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L Pendyala

Publications and source records attributed to L Pendyala.

52 records · Page 3Linked to original sources
PubMed1983

Phase I clinical trial of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) (CHIP).

cis-Dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) (CHIP), a second-generation platinum complex with little or no nephrotoxicity in preclinical studies, has undergone phase I clinical testing and initial pharmacokinetic evaluation in 26 patients with solid tumors who received 40 courses of treatment. Doses of 20-350 mg/m2 were evaluated as single 2-hr infusions given every 3 weeks for two doses, with 2 L of pretreatment hydration (but no diuretics) in all but five patients. Nausea and vomiting was almost universal but was severe in only three courses. The dose-limiting toxic effect was myelosuppression, with a median wbc count nadir of 2500/mm3 and a median platelet count nadir of 32,000/mm3 at the maximum tolerated dose of 350 mg/m2. No increase in serum creatinine or decrease in creatinine clearance was seen. No pretreatment hydration was given in five of the seven patients treated at 350 mg/m2. Two cases of hypersensitivity were seen. No hearing loss was observed and no other toxic effects were noted. Plasma decay of total platinum was biexponential with a prolonged beta phase. Recovery of platinum in the urine was rapid up to 8-10 hrs and slow thereafter. Recoveries were incomplete and variable (16.5%-62% of the dose at 48 hrs).

Adult↗
PubMed1982

Studies on the pharmacokinetics and metabolism of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) in the dog.

cis-Dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) (CHIP), a new antineoplastic platinum compound, was administered iv to dogs at a dose of 10 mg/kg. Thin-layer chromatography and high-pressure liquid chromatography (HPLC) were used to evaluate the pharmacokinetics of total Pt and of unchanged drug separated from the metabolites in urine. Both chromatographic procedures indicated a half-life of 0.3-0.5 hr for the unchanged CHIP (based on urinary excretion rates). Decay of total Pt after administration of CHIP was biphasic, with an alpha-half-life of 0.6 hr and a beta-half-life of 39.4 hrs. The long beta-half-life thus appears to be due to the retention of metabolites. Unchanged CHIP was separated from two groups of more polar Pt-containing metabolites by HPLC, as well as from another less polar Pt-containing complex that is found in urine of untreated dogs to which CHIP was added. AFter the administration of CHIP, with the simultaneous decline in its level, the proportion of the very polar Pt-containing metabolite(s) accumulated in the dog urine. Unlike cisplatin, CHIP did not bind to plasma proteins in vitro.

Animals↗
PubMed1980

Purine biosynthesis and its regulation in Neurospora crassa.

Purine biosynthesis and its regulation was studied in Neurospora crassa by the incorporation of label from [14C]formate into total cellular purines. In general, the purine biosynthesis resulted in slightly more cellular guanine than adenine nucleotides. The acid-soluble pool however, contained more adenine compounds than guanine. Exogenous adenine was found to be an effective regulatory of the proximal steps of the de novo biosynthesis, while both adenine and guanine were equally effective in regulating the branch point activities. 6-Methyl purine inhibited the proximal steps of the purine synthesis more effectively than the branch point leading to adenine biosynthesis. A 6-methyl purine resistant mutant, Mepr-10, with defective adenine phosphoribosyl pyrophosphate transferase showed no inhibition of purine synthesis by 6-methyl purine, while 6-methyl purine resistant strains Mepr-3 and Mepr-1 showed partial inhibition. It has been suggested that Mepr-3 and Mepr-1 may be mutants of glutamine amidotransferase with altered affinities for 6-methyl purine. The rate of purine biosynthesis increased during the first 8 h of incubation of conidia in minimal medium, after which it declined even though the growth continued.

Drug Resistance↗
PubMed1980

Guanosine metabolism in Neurospora crassa.

Two aspects of guanosine metabolism in Neurospora have been investigated. (a) The inability of adenine mutants (blocked prior to IMP synthesis) to use guanosine as a nutritional supplement; and (b) the inhibitory effect of guanosine on the utilization of hypoxanthine as a purine source for growth by these mutants. Studies on the utilization of guanosine indicated that the proportion of adenine derived from guanosine may be limiting for the growth of adenine mutants. In wild type, adenine is produced through the biosynthetic pathway when grown in the presence of guanosine. The amount of adenine produced through the de novo biosynthesis in wild type increases with increasing concentrations of guanosine in the medium. However, the total purine synthesis does not increase. Guanosine inhibits the uptake of hypoxanthine severely. In addition, guanosine and its nucleotide derivatives also inhibit the hypoxanthine phosphoribosyltransferase activity, at the same time stimulating the adenine phosphoribosyltransferase activity. Guanosine's effects on the uptake of hypoxanthine and its conversion to the nucleotide form may be the reasons why guanosine inhibits the utilization of hypoxanthine but not adenine by these mutants.

