Biomedical subjects

Y B Cho

Publications and source records attributed to Y B Cho.

At least 19 recordsLinked to original sources

PubMed2006

A novel four-dimensional radiotherapy method for lung cancer: imaging, treatment planning and delivery.

We present treatment planning methods based on four-dimensional computed tomography (4D-CT) to incorporate tumour motion using (1) a static field and (2) a dynamic field. Static 4D fields are determined to include the target in all breathing phases, whereas dynamic 4D fields are determined to follow the shape of the tumour assessed from 4D-CT images with a dynamic weighting factor. The weighting factor selection depends on the reliability of patient breathing and limitations of the delivery system. The static 4D method is compared with our standard protocol for gross tumour volume (GTV) coverage, mean lung dose and V20. It was found that the GTV delineated on helical CT without incorporating breathing motion does not adequately represent the target compared to the GTV delineated from 4D-CT. Dosimetric analysis indicates that the static 4D-CT based technique results in a reduction of the mean lung dose compared with the standard protocol. Measurements on a moving phantom and simulations indicated that 4D radiotherapy (4D-RT) synchronized with respiration-induced motion further reduces mean lung dose and V20, and may allow safe application of dose escalation and CRT/IMRT. The motions of the chest cavity, tumour and thoracic structures of 24 lung cancer patients are also analysed.

Artifacts↗

PubMed2006

Endoscopy-aided laser therapy for intractable granular myringitis.

OBJECTIVE: We report our technique and results for endoscopy-aided CO2 laser therapy for the treatment of intractable granular myringitis, as an out-patient office procedure. MATERIALS AND METHODS: A total of 21 patients (14 women and seven men; mean age 32.6 years) were retrospectively reviewed, all of whom suffered from intractable granular myringitis and had undergone endoscopy-aided laser treatment. Granulation tissue was vaporized for one to two seconds with a CO2 laser (spot size 0.5-1 mm with a power setting of 5-10 W in continuous mode). The mean follow-up period was 11 months. RESULTS: Eighteen of the 21 patients (85 per cent) were cured after a single treatment. Three patients with the diffuse form of the disease required repeat laser treatments coupled with self-irrigation with a diluted vinegar solution. We noted no perforations of patients' tympanic membranes after laser vaporization. We also observed no recurrences over follow-up periods ranging from three months to 2.6 years. Our laser procedure produced no adverse effect on hearing thresholds, nor were any other complications observed. CONCLUSION: Our results suggest that endoscopy-aided CO2 laser ablation is a reliable and minimally invasive method associated with low rates of recurrence and a low incidence of complications. It can be conducted as an office procedure.

Adult↗

PubMed2001

A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) in patients with advanced malignancies.

BACKGROUND: A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies. METHODS: Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m(2) up to 480 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine. RESULTS: All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m(2). At 480 mg/m(2), two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m(2) to 480 mg/m(2) without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS: The MTD of SKI 2053R was 480 mg/m(2). The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m(2) once every 4 weeks.

Adult↗

PubMed2001

Effect of SKI 306X, a new herbal anti-arthritic agent, in patients with osteoarthritis of the knee: a double-blind placebo controlled study.

SKI 306X is a purified extract from a mixture of three oriental herbal medicines (Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris) that have been widely used for the treatment of inflammatory diseases such as lymphadenitis and arthritis in far East Asia. A double-blind, controlled study was performed to evaluate the efficacy and safety of SKI 306X with placebo in 96 patients with classical osteoarthritis of the knee. Patients were randomized to four treatment groups: placebo, 200 mg, 400 mg and 600 mg of SKI 306X t.i.d.. Clinical efficacy and safety were evaluated for 4 weeks continuous treatment. SKI 306X demonstrated its clinical efficacy, as assessed by 100 mm visual analogue scale (VAS), Lequesne index and patients' and investigators opinion of the therapeutic effect compared with placebo (p<0.01). No significant adverse events were observed in patients treated with SKI 306X. This study demonstrated that SKI 306X, a new herbal anti-arthritic agent provided clinical efficacy in patients with osteoarthritis.

Adult↗

PubMed2000

Pharmacokinetic/pharmacodynamic evaluation of a novel potassium channel opener, SKP-450, in healthy volunteers.

