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L Pendyala

Publications and source records attributed to L Pendyala.

At least 37 records · Page 2Linked to original sources
PubMed1995

Phase I study of paclitaxel and carboplatin: implications for trials in head and neck cancer.

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.

Adenocarcinoma↗
PubMed1993

In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin.

The in vitro cytotoxicity, protein binding, partitioning of platinum from whole blood into erythrocytes, its exchange back into plasma, and the in vitro biotransformation in plasma were studied for the new nonnephrotoxic platinum analogue oxaliplatin. The cytotoxicity studies were carried out against a panel of human tumor cell lines derived from carcinomas of the ovary (A2780, A2780/cp), bladder (TCCSUP, RT4), colon (HT-29), melanoma (SKMEL-2, HTB144), and glioma (U373MG and U87MG). The relative potency of the five platinum complexes was oxaliplatin = tetraplatin > cisplatin > iproplatin > carboplatin. Oxaliplatin was active against HT-29 and only minimally cross-resistant with cisplatin against A2780/cp. Both bladder carcinoma cell lines, both melanoma cell lines, and one of the two glioblastoma cell lines were resistant to both oxaliplatin and tetraplatin. The cytotoxicity profiles of the drug pairs oxaliplatin-tetraplatin and cisplatin-carboplatin showed statistically significant correlation by the Spearman rank correlation test. Oxaliplatin was similar to cisplatin and tetraplatin in protein binding; 85-88% of all platinum from oxaliplatin (5, 10, or 20 micrograms/ml) was bound to plasma proteins within the first 5 h with an average half-life of 1.71 +/- 0.06 h. When oxaliplatin was incubated in whole blood (5, 10, and 20 micrograms/ml), the erythrocytes took up 37.1 +/- 2.1% of the total platinum in 2 h (maximum uptake) which was not exchangeable into plasma. Thus the erythrocyte-bound fraction does not serve as a reservoir of drug. In plasma, oxaliplatin was unchanged at 0.5 h, but at 1 h, 30% of the total platinum in plasma was in a peak which had identical retention to that of (trans-1,2-diaminocyclohexane)dichloroplatinum(II), the major biotransformation product of tetraplatin. At 2 h, (trans-1,2-diaminocyclohexane)dichloroplatinum(II) and three other platinum-containing peaks were detected but no unchanged oxaliplatin. All the platinum eluted in a single peak near the solvent front at 4 h. The marked similarity in cytotoxicity between oxaliplatin and tetraplatin may be due to the formation of (trans-1,2-diaminocyclohexane)dichloroplatinum(II) in tissue culture media.

Antineoplastic Agents↗
PubMed1991

Clinical pharmacokinetics of 3-deazaguanine.

3-Deazaguanine (3DG), an antipurine antimetabolite, has recently completed a phase I clinical trial at this Institute. The drug was given on a daily x 5 schedule by i.v. infusion over 0.25-2.16 h. The pharmacokinetics of 3DG during 16 courses were studied in 12 patients at doses of 200-800 mg/m2. 3DG in plasma was measured by an isocratic reverse-phase high-performance liquid chromatographic (HPLC) procedure carried out on IBM phenyl columns at 40 degrees C using 10 mM phosphate buffer (pH 7) as the mobile phase and detection at 300 nm. Plasma decay of 3DG was biexponential in all patients. The AUC correlated linearly with dose at 200-600 mg/m2 but deviated from linearity at doses greater than 600 mg/m2. The drug was cleared rapidly from plasma; at doses of 200-600 mg/m2, the mean plasma clearance was 61.64 +/- 9.97 l/h and the mean terminal-phase elimination half-life was 1.6 +/- 0.6 h. The steady-state volume of distribution (98.9 +/- 29.1 l) and distribution coefficient (1.24 +/- 0.39 l/kg) indicated extensive tissue distribution for the drug. No statistically significant difference was observed between the pharmacokinetics of 3DG on day 1 and that on day 4 as evaluated in three patients for whom complete plasma data were available on both days.

