Search PubMed⌕ Search

Biomedical subjects

L M Allen

Publications and source records attributed to L M Allen.

At least 37 records · Page 2Linked to original sources
PubMed1981

The relationship of blood vessel proximity and time after radiolabeled thymidine administration to tumor cell population kinetics in a transplanted mouse mammary tumor.

The relation between the time of administration of tritiated thymidine and the proximity of cells to blood vessels and their labeling index, grain density per labeled cells, mitotic index, and growth fraction have been determined autoradiographically in a transplanted mammary tumor of mice. The tumor was rich in blood vessels, and the cells were densely packed, showing a few glandular structures. Shortly after tritiated thymidine administration, cells closer to the blood vessels (0-70 mu) showed a higher percentage of labeled and mitotic cells, more grains per labeled cells, and a higher growth fraction than the cells located in the outer zone (70-140 mu). Eight days later the values of these parameters were similar in both areas. The cell cycle time, the duration of mitosis, the S phase, the G1 phase and the G2 phase were essentially the same in both zones. These results could be attributed either to reutilization of nucleic acid metabolites or release of the original precursor from cells. It is suggested that label redistribution, which may perturb the measurement of the apparent turnover of labeled proliferating cellular systems in the body should be considered in all cases of autoradiographic or labeled purine-pyrimidine turnover studies.

Animals↗
PubMed1980

Analysis of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyranoside) by high-pressure liquid chromatography.

A rapid and specific high-pressure liquid chromatographic assay is described for the quantitative analysis of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyranoside) (I) in plasma. After chloroform extraction, I was analyzed by reversed-phase chromatography and UV detection (252nm). The maximum sensitivity was 0.1 microgram/ml. Quantitation was by relative response factor calibration using an integrating microcomputer. Over the concentration range of 0.5-90 microgram/ml, the average recovery of I from plasma was 95.4 +/- 3.8% (SD).

Antineoplastic Agents↗
PubMed1980

The effect of the glutamine analog, AT-125, on the cell cycle of MCF-7 and BT-20 human breast carcinoma cells using DNA flow cytometry.

It was found by DNA flow cytometry that AT-125 preferentially inhibited the cell cycle progression in G1-phase of BT-20 more so than MCF-7 breast carcinoma cells in vitro and that cells washed free of the drug now possessed S-phase DNA content. It was also found that gamma-glutamyl transpeptidase levels were more than 2 times higher in BT-20 than in MCF-7 cells.

Antineoplastic Agents↗
PubMed1980

Immunological modification of adriamycin cardiotoxicity.

Adriamycin-specific antibody has been shown to increase the survival of mice receiving an acute cardiotoxic dose of adriamycin. The concentrations of adriamycin in heart tissue were reduced and those in tumor elevated for more than 2 days in animals that received the antibody. The adriamycin-specific antibody prevented and reversed adriamycin inhibition of cardiac microsomal Na-K ATPase.

Animals↗
PubMed1980

Studies on the pharmacology and cytokinetics of 2,3-dihydro-1H-imadazo[1,2-b]pyrazole (NSC 51143) with P815 mastocytoma cells.

A study has been made of the biochemical, cytokinetic, and pharmacological effects of pyrazole-imidazole (NSC 51143) (IMPY) on P815 mastocytoma ascites cells maintained in mice and of cells maintained in culture. The distribution phase of IMPY equivalents from the peritoneal fluid of the mouse was found to be two hr, with an elimination phase of 69 hr. No consistent alteration in the ribonucleotide pools of the ascites tumor cells in vivo was observed by high-pressure liquid chromatography using i.p. doses of IMPY up to 1000 mg/kg (25% increase in survival). Correspondingly, no significant alteration occurred in the proportion of cells in G0, G1, S, or G2 + M in vivo by flow cytometric analysis. This is in contrast to the in vitro data which showed a signifcant blockage in S phase (50% effective dose, 1.6 x 10(-4) M). Using Dowex 1 chromatography of extracts from ascites tumor cells treated with IMPY in vivo, several intracellular drug metabolites were detected, and their proportion was noted to change with time. No such metabolism was detected in vitro. Some radiolabeled drug was detected in RNA and DNA from the cold, acid-insoluble fraction of ascites tumor cells. Analysis of alkaline sucrose sedimentation indicated that part of the radiolabeled IMPY was in the heavy-sedimenting DNA fraction.

Animals↗
PubMed1979

Hymenolepis diminuta: the role of the tail in determining the position of the worm in the intestine of the rat.

