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Biomedical subjects

K K Chan

Publications and source records attributed to K K Chan.

At least 181 records · Page 10Linked to original sources
PubMed1985

Bioequivalence of carbamazepine chewable and conventional tablets: single-dose and steady-state studies.

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 X 200-mg conventional tablets (CT), 4 X 100-mg chewable tablets swallowed whole (SW), and 4 X 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 X 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Kinetics of phosphoramide mustard hydrolysis in aqueous solution.

Hydrolysis of phosphoramide mustard was investigated using HPLC, 31P NMR, and GC-MS with specific deuterium labels. The hydrolysis of phosphoramide mustard in sodium phosphate buffers was found to follow apparent first-order kinetics. The rate of hydrolysis was temperature and pH dependent, being slower under acidic conditions. The hydrolysis was not catalyzed by hydroxyl ion, and its pH dependence appeared to be the result of a change in the mechanism of hydrolysis at different pH values. At a pH value approximately above the pKa of the phosphoramide mustard nitrogen, the major hydrolytic pathway of phosphoramide mustard was via the formation of the aziridinium ion, followed by nucleophilic attack. At pH values below its pKa, cleavage of the P-N bond predominated. At pH 7.4, the formation of an aziridinium ion was followed by a rapid hydrolysis to yield the monohydroxy and, subsequently, the dihydroxy products. The hydrolysis at this pH was adequately described by consecutive first-order kinetics. Seven species in the hydrolytic mixture have been identified as intact phosphoramide mustard, N-(2-chloroethyl)-N-(2-hydroxyethyl)phosphorodiamidic acid, N,N-bis-(2-hydroxyethyl)phosphorodiamidic acid, phosphoramidic acid, phosphoric acid, N,N-bis-(2-chloroethyl)amine, and N-(2-chloroethyl)-N-(2-hydroxyethyl)amine by GC-MS with the aid of deuterium labels. Phosphoramide mustard was found to be stabilized by chloride ion. The stabilization was linearly related to the chloride ion concentration, and the mechanism was found to be via the formation of phosphoramide mustard from the aziridinium and chloride ions. Phosphoramide mustard was significantly more stable in human plasma and in 5% human serum albumin as compared to aqueous buffers, an observation that may be important in vivo.

Bromides↗
PubMed1985

High-dose intravenous metoclopramide and intermittent intramuscular prochlorperazine and diazepam in the management of emesis induced by cis-dichlorodiammineplatinum.

Intravenous metoclopramide and IM prochlorperazine and diazepam were compared in the management of vomiting occurring during treatment with cis-dichlorodiammineplatinum (cis-platinum). A total of 104 cycles in 30 patients were evaluated. Twenty-two patients took part in a cross-over study in which emetic profiles for each patient managed with each anti-emetic schedule were compared. In all, 44 cycles of treatment in 22 patients were evaluated as part of a cross-over study. No significant difference in emetic control was observed between the two anti-emetic regimens. The side-effects observed using IV metoclopramide included extrapyramidal phenomena (19%) and flushing attacks (16%).

Antiemetics↗
PubMed1985

Inhibition of proliferation without affecting the generation of cytotoxicity in the human mixed lymphocyte reaction.