To evaluate the pharmacokinetic/pharmacodynamic characteristics of SKP-450, a novel K+ channel opener, a single blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 28 healthy volunteers. The volunteers were randomly allocated to dosage groups of 50 micrograms, 100 micrograms, 200 micrograms, and 300 micrograms. Single doses of SKP-450 were administered orally, after overnight fasting, and serial blood sampling and pharmacodynamic measurements were performed up to 48 hours after the drug was administered. The 200 micrograms group was further studied for food interactions in a crossover fashion. Drug concentrations in plasma were determined by HPLC. Hemodynamic changes after drug administration were evaluated by serial measurements of blood pressure (BP), pulse rate (PR), cardiac index (CI), and total peripheral resistance (TPR), using computerized impedance cardiography. Changes in plasma renin activity (PRA) and aldosterone concentrations (PAC) were determined 4 and 24 hours after drug administration. Both SKP-450 and SKP-818, an active metabolite, showed linear pharmacokinetic characteristics, and food intake did not significantly affect the pharmacokinetic characteristics of either compound. Dose-related pharmacological effects were obvious for both the 200 micrograms and 300 micrograms groups. Hemodynamic parameters related to vasodilation and reflex tachycardia, such as maximum changes in diastolic BP, PR, CI, and TPR, showed significant dose-dependent changes. The area under the time-effect curve (AUEC) of the parameters also showed a similar dose-dependent pattern. The PRA and PAC exhibited significant changes 4 hours after drug administration in the 300 micrograms group. Adverse effects, such as headaches, were more frequently observed at the higher dose levels. SKP-450 was generally well tolerated by these normotensive subjects. The antihypertensive efficacy of SKP-450 needs to be evaluated in hypertensive patients after multiple dosing.

Administration, Oral↗

PubMed1999

Synthesis and evaluation of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1- yl)purines as potential prodrugs of penciclovir.

A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purin es (1-8) and 2-amino-9-(3-alkoxycarbonyl-oxymethyl-4-alkoxycarbonyloxybut -1-yl)purines (9-12) were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH.H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, 17 or 18, in excellent yields of 95 and 92%, respectively. Reactions of 17 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80 degrees C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, 1-8, in 86 94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives 9 12 in 81-83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (4) achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds 2 (35%), 6 (35%), 7 (34%), 10 (34%), 8 (32%), 3 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from 4 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of 4 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time ( > 21, 13+/-5.0 (SEM), and 13+/-1.6 days). Compound 4 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment.

Acyclovir↗

PubMed1999

Phase II trial of a novel platinum analog, SKI 2053R, in patients with previously untreated extensive-stage small-cell lung cancer.

A phase II trial of a novel platinum analog, SKI 2053R, was performed in patients with previously untreated extensive-stage disease (ED) small-cell lung cancer (SCLC). SKI 2053R was administered at the dose of 400 mg/m2 every 3 to 4 weeks as a 1-h infusion. After the first cycle, the dose was escalated to 440 mg/m2 based on toxicity. Thirty-eight patients (31 male) were enrolled between June 1995 and August 1997. The median age was 61 years (range, 36-70 years). Six of 37 evaluable patients achieved a partial response (16.2%; 95% confidence interval [CI], 4.4-28.0%). The durations of response were 1.1, 1.5, 1.7, 1.9, 3.4, and 4.6 months. The estimated median survival time was 7.4 months (95% CI, 5.1-9.7 months). Grade 3 or 4 toxicities were not observed. Grade 1 to 2 leukopenia, anemia, and thrombocytopenia were seen in 5 of 68 cycles, 16 of 68, and 2 of 68, respectively. Nonhematologic toxicities included grade 1 to 2 nausea or vomiting (30 of 68 cycles), nephrotoxicity (27 of 68), and hepatotoxicity (13 of 68). SKI 2053R showed a modest antitumor activity with limited toxicities in patients with ED SCLC. Further clinical trials are warranted in SCLC with a higher dose of SKI 2053R.

Adult↗

PubMed1999

Simultaneous analysis of urinary 2-thiothiazolidine-4-carboxylic acid and thiocarbamide as a biological exposure index for carbon disulfide exposure.

