6) U/m2, 50 X 10(6) U/m2, and 50 X 10(6) U/m2 plus cimetidine. The overall response rate was 22%, with median times to disease progression and survival of 3.9 and 11.3 months, respectively. For all study participants, the median times to disease progression and survival were 1.5 and 5 months, respectively. Most regressions occurred within the first month of treatment and were predominantly in soft tissue, although three patients are responding 2-3 years after onset of treatment. The most noteworthy toxic effects included a flu-type illness, anorexia, and fever (38.3-39.4 degrees C). The median weight loss was 2.1 kg on the low-dose regimen and 5.6 kg on the high-dose program. Recombinant leukocyte A interferon in the dosages and schedule that we used has definite but limited efficacy for patients with disseminated malignant melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone.

Evidence from three types of experiments indicates that platelet activating factor (PAF)1 is an important mediator of endotoxin-induced hypotension in rats. a) Endotoxin infusion stimulates the time-dependent appearance of PAF in the blood. b) PAF infusion results immediately (less than 30 sec) in hypotension while endotoxin-induced hypotension takes 3-5 min to occur, allowing time for PAF production. c) Infusion of the specific PAF-receptor antagonist kadsurenone (2.2 mumole/kg bolus, 0.9 mumoles/min/kg continuous infusion), which inhibits PAF-induced hypotension by 67%, causes a 67% reversal of endotoxin-elicited hypotension. An additional finding of this study is that rats respond hypotensively to each of a series of low-dose PAF infusions but only to the first low-dose endotoxin infusion. These endotoxin-refractory rats do respond to subsequent PAF infusions.

Animals↗