One-worm infections of Hymenolepis diminuta in rats had their strobila severed surgically, in the neck region, on day 14 of an infection. The scolex and remaining strobila survived but were recovered from a more posterior region of the intestine where small worms are attached during development. The movement to the new region was usually not complete in 24 h, but was complete by 72 h, and probably by 48 h. The operation, involving laparotomy and an incision in the duodenal wall which avoided severing the strobila, had no effect on the position of the worm but did depress the growth of the worm during the ensuing 24 h. It is suggested that (1) the preferred site for H. diminuta is 30-50% down the small intestine, (2) the worm monitors information about its position from all over its strobila and (3) as the worm grows, its position is determined by balancing the input of adverse information from its tail and head ends. The slowness with which surgically shortened worms return to the preferred site may be due either to delay in the worm "realising" it has no tail, or to the location stimuli in the intestine being disturbed for 24 h by the operation.

Animals↗
PubMed1979

The effect of early intervention and pre-school stimulus on the development of the Down's syndrome child.

This paper describes the effect on a group of D.S. children of early and continuous parental counselling together with intensive pre-school stimulation in which the parents were fully involved. The stimulated group is compared with a similar group who developed unaided in their own homes, and with a third group who were institutionalised before their second birthday. Developmental Clinics in East Kent providing the stimulus are described. The effects of social class, parental age and family pattern were noted. The tests used were the Griffiths' Developmental and Stanford-Binet Scales, and the school placement at five years was studied. The results show that the stimulated group score higher on the IQ and DQ tests and particularly on Personal Social and Speech Development. School placement acts as an unbiased measurement of progress, and suggests that they are more easily integrated into the normal community.

Child Development↗
PubMed1978

Multicompartment pharmacokinetic model of 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) in humans.

The formation and elimination of the metabolite of 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) (I) were studied in seven patients with advanced cancer who received I intravenously. The plasma concentration-time data best fit a triexponential equation. The volume of the metabolite compartment (27.5 liters) was calculated as a fraction of the extrapolated volume. A larger body clearance (111.7 ml/min) of metabolite as compared to the renal clearance (31.3 ml/min) indicates that the metabolite is lost from the plasma equivalent space by another elimination route. The combination of metabolite data presented here with previously published data for unchanged I leads to a multicompartment model for the distribution, metabolism, and excretion of I and its metabolite. A comparison of algebraically derived model transfer constants with those evaluated by computer fitting the system of differential equations is presented.

Etoposide↗
PubMed1978

Cell population kinetics of fast- and slow-growing transplantable tumors derived from spontaneous mammary tumors of the DBA/2 Ha-DD mouse.

The proliferation kinetics of a fast-growing spontaneous mouse mammary tumor subline (SMT-F) and a slow-growing spontaneous mouse mammary tumor subline (SMT-S) tumor have been determined autoradiographically at 2 different stages of tumor growth. The length of the cell cycle and the growth fraction for SMT-F were 11.2 hr and 0.85, respectively, on Day 14 and 12.1 hr and 0.78 on Day 28. For SMT-S these same parameters were 15.6 hr and 0.50 on Day 14 and 16. 1 hr and 0.45 on Day 28. On Days 14 and 28 the mitotic indices were 1.3 and 1.0%, respectively, for SMT-S, compared to 2.2 and 1.9% for SMT-F. The cell loss rate, cell loss factor, and cell loss were significantly higher for SMT-F than for SMT-S. The difference in the growth rates for these 2 tumor lines was attributable to a slight prolongation of the length of the cell cycle and a reduction in the growth fraction of SMT-S.

Adenocarcinoma↗
PubMed1976

Pharmacokinetics of divided-dose ifosfamide.

The pharmacokinetics of a divided-dose schedule of ifosfamide was investigated in 3 patients given 1, 600 to 2,400 mg/sq m/day for 3 days, with a second course of treatment 21 days later. In contrast to the biexponential decay seen with single-dose ifosfamide (5,000 mg/sq m), data for divided low-dose plasma ifosfamide are best fitted by a monoexponential decay function compatible with a one-compartment open model. Plasma half-life for ifosfamide given in the divided-dose schedule was 6.9 hr, less than half that previously reported for high single-dose ifosfamide. Renal excretion rates and clearances for unchanged drug were similar in both schedules. The proportion of drug metabolized was larger and amount of unchanged drug excreted in the urine was smaller than after single large doses. The elimination constant for unchanged ifosfamide increased from day 1 to day 2 of treatment and remained relatively stable from day 2 to day 3 in the multidose regimen, with all parameters reverting to the pretreatment values 21days later.