The objectives of this study were to develop optimal analytic methods for detecting urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) and thiocarbamide simultaneously and to evaluate the usefulness of these metabolites to a biological exposure index (BEI) for carbon disulfide (CS2) exposure. For this experiment, synthesized TTCA and thiocarbamide were used. The synthesized TTCA was identified by infrared spectrophotometer, nuclear magnetic resonance spectrometer and thin layer chromatography. The recovery rates of both metabolites were calculated to find the optimum analytical method. The amounts of urinary TTCA and thiocarbamide were measured by using an ultraviolet detector connected to high performance liquid chromatography (HPLC) after the administration of CS2 (350, 700 mg/kg) into Sprague-Dawley rats intraperitoneally. The maximum absorbance wave lengths for TTCA and thiocarbamide were 272 and 236 nm, respectively. Ethyl acetate extraction with NaCl as a salting-out reagent was used as a simultaneous extraction method for these metabolites. HPLC conditions for these metabolites included using a NH2 column, 50 mM KH2PO4: acetonitrile (85:15) and pH 3. Excreted amounts of urinary TTCA and thiocarbamide were increased significantly following CS2 administration. TTCA, which was already adopted as a BEI for CS2 by the American Conference of Governmental Industrial Hygienists (ACGIH), seems to be a more useful BEI for CS2 exposure than thiocarbamide. However further studies are needed to increase analytical efficiency before thiocarbamide can be adopted as a BEI and to apply this analytic method for simultaneous analysis of these metabolites in workers exposed to CS2.

Animals↗

PubMed1998

Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.

A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) of 88, >200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O (138.8 mg/mL, 20 degrees C).

Acyclovir↗

PubMed1998

Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) .

The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.

Adenocarcinoma↗

PubMed1996

Pharmacokinetics of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum(II) in rats.

The blood concentration-time profile, distribution, and excretion of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum(II) (CAS 146665-77-2, SKI 2053R), a new potential anticancer agent, were investigated in rats after intravenous administration of 14C-SKI 2053R. After a single intravenous administration, the radioactivity of blood declined in a biexponential fashion with the initial half-lives of 0.42 h and 0.37 h and with the terminal half-lives of 68.67 h and 64.67 h in male and female rats, respectively. Radioactivity was distributed very rapidly and extensively into all tissues except the central nervous system. The major amount of the radioactivity was found in the gastrointestinal contents, urine, and organs of elimination at all time points. The distribution pattern of 14C-SKI 2053R observed by the measurement of tissue concentrations was in accordance with that observed by whole-body autoradiography. The 0-7 days cumulative urinary and fecal recoveries of total radioactivity after a single dose were 83.0 +/- 4.5 (mean +/- S.D.) and 11.3 +/- 1.0% in male rats and 85.1 +/- 2.6 and 11.3 +/- 2.3% in female rats, respectively, resulting in total recoveries of 94.3 +/- 3.6% in male rats and 96.3 +/- 1.1% in female rats. The 0-24 h cumulative excretions of total radioactivity in the bile after a single dose were 8.7 +/- 0.4 and 15.8 +/- 3.5% in male and female rats, respectively, showing a significant sex difference.

Animals↗

PubMed1996

Mammary excretion and placental transfer of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II) in rats.

The mammary excretion and placental transfer of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e] platinum(II) (CAS 146665-77-2, SKI 2053R), a new potential anticancer agent, were investigated in the lactating or pregnant rats after a single intravenous administration of 14C-SKI 2053R (20 mg/kg, 100 microCi/kg). The radioactivity of the milk declined in a biexponential fashion with an initial half-life of 0.39 h and with a terminal half-life of 14.05 h in the lactating rats. The radioactivity of the milk was lower than that of plasma until 1 h after dosing, but was higher than that of plasma from 4 h after dosing. 14C-SKI 2053R was well distributed to most tissues including uterus and placenta in the pregnant rats, but the levels of radioactivity in the amniotic fluid and fetuses were markedly lower than that in the maternal plasma. Therefore, it is concluded that SKI 2053R scarcely passes the blood-placenta barrier, which was confirmed by the whole-body autoradiography study.

Animals↗

PubMed1995

Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2- isopropyl-1,3-dioxolane]platinum(II), a new platinum analogue, as an anticancer agent.

The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4,5- bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug.

Adenocarcinoma↗

PubMed1995

Antitumor activity of five new platinum complexes having a glycolate leaving ligand.