Phosphoramide mustard (PM) is considered to be the major tumoricidal metabolite of cyclophosphamide in vivo. The effects of this metabolite in vitro on several immune functions of human lymphocytes have been investigated. Very low concentrations (10(-7) to 10(-9) M) of PM added to lymphocyte cultures inhibited proliferation of the lymphocytes in response to mitogens and alloantigens. At these concentrations, inhibition of proliferation appeared to be due to a direct action of PM on the proliferative cells. Thus, concanavalin A-stimulated lymphocytes still acquired IL-2 receptors (Tac antigen) normally in the presence of PM (10(-6) to 10(-9) M). Only exceedingly high concentrations of PM (10(-5) M or greater) prevented the acquisition of Tac antigen. Similarly, the inhibition of proliferation was probably not related to endogenous IL-2 levels: addition of exogenous IL-2 to PM-containing cultures did not result in any restoration of proliferation. Further evidence that PM directly affected proliferative cells was that low concentrations of PM inhibited the proliferation of T cells continuously growing in IL-2. The exposure time to PM necessary for inhibition was essentially identical to those for lymphoproliferative responses to mitogens and alloantigens. Paradoxically, however, the generation of cytotoxic lymphocytes in mixed lymphocyte reactions (MLRs) and mixed lymphocyte tumor cell cultures (MLTCs) was very resistant to PM. In parallel MLRs and MLTCs the cytotoxic responses were resistant to approximately 1000-fold more PM than were the proliferative responses. Only at 10(-5) M PM were these inhibited. These data suggest that clonal expansion of cytotoxic lymphocytes or their precursors by proliferation is not an absolute requirement for the generation of cytolytic activity.

Antigens, Surface↗
PubMed1985

Assessment of bleomycin, adriamycin and mitomycin-C in the treatment of recurrent cervical cancer.

Twenty women with recurrent squamous cell carcinoma of the cervix were treated with bleomycin followed by adriamycin and mitomycin-C. Treatment was repeated every 28 days. In 18 patients who could be assessed there was one complete response and five partial responses (response rate 33%). Two partial responses were seen in 13 lesions arising from previously irradiated sites of disease (response rate 23%). Three complete responses and three partial responses were observed in 10 lesions arising from non-previously irradiated sites of disease (response rate 60%). In all responding cases tumour regression was noted before the end of the third cycle of treatment. Toxicity was predictable and manageable. These results suggest that chemotherapy may be used as a cytoreductive procedure before radical local treatment.

Adult↗
PubMed1985

Structural features of 4-amino antifolates required for substrate activity with mammalian folylpolyglutamate synthetase.

The activity of a series of folic acid analogues as substrates for partially purified mouse liver folylpolyglutamate synthetase was determined and the effects of substituents on the binding to, and catalytic processes of, this enzyme were inferred. A 4-amino group improved substrate activity primarily by decreasing the apparent Km while N10-methyl substitution substantially diminished utilization as a substrate, again, by effects on Km. Isosteric replacement of N-10 altered substrate activity. A free alpha-carboxyl group in the amino acid side chain was required for catalysis as was the presence of the side chain amide carbonyl group. Modification of the amino acid side chain length profoundly affected activity. Several observations were made that may be relevant to chemotherapy with folate antimetabolites: 1) 7-hydroxymethotrexate was a substrate for this enzyme; 2) substrate activity and substrate inhibition were observed with CB 3717, a potent inhibitor of thymidylate synthase; 3) potent classical dihydrofolate reductase inhibitors were identified that were either not substrates for mouse liver folylpolyglutamate synthetase (e.g., 4-amino-4-deoxy-N10-methylpteroyl-L-alpha-aminoadipate) or were much better substrates than methotrexate for this enzyme (e.g., aminopterin); and 4) leucovorin and methotrexate appeared to be substrates for the same synthetase, but leucovorin saturated the reaction at much lower concentrations. These results have implications for the design of folylpolyglutamate synthetase inhibitors and for the selection of dihydrofolate reductase inhibitors that are either not polyglutamated or are efficiently polyglutamated in vivo.

Amines↗
PubMed1984

Kinetics of cold-induced denaturation of metmyoglobin.

Using a slow temperature-jump spectrophotometer, we have studied the kinetics of cold-induced denaturation of metmyoglobin between 0 degrees C and 20 degrees C at acidic pH. The time-scale of the transition is slow and is of the order of minutes. The results are consistent with the transition's involving a total of three states, native (N), transient intermediate (I) and denatured (D), which are converted from one to the other in that order.

Animals↗
PubMed1984

Evaluating drug absorption after oral administration. Some problems and some solutions.