Adenine↗
PubMed1979

Nature of 6-methylpurine inhibition and characterization of two 6-methylpurine-resistant mutants of Neurospora crassa.

6-Methylpurine, an analog of adenine, inhibits the growth of Neurospora crassa. From kinetic studies it was found that 6-methylpurine is converted to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7), and inhibits the de novo purine biosynthesis. Adenine relieves the growth inhibition caused by 6-methylpurine, whereas hypoxanthine is not very effective. Studies dealing with hypoxanthine utilization in the presence of 6-methylpurine indicated a severely reduced uptake of hypoxanthine and a general slowdown in its further metabolism. Two mutants (Mepr-3 and Mepr-10) which are resistant to 6-methylpurine were characterized. Studies of purine base uptake and the in vivo and in vitro conversion to nucleotides indicated that Mepr-10 may be an adenine phosphoribosyltransferase-defective mutant, whereas Mepr-3 may be a mutant with altered feedback response to 6-methylpurine. Both mutants showed a severely lowered hypoxanthine phosphoribosyltransferase activity, but because 6-methylpurine did not have any effect on the conversion of hypoxanthine to IMP in the wild type, it was concluded that 6-methylpurine resistance in these mutants cannot be due to lowered hypoxanthine phosphoribosyltransferase activity, but rather that the lowering of enzyme activity may be a secondary effect.

Adenine Nucleotides↗
PubMed1977

Developmental-stage-dependent adenine transport in Neurospora crassa.

Although germinated conidia of Neurospora crassa transport adenine through two different systems, only one of these, namely, the general purine transport system, which transports adenine, hypoxanthine, guanine, and 6-methylpurine, is present in freshly harvested conidia of the wild type. The second system develops during germination. The latter system can transport adenine and 6-methylpurine. Time course and kinetic studies of adenine transport in freshly harvested conidia of an ad-8 mutant indicated that, in contrast to the wild type, the general purine transport activity is very low in this strain and that the second adenine transport system is possibly present in the ungerminated conidia. A study of adenine and hypoxanthine uptake in ad-8 and ad-4 mutants, both of which cannot utilize hypoxanthine for growth, isolated that the two transport systems may be under different metabolic controls.

Adenine↗
PubMed1977

Uptake and efflux of adenine and its derivatives in Neurospora crassa.

Conidia of wild-type Neurospora crassa, preincubated for 3 1/2 h in growth medium, showed a typical triphasic pattern of adenine uptake. The three phases consisted of a quick initial uptake, followed by a plateau phase, and then by a resume lowered uptake. A study of the relative influx and efflux of [14C] adenine showed that the plateau phase in fact is a period of transmembrane movement of adenine and adenine metabolites. The efflux during the plateau phase essentially cancelled out all the influx during the same period. The uptake curve derived after taking into account the effluxed portion of radioactivity indicated that the second phase represents a period of lowered uptake activity. The beginning of the lowered uptake activity during the second phase is correlated with the presence of a high intracellular level of ATP derived from exogenous [14C]adenine. At the end of the secod phase, the intracellular level of ATP is much smaller and the rate of adenine uptake increases again. Analysis of the acid-soluble pool after feeding [14C]adenine indicated the presence of other 14C-nucleotides, but no detectable levels of bases and nucleosides were present. However, chromatographic analysis of the medium indicated that efflux results essentially in the accumulation of bases. The significance of this finding in relation to efflux is discussed.

Adenine↗
PubMed1975

Endogenous purine metabolism in the conidia of wild type and certain adenine mutants of Neurospora crassa. I. The nature of the reserve pools and pool utilization during adenine starvation.

Conidia of four adenine auxotrophs (ad 9, ad 3B, ad 8 and ad 4) of Neurospora crassa differ in their ability to germinate on adenine-deficient medium. A large percentage of the ad 9 and ad 3B mutant conidia germinate while those of ad 8 and ad 4 mutant do not. No correlation was found between the size of the conidial purine reserves and the conidial ability to germinate. In all the strains the major fraction of the conidial purine reserve pools was inosine. The ad 8 and ad 4 mutants are blocked after IMP formation in the adenine biosynthetic pathway and therefore cannot use the stored inosine for germination. Pool-utilization studies indicated that in all strains investigated some of the purine reserves were lost from the conidia during incubation. In the most readily germinating strain, ad 9, only small amounts of the purine pool were lost from the conidia and a large portion of the reserve pool was used for nucleic acid synthesis. The nature of the purine reserves present in the conidia, and the ability of the strains to prevent loss of the stored purines from the conidia appear to be among the factors influencing the conidial germination of the adenine mutants of N. crassa.

Adenine↗
PubMed1975

Effect of histidine on purine nucleotide synthesis and utilization in Neurospora crassa.