Antimetabolites, Antineoplastic↗
PubMed1991

Pharmacokinetics and metabolism of nilutamide.

Data are available on the pharmacokinetics and metabolism of nilutamide in the rat, dog, and human (normal volunteers and patients with advanced prostatic carcinoma). Studies using 14Carbon-nilutamide, radioimmunoassay, and high-performance liquid chromatography (HPLC) are reviewed. In the rat, bioavailability by the oral route was complete. The majority of the plasma radioactivity was unchanged nilutamide up to six hours, t1/2 was seven hours, and clearance was 150 mL/hour/kg body weight. Metabolism studies identified 6 urinary metabolites. The major metabolites result from reduction of the nitro group initially to an hydroxylamine (17%) and then to a primary amino (26%) group. In normal volunteers the compound was rapidly absorbed, displayed linear kinetics over a dose range of 100-300 mg, and declined slowly in plasma with a terminal phase t1/2 of forty-three to forty-nine hours. In studies in 12 patients with advanced (Stage D) prostatic carcinoma, single-dose kinetics after 14C-nilutamide and kinetics with repetitive twice-daily dosing of two to seven weeks were measured. Terminal phase plasma t1/2 of unchanged nilutamide was 56 +/- 19 hours and of total radioactivity 87 +/- 27 hours (mean +/- SD). Area under the curve of plasma radioactivity was 23 to 38 percent unchanged nilutamide. Urinary excretion of radioactivity was slow and incomplete because the collection time was not long enough in regard to t1/2 (mean after 5 days, 62 +/- 10%) and consisted almost entirely of metabolites. Steady-state plasma levels of nilutamide were reached in about two weeks. It can be concluded that in humans, unlike other species, plasma decay of nilutamide is very slow. Elimination is almost exclusively by metabolism. Single-daily dosing is appropriate. Hepatic impairment could be expected to prolong plasma decay; renal impairment is likely to have little effect.

Adult↗
PubMed1990

DNA binding of iproplatin and its divalent metabolite cis-dichloro-bis-isopropylamine platinum (II).

The quadrivalent second-generation platinum complex iproplatin and an in vivo divalent metabolite of iproplatin, cis-dichloro-bis-isopropylamine platinum (CIP) were tested for binding to DNA in vitro. DNA binding was determined according to radioactivity measured using [14C]-iproplatin and [14C]-CIP and also by platinum content. Results indicate that (a) iproplatin shows negligible binding to DNA, (b) CIP binds to DNA in a time-dependent fashion, and (c) the isopropylamine ligand is intact when CIP is bound to DNA. Glutathione (GSH) inhibits the binding of CIP to DNA, possibly by inhibiting binding to DNA of the aquated form of CIP.

Animals↗
PubMed1989

Studies on the human metabolism of iproplatin.

We have previously shown that a significant portion of the total platinum in the plasma of patients receiving iproplatin is protein-bound. We have also identified cis-dichloro-bis-isopropylamine platinum(II) (CIP) as a major metabolite of iproplatin. To understand the nature of the bound platinum, we carried out in vitro comparative protein-binding studies for iproplatin and CIP. These studies indicate that when CIP is incubated in plasma, protein binding occurs, with a 2.7-h half-life for the disappearance of CIP; the parent complex does not bind and is stable in plasma for at least 48 h. The time dependence of protein binding with CIP suggests the formation of other chemical species from CIP that may be responsible for the observed protein binding. The results indicate that in patients receiving the drug, the reduction of iproplatin to CIP must take place intracellularly and that CIP or its protein-binding derivatives must efflux from the cells into the plasma. Efflux studies carried out to explore this possibility with cells in the whole blood showed that iproplatin was taken up into cells, but the efflux of protein-binding iproplatin metabolites did not occur. To understand further the nature of the metabolites of iproplatin, we carried out 195Pt-NMR (nuclear magnetic resonance) studies with urine from two patients who received a high dose of iproplatin (500 mg/m2). The predominant signals from the 195Pt-NMR corresponded to the divalent platinum complexes and not to quadrivalent complexes, indicating that the iproplatin metabolites in urine are divalent in nature.