Quantitative assessment of drug absorption remains a difficult task, because the multiple-compartment disposition of a drug may not be obvious after oral administration (the problem of the vanishing exponential) and the macroconstants are indistinguishable. For these reasons, proper analysis of the drug absorption based on the apparent behavior of oral data without intravenous reference curve rarely provides absorption information useful for in vivo - in vitro correlations. When intravenous reference curve is available, compartment model used for analysis of the oral data should be corresponding to the iv data such as the Loo - Riegelman method. The model independent statistical moments method is one of the preferable alternatives because of its ease of computation and its potentially smaller error, if absorption can be assumed to be first-order.

Administration, Oral↗
PubMed1984

The effect of incorporation of indomethacin with polyethylene glycol 6000 in a solid dispersion on its in vivo properties in the rat.

Preparations of indomethacin and indomethacin in combination with PEG 6000 were administered in solid form by the oral route to male rats. No significant differences in anti-oedema activity were observed between the different preparations of indomethacin, but high blood levels of drug were observed following dosing with indomethacin, in a PEG 6000 melt. Rapid dispersion formulations of indomethacin were also found to be gastro-toxic.

Animals↗
PubMed1984

Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results.

Of 157 consecutive patients who had histologically diagnosed hepatocellular carcinoma, 52 with a good performance score, bilirubin less than 2 mg/dl, and absence of bloody ascites were treated with a 75-mg/m2 dose of doxorubicin (unadjusted for hepatic function) every 3 weeks in a prospective trial. Forty-six patients were treated in West Africa and six in Southern California. No complete responses were seen and only six patients (11%) achieved partial objective responses. Plasma concentrations of doxorubicin and doxorubicinol (adriamycinol) were determined at four selected time points for up to 72 hours, corresponding to the terminal phase of disposition in eight African patients. The African patient results were compared to those seen in North American patients with hepatocellular carcinoma and other malignancies. In African patients with hepatocellular carcinoma, terminal half-life of doxorubicin was prolonged at 39.8 +/- 15.9 hours. The ratios of the corresponding concentration X time values of doxorubicinol to doxorubicin, which reflect the overall metabolite to parent drug ratio, ranged from 0.7 to 4.6, with a mean ratio of 2.03 +/- 1.20 in the African patients with hepatocellular carcinoma compared to a mean ratio of 0.76 +/- 0.31 in North American patients with other malignancies. Pharmacokinetic findings in hepatocellular carcinoma patients in North America and Africa were similar, reflecting elevation and prolongation of doxorubicinol metabolite relative to doxorubicin in the plasma of patients with this disease from both areas. We conclude that: (a) doxorubicinol disposition is altered in African as well as North American patients with hepatocellular carcinoma; and (b) even when given in full dose to patients with favorable prognostic features, iv doxorubicin has only limited activity against hepatocellular carcinoma.

Adult↗
PubMed1984

Second-look laparotomy in the management of epithelial ovarian carcinoma: an evaluation of fifty cases.

Fifty patients with ovarian cancer had a second-look laparotomy performed after chemotherapy. Complete histologic response was confirmed in 12 patients, microscopic disease was found in 12 patients, and macroscopic disease was found in 26 patients. Fifteen patients with macroscopic disease had total tumor clearance at second look. Surgical response to chemotherapy was found to correlate well with disease volume at the onset of chemotherapy. The operation is a safe, accurate technique for assessing the ovarian cancer patient. The findings and outcome probably depend upon the timing of the procedure. Any survival benefit from the operation remains to be proved.

Adult↗
PubMed1982

Tissue disposition of doxorubicin in experimental animals.

Doxorubicin was administered via peripheral vein to rabbits with or without VX-2 carcinoma and to rats with 13762 mammary adenocarcinoma. In rabbits, the doxorubicin tissue levels showed a decreasing order as follows: kidney, spleen, lung, heart, marrow, liver, gut, tumor, muscle, and fat. In rats, the order of doxorubicin concentration in organs from high to low appeared similar, except lung concentration was closer to spleen and kidney; and doxorubicin level in fat was higher than that in muscle. When different doses of doxorubicin were given, the tissue concentrations were proportional to the dose. At 24 hr after administration, the concentration of doxorubicin in liver was much higher in rats that received the drug injected directly into the hepatic artery or mesenteric-portal vein than in those that received the drug via the peripheral vein. In the discussions, our results in rats and rabbits were compared with what had been reported in the literature of tissue uptake studies in mice, dogs, and patients.