Alkylating Agents↗
PubMed1976

Studies on the human pharmacokinetics of isophosphamide (NSC-109724).

The pharmacokinetics of isophosphamide (IP) in man has been studied using 14C-labeled drug and differential extraction of unchanged drug from metabolites by CHCl3 extraction of plasma and urine. The plasma decay of IP is biphasic with a terminal half-life of 15.2 hours which is twice that reported for cyclophosphamide (CP). The fraction of drug metabolized is 49% for IP compared to 88% reported for CP. This is consistent with the six-times larger pseudometabolic pharmacokinetic rate constant reported for CP (0.26 hr-1) than found by us for IP (0.04 hr-1). The renal clearance for IP (21.3 ml/min) is two times that of CP (10.7 ml/min). In addition to an analysis of the kinetics of disposition and elimination of unchanged IP, an analysis of the pharmacokinetics of total metabolite of IP in plasma and urine was made. A nonlinear pharmacokinetic model which includes a term for biotransformation according to Michaelis and Menten revealed that the total metabolites do not diffuse from a small plasma space of 2.1 liters but are excreted directly via the urine. In contrast to the biexponential plasma decay of single, high-dose IP (5 g/m2), multiple-dose IP (2.4 g/m2/day X 3) shows a monoexponential decay with a half-life of 6.9 hours, a pseudometabolic rate constant of 0.08 hour-1, and a renal clearance of 18.7 ml/minute. The fraction of drug metabolized (79.7%) calculated from the pharmacokinetic parameters agrees with the fraction of drug recovered in urine as total metabolites (72.8%). This is distinctly different from high-dose IP (48.6%) but similar to the fraction of drug metabolized as reported for CP (88.0%). This suggests that the pharmacokinetic transfer constant for IP metabolism is dose dependent, an observation that may be useful in developing new IP regimens.

Cyclophosphamide↗
PubMed1976

Thalicarpine (NSC-68075): plasma decay and urinary excretion in man.

The plasma decay and urinary excretion of 3H-thalicarpine were studied in a total of 19 patients at doses of 300-1900 mg/m2. Plasma decay was triexponential with a terminal phase half-life of 198-1386 hours in five patients. Urinary excretion was slow and erratic, a total of 19.84% of the dose being excreted in 285 hours in nine patients. Only small amounts of unchanged thalicarpine appeared in the cerebrospinal fluid. The data indicate extensive localization of thalicarpine in the tissues and the danger of drug accumulation if it is given at short dose intervals.

Aporphines↗
PubMed1975

Pharmacokinetics of ifosfamide.

A multicompartment pharmacokinetic model for ifosfamide has been employed using a system of first-order differential equations, which includes a term for metabolism according to Michaelis-Menten kinetics in order to describe the distribution and elimination parameters of ifosfamide in man. The model satisfactorily accounts for all the administered drug. The pseudometabolic rate constant for ifosfamide in man is found to be less than 20 percent of that reported for cyclophosphamide in man, in agreement with the more extensive metabolism of cyclophosphamide than ifosfamide. A number of the pharmacokinetic parameters for ifosfamide differ substantially from those reported for cyclophosphamide. The volume of distribution for ifosfamide metabolites was found to be approximately equal to the plasma space volume. The central compartment volume for intact ifosfamide is slightly larger than for cyclophosphamide and includes the easily diffusible extravascular space of the body and suggests lack of protein binding. The renal clearance of ifosfamide is low and about twice that of cyclophosphamide. The model indicates that only a small fraction of the total metabolites distribute into the peripheral compartment and suggests that multiple doses of the drug may be useful.

Antineoplastic Agents↗
PubMed1975

EPEG, a new antineoplastic epipodophyllotoxin.

Nine patients were studied with tritium-labeled EPEG, a new epipodophyllotoxin antineoplastic agent. Four patients received 220 and 5 received 290 mg/sq m body surface area intravenously in 500 ml in 1 hr. Postinfusion plasma decay was biphasic with mean values for the parameters at 220 mg/sq m, A, 25.8 mug/ml; B, 3.35 mug/ml: alpha, 0.50 hr-1; beta, 0.074 hr-1, and mean values at 290 mg/sq. m, A, 33.7 mug/ml; B, 4.35 mug/ml; alpha, 0.36 hr-1; beta, 0.066 hr-1. Mean volume of distribution was 32.07% of body weight. Urinary recovery was 43.5%, of which 66.8% was unchanged drug. Penetration of drug into