Antineoplastic Agents↗
PubMed1989

Uptake and metabolism of iproplatin in murine L1210 cells.

Iproplatin is structurally unique among the platinum (Pt) agents in the clinic because it is a quadrivalent complex. On the basis of the redox parameters for the Pt(IV) and Pt(II) oxidation states in a chloride system, it has been suggested that Pt(IV) complexes will be reduced to Pt(II) complexes in a biological environment. To test this hypothesis, uptake and metabolism studies of [14C]-iproplatin were carried out in L1210 cells. The L1210 cells raised in DBA2/J mice were incubated in vitro with 50 and 100 microM [14C]-iproplatin at 37 degrees C in Hanks' balanced salt solution, and total uptake and radioactivity associated with acid-insoluble fractions were measured for up to 3 h. Under these conditions, the uptake of iproplatin was linear with time and increased with increasing concentrations of iproplatin in the medium. At all times measured, greater than 35% of radioactivity was associated with the acid-insoluble fraction, suggesting binding to macromolecules. The [14C]-labelled compounds in neutralized acid extracts of cells were separated by reverse-phase high-performance liquid chromatography (HPLC). Three labelled compounds were detected; based on chromatographic elution times, they appeared to be iproplatin, cis-dichloro-bis-isopropylamine platinum(II) (CIP), the reduction product of iproplatin, and a third compound more polar than iproplatin and CIP. The finding of free CIP and the macromolecular binding of radioactivity in the cells suggests that iproplatin is reduced intracellularly.

Animals↗
PubMed1988

Identification of cis-dichloro-bis-isopropylamine platinum(II) as a major metabolite of iproplatin in humans.

Iproplatin is a quadrivalent second-generation platinum complex undergoing clinical evaluation. In plasma and urine of patients receiving this drug, iproplatin- and platinum-containing metabolites of iproplatin were separated by reverse-phase gradient high performance liquid chromatography. One of the metabolites was identified by cochromatography and electron impact mass spectrometry as cis-dichloro-bisisopropylamineplatinum(II), a metabolite formed by reduction of iproplatin. Incubation of iproplatin with ascorbic acid and cysteine, in vitro, indicates that iproplatin can be easily reduced to cis-dichloro-bis-isopropylamineplatinum(II) by reducing agents. It is hypothesized that the reduction of the quadrivalent complex iproplatin to cis-dichloro-bisisopropylamineplatinum(II) occurs intracellularly.

Antineoplastic Agents↗
PubMed1988

Pharmacokinetics of Anandron in patients with advanced carcinoma of the prostate.

The pharmacokinetics of total radioactivity and unchanged drug were studied in patients receiving Anandron (Nilutamide, RU 23908) after a single dose of [14C] Anandron and after q12 h dosings of unlabelled drug for 2-7 weeks. The results indicate that the radioactivity in plasma consists of unchanged drug and metabolites. The plasma decay of Anandron after the absorption phase was biexponential in all patients, with the terminal phase half-life ranging from 23.3-87.2 h. The plasma decay of total radioactivity after the absorption phase was biexponential in 3/12 and monoexponential in 9/12 patients. The calculated terminal phase half-lives for total radioactivity after [14C] Anandron were 34.5-137.3 h. The AUC0-infinity of the unchanged drug in plasma represented 23%-38% of the AUC0-infinity of total radioactivity. Urinary radioactivity consisted primarily of metabolites, the majority of which were chloroform-nonextractable. Urinary excretion of radioactivity at 120 h ranged from 49%-78% of the administered dose; the unchanged Anandron (at 72 h) was 0.6%-1.3% of the dose. In three patients studied, the fecal excretion of Anandron was 1.4%-7.0%. Steady-state plasma levels (4.4-8.5 micrograms/ml) were attained within approximately 2 weeks from the initiation of twice daily dosing of Anandron. When the plasma pharmacokinetics of radioactivity and unchanged drug after the first single dose were compared with that during steady state, AUC0-12h of unchanged Anandron during steady state was significantly higher than the AUC0-infinity after the first single dose, suggesting that the plasma clearance of Anandron is lowered upon chronic administration of the drug, assuming that the bioavailability is constant.