Animals↗
PubMed1982

Estimation of statistical moments and steady-state volume of distribution for a drug given by intravenous infusion.

Although it is generally recognized that estimates of the area under the drug concentration vs. time curve (AUC) after a dose is rather insensitive to curve-fitting procedures, little is known about estimates of mean residence time (MRT) or volume of distribution at steady-state (Vss), both of which can be derived from area estimates. This question is of particular concern when a drug is given as a short-term constant rate i.v. infusion since the infusion phase is often ignored and blood sampling restricted to the postinfusion period. Two nonexperimental methods for approximating concentration data during infusion termed the linear approximation method and the imaginary bolus method were found to be useful under certain conditions. Both methods provide reasonable estimates of AUC and the area under the first moment of the drug concentration-time curve (AUMC) for drugs with a wide range of pharmacokinetic characteristics. The imaginary bolus method was found to be the better of the two for estimation of MRT and to be widely applicable for this purpose. Vss proved to be highly sensitive to the approximation methods; although the imaginary bolus method is superior to the linear approximation method for estimating Vss, it does not work particularly well for drugs with pronounced multicompartment characteristics. In general, accurate estimation of Vss of drugs given by short-term i.v. infusion requires that at least one drug concentration be determined during infusion.

Infusions, Parenteral↗
PubMed1982

Metabolite kinetics: formation of acetaminophen from deuterated and nondeuterated phenacetin and acetanilide on acetaminophen sulfation kinetics in the perfused rat liver preparation.

The role of hepatic intrinsic clearance for metabolite formation from various precursors on subsequent metabolite elimination was was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors: [14C] phenacetin-d5 and [3H] phenacetin-do, [14C] acetanilide and [3H] phenacetin were delivered by constant flow (10 ml/min/liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The data showed that the higher the hepatocellular activity (intrinsic clearance) for acetaminophen formation, the greater the extent of subsequent acetaminophen sulfation. The findings were explained on the basis of blood transit time and metabolite "duration time." Because of blood having only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite sulfation and the less will be the degree of subsequent sulfation. Conversely, when the drug forms the primary metabolite rapidly, a longer time will remain for the metabolite to be sulfated in liver to result in a greater degree of metabolite sulfation. Finally, the effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed.

Acetaminophen↗
PubMed1982

Clinical and pharmacokinetic effects of combined warfarin and 5-flourouracil in advanced colon cancer.

Twenty-five patients with advanced measurable adenocarcinoma of the colon were treated with 5-fluorouracil (FUra), 15 to 20 mg/kg/week i.v., plus warfarin p.o. at a dosage which maintains therapeutic levels of anticoagulation. Sixty-four % of patients achieved either objective response (20%) or stable disease (44%). Overall median survival was 19.2 months. Three patients (all with intraluminal lesions) developed gastrointestinal blood loss requiring transfusion and discontinuation of anticoagulation. The interaction between warfarin and FUra as measured by plasma levels was investigated in seven rabbits and three patients. Plasma samples were obtained for 2 hr after FUra administration, both before and after anticoagulation with warfarin. FUra was measured by gas chromatography, and warfarin was assayed using a thin-layer chromatographic fluorescence method. In rabbits, prolongation of FUra plasma t1/2 was seen with high (0.6 mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. In patients, FUra t1/2 was not changed by therapeutic warfarin anticoagulation. Thus, (a) plasma clearance interaction between FUra and warfarin does not occur in patients receiving therapeutic levels of anticoagulation; (b) FUra and warfarin anticoagulation can be safely given and frequently result in stable disease status for patients with advanced colon cancer. Further trials of this combination are warranted in adenocarcinoma of the colon.

Adenocarcinoma↗