Histidine affects de novo purine nucleotide synthesis and purine nucleotide pool utilization in Neurospora crassa. The former effect was assessed qualitatively by the presence or absence of purple pigment production in ad3B and ad3A mutants. Tryptophan also affected the de novo purine nucleotide synthesis. The effect of histidine on purine nucleotide pool utilization resulted in stimulated germination of ad8 and ad4 mutant conidia in adenine-deficient medium. Increased germination was correlated with increased net levels of nucleic acids in these strains. Possible mechanisms for the dual action of histidine are discussed.

Adenine↗
PubMedDate not supplied

Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial.

A Phase I, pharmacokinetic and pharmacodynamic study of N-acetylcysteine (NAC), a potential chemopreventive agent, given daily p.o. for 6 months was carried out in 26 volunteers at higher than normal risk of malignancy. The goals of the study were to define the highest nontoxic dose, the toxicity profile, and the pharmacokinetics and pharmacodynamics of NAC. The pharmacodynamic end points studied included glutathione (GSH) in plasma, RBC and peripheral blood lymphocytes (PBL), cysteine in plasma, and two GSH-metabolizing enzymes glutathione S-transferase and oxidized glutathione reductase in PBL. The study was carried out in 2 stages. The first stage consisted of an inter- and intrasubject dose escalation; the second, an assessment of a single daily dose. Starting doses for the first 4 cohorts of 3 subjects were 400, 800, 1600, and 3200 mg/m2/day in divided doses doubled at the end of each month in the absence of toxicity to a final dose of 6400 mg/m2/day. The total planned period on NAC for each subject was 6 months. Pharmacokinetic and pharmacodynamic measurements were carried out at the beginning of the study and at the end of each month. The second stage of the study consisted of a daily dose of 800 mg/m2/day. During this part of the study, NAC in plasma and GSH and oxidized glutathione reductase (GRD) in PBL were measured on day 1 and again at the end of first, second, and sixth month on NAC. Major toxicities were bad taste and gastrointestinal disturbances. The highest nontoxic dose was 800 mg/m2/day in most of the subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMedDate not supplied

Urinary and erythrocyte polyamines during the evaluation of oral alpha-difluoromethylornithine in a phase I chemoprevention clinical trial.

Pharmacokinetics of alpha-difluoromethylornithine (DFMO) in plasma and polyamine levels in urine and erythrocytes (RBC) of subjects considered to be at a higher-than-normal risk for developing cancer and receiving DFMO in a phase I chemoprevention trial were monitored over a period of 6 months at DFMO doses ranging from 200 to 6400 mg/m2/day. DFMO pharmacokinetics was linear and attained an average peak plasma concentration of 58 micrograms/ml and an average area under the concentration x time curve from 0 to 6 h of 240 micrograms/ml.h at an administered dose of 1600 mg/m2. Transient decreases in RBC polyamine levels were observed in only 3 of 22 subjects; all of the others showed an increase in the levels at some time during DFMO administration. In contrast to these findings, 17 of 22 subjects showed a decline in urinary polyamines; 10 of 22 showed this decline by the end of the first month and the remaining subjects during subsequent administration of the drug. One subject with familial polyposis who had high RBC and urinary polyamine levels prior to DFMO treatment showed a significant decline in urinary polyamines and responded to DFMO treatment with nearly complete resolution of the polyps in the rectal stump. Our results suggest that (a) DFMO concentrations achieved in this study are adequate to modulate polyamine pools as reflected by their reduced urinary excretion; (b) the red blood cell polyamines are not reliable indicators of DFMO activity; and (c) the modulation of polyamines occurs at doses of DFMO that are tolerated by a majority of the subjects.

Administration, Oral↗
PubMedDate not supplied

Evaluation of alpha-difluoromethylornithine as a potential chemopreventive agent: tolerance to daily oral administration in humans.

An initial clinical trial of alpha-difluoromethylornithine given p.o. daily for 6 months was carried out in 27 subjects free of disease following surgery for malignancy or in a defined high-risk group for cancer. The aim was to determine the highest nontoxic dose, principal side effects, and pharmacokinetic parameters. The starting dose was 200 mg/m2/day in divided doses with escalation each month in the absence of toxicity to 6400 mg/m2/day or to the highest nontoxic dose, whichever was lower. When the highest nontoxic dose was reached, this dose was continued to complete 26 weeks of treatment. Twenty-two subjects completed 26 weeks of alpha-difluoromethylornithine treatment of whom 20 reached a nontoxic dose of at least 1600 mg/m2/day. The dose-limiting toxicity was loss of high-tone auditory acuity on an audiogram. Other side effects included diarrhea, fatigue, joint pain, insomnia, and rash. Pharmacokinetics were linear with dose. Area under the plasma concentration x time curve and maximum plasma concentration of alpha-difluoromethylornithine did not predict for development of ototoxicity. The dose for phase II chemoprevention studies should not exceed 1600 mg/m2/day.

Administration, Oral↗