Aged↗
PubMed1987

Phase I clinical trial of ethyl 6-deoxy-3,5-di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809).

A phase I study of single i.v. doses of a new sugar containing nitrosourea 6-deoxy-3,5 di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809, EDMN) has been carried out in 47 patients with advanced solid tumors. Nine dose levels between 200 and 4500 mg/m2 were examined. Nausea and vomiting were seen in most patients but were controlled with antiemetics. Myelosuppression was minimal. The dose-limiting toxicity was hepatotoxicity, occurring early (peak at days 2-4) and resolving rapidly. No cumulative toxicity was seen with an every 6 weeks schedule. Other toxicities were abdominal pain, diarrhea, arm pain, restlessness, and headache. Pharmacokinetic studies in 20 patients using an HPLC assay and in 5 patients using [14C]EDMN showed a short half-life, rapid plasma clearance, rapid metabolism, and minimal excretion of unchanged drug. There was one partial response in a patient with colon carcinoma. The recommended dose for phase II studies in 3750 mg/m2 every 6 weeks.

Adult↗
PubMed1987

Phase I clinical trial of 1-(2-[2-(4-pyridyl)-2-imidazoline-1-yl]-ethyl)-3-(4-carboxy-phenyl) urea (CGP 15720A).

A phase I clinical trial of the intravenous administration of a novel pyridyl imidazoline ethyl carboxy phenyl urea was carried out in 42 patients with advanced solid tumors. Five schedules were evaluated: I, daily X 5; II, daily X 10; III, daily X 15; IV, continuous infusion for 5 days; V, continuous infusion for 7 days. Toxicity was not seen in schedule I (maximum dose 3 g/m2/day) and was minimal in schedule IV (6 g/m2/day). In schedule II it was seen at 2 and 3 g/m2/day, in schedule III at 2 g/m2/day and in schedule V at 6 g/m2/day. Dose-limiting toxicity consisted of a syndrome of lethargy and fatigue. There were no definitely drug-related changes in hematologic or serum chemistry parameters. No responses were seen, but relief of pain in three patients with prostate cancer was noted. Pharmacokinetics indicate a short half-life, limited volume of distribution, and rapid renal clearance. The recommended dose for phase II studies is 3 g/m2/day X 10 or 2 g/m2/day X 15 days.

Adult↗
PubMed1986

Clinical development of iproplatin (CHIP).

The clinical development of the second generation platinum complex iproplatin (CHIP) is reviewed. The compound was virtually non-nephrotoxic in preclinical toxicology studies and had myelosuppression as its dose-limiting toxicity in rats and dogs. A phase I study of 20-350 mg/m2 given every 3-4 weeks showed the compound to have myelosuppression as its dose-limiting toxicity in humans, with thrombocytopenia being the most prominent feature. Nausea and vomiting were almost universal, but were less severe than with cisplatin. Diarrhoea and skin rash were also noted but nephrotoxicity, neurotoxicity and ototoxicity were not seen. The maximum tolerated dose was 350 mg/m2, with or without pretreatment hydration. In pharmacokinetic studies three platinum-containing species were measured: total Pt, non-protein bound Pt and unchanged iproplatin. Plasma decay of total Pt was biphasic with a beta-phase half-life of 69.3 h. Plasma decay of unchanged iproplatin was monophasic with a half-life of about 1.17 h. Plasma decay of filterable Pt followed a monophasic pattern at low doses and a biphasic pattern at high doses. Urinary excretion of Pt was widely variable and incomplete. Early data from phase II studies indicate a high degree of activity in small-cell lung cancer; high activity in ovarian carcinoma has been reported by others.