In an attempt to develop a new anticancer platinum complex with greater or equivalent antitumor activity but reduced side effects compared with cisplatin (CDDP), a series of new platinum complexes having a glycolate leaving ligand was synthesized. Among them, five complexes were selected for further development on the basis of adequate water solubility, low nephrotoxicity and high antitumor activity in a murine system. The chemosensitivity of these five complexes was examined in MTT assay against two human pulmonary adenocarcinoma cell lines, PC-9 and PC-14, and two human stomach adenocarcinoma cell lines, MKN-45 and KATO III. Their IC50 and relative antitumor activity (RAA) values were compared with those of CDDP and 254-S, a second-generation platinum complex with a glycolate leaving ligand under phase III clinical trial. The lowest mean IC50 value was observed in CDDP, followed by SKI 2034R and SKI 2033R. In this study, the antitumor activity was evaluated in terms of RAA values and SKI 2034R showed the highest RAA value. The order of RAA values was SKI 2034R > CDDP > SKI 2032R > SKI 2033R > SKI 2030R > SKI 2029R > 254-S. Based on the RAA order, we have recommended SKI 2034R as the most promising candidate for further development of a clinically useful platinum complex.

Antineoplastic Agents↗

PubMed1995

Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II), as determined by ex vivo pharmacodynamics.

The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0-->infinity) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72 +/- 2.74 micrograms h ml-1 (mean +/- SD), with an initial half-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57 +/- 0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P < 0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.

Animals↗

PubMed1995

Pharmacokinetics, tissue distribution, and excretion of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3- dioxolane]platinum(II) in dogs.

The pharmacokinetics, tissue distribution, and excretion of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3- dioxolane]platinum(II) (SKI 2053R), a new potential anticancer agent, were investigated in dogs after a single intravenous administration of [14C]SKI 2053R (7 mg/kg, 100 microCi/kg). Total radioactivity in the plasma and ultrafiltrable plasma declined in a biexponential fashion with the initial half-lives of 0.63 +/- 0.05 hr (mean +/- SD) and 0.53 +/- 0.05 hr, and with the terminal half-lives of 51.08 +/- 3.26 hr and 15.19 +/- 3.75 hr, respectively. Radioactivity was well distributed into all tissues except the central nervous system. The majority of the radioactivity was found in the gastrointestinal contents, urine, and organs of elimination at all time points. The distribution pattern of [14C]SKI 2053R in the whole-body autoradiograms was consistent with that observed by the measurement of tissue concentrations. The 0-7 days cumulative urinary and fecal recoveries of total radioactivity were 87.30 +/- 2.93% and 8.68 +/- 1.30%, respectively, resulting in a total recovery of 95.98 +/- 1.61% of the administered dose. A large portion of [14C]SKI 2053R was distributed into the cellular fraction of mouse or rat blood, but was not into that of dog or human blood in vitro. The in vitro and in vivo binding of [14C]SKI 2053R to plasma protein was minimal to moderate.

Animals↗

PubMed1994

Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes.

The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.

Animals↗

PubMed1993

The localization of synaptophysin in the organ of Corti of the human as shown by immunoelectron microscopy.

Synaptophysin, or p38, a polypeptide of molecular weight 38 kD, is a calcium-binding membrane protein found in synaptic vesicles of neurons and smooth surfaced vesicles of neuroendocrine cells. Six human neonatal and infant temporal bones were fixed in paraformaldehyde and glutaraldehyde, decalcified in EDTA and were than immunoreacted for synaptophysin (ICN Biomedicals) using the avidin-biotin reaction (ABC kit, Vector Labs). The tissue was then prepared for light microscopic surface preparation, radial sections of 5 microns, and serial section electron microscopy. At a light microscopic level, the inner spiral bundle, tunnel spiral bundle, upper tunnel crossing fibers and the base of outer hair cells were stained. At the base of outer hair cells, the immunoreactivity was seen to decrease from the base to the apex and from the first to third outer hair cells. At an electron microscopic level, immunoreactivity at the base of outer hair cells was limited to vesiculated efferent fibers. The degree of immunoreactivity between adjacent efferent fibers varied significantly. Immunoreactive vesiculated endings were also found in the supranuclear region of outer hair cells.

Hair Cells, Auditory↗