Antineoplastic Agents↗
PubMed1985

Human pharmacokinetics of 1-[2-[2-(4 pyridyl)-2-imidazolinyl-(1)]-ethyl]-3-(4-carboxyphenyl) urea (CGP 15720A).

Pharmacokinetics of CGP 15720A have been studied in patients receiving this drug in a short I.V. infusion during its phase I clinical trial. Plasma decay was biphasic with a mean t1/2 beta of 4.9 +/- 2.47h. The drug was cleared rapidly from plasma (7.02 +/- 5.95 L/h). Renal clearance (4.13 +/- 1.65 L/h) appears to be the major clearance pathway. The steady state volumes of distribution of the drug indicate limited tissue distribution for the drug. Studies with plasma and urine of patients receiving 14[C] GCP 15720A indicate that the drug is not metabolized. CGP 15720A could be measured in cerebrospinal fluid.

Aged↗
PubMed1985

Evaluation of the nephrotoxicity of iproplatin (CHIP) in comparison to cisplatin by the measurement of urinary enzymes.

Levels of three enzymes, leucine aminopeptidase (LAP), N-acetyl-beta-D-glucosaminidase (NAG), and beta-glucuronidase (BGA) were measured in the urine of patients receiving hematologically toxic doses of iproplatin (a) with or (b) without pretreatment hydration. The maximum post-treatment increases in the levels of each of the enzymes were compared between these two groups of patients. In addition, the maximum increases in urinary enzyme levels in iproplatin-treated patients were compared with those in patients treated with 40 mg/m2 cisplatin, a known nephrotoxic agent. Increases in LAP levels after cisplatin treatment in the periods studied are significantly higher than those after iproplatin treatment (P less than 0.05). No differences were found in the increases in BGA and NAG levels between iproplatin treatment and cisplatin treatment. No differences were found in the increases in levels of any of the enzymes between patients receiving iproplatin with pretreatment hydration and no prior hydration.

Acetylglucosaminidase↗
PubMed1985

Effect of renal function impairment of iproplatin pharmacokinetics and relation to toxicity.

The pharmacokinetics of iproplatin, a quadrivalent second-generation platinum complex the dose-limiting toxicity of which is myelosuppression, was studied in patients with different degrees of renal function impairment. The drug was administered in a 30-min i.v. infusion. The plasma decay of iproplatin was biphasic, with an overall median terminal phase half-life of 3.16 +/- 2.6 (SD) h. The overall mean volume of distribution (Vss) was 39.9 +/- 25.0 liters, with a total body clearance of 14.25 +/- 3.99 liters/h. The total body clearance of iproplatin showed a linear correlation, with renal function measured as creatinine clearance. The toxicity of the drug, expressed as percentage of reduction in platelet count, correlated linearly with the area under the concentration X time curve.

Antineoplastic Agents↗
PubMed1983

Pharmacokinetics of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) in patients with advanced cancer.

The pharmacokinetics of a second-generation platinum (Pt) analog cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (CHIP) have been studied in 12 patients at doses from 20 to 350 mg/m2. Three Pt species have been measured: total Pt and non-protein-bound Pt by atomic absorption spectrophotometry, and unchanged CHIP by separation on high-performance liquid chromatography followed by atomic absorption spectrophotometry. Plasma decay of total Pt was biexponential at all doses with a beta-phase half-life of 32.1-124 h. Plasma decay of filterable Pt was monoexponential at low doses but biexponential at high doses, with a terminal-phase half-life of 17.8-54.6 h. Plasma decay of unchanged CHIP was monoexponential at all doses, with a half-life of 0.64-1.27 h. Excretion of Pt after CHIP was rapid up to 10 h after the end of infusion and then slow. The total recovery of Pt was 15%-61% of the dose at 24 h in 19 patients. The data indicated that essentially all plasma Pt after 12 h is in the form of metabolites, most of which are protein-bound. The most striking difference between CHIP and reported data for cisplatin is the biexponential decay of non-protein-bound Pt.

Antineoplastic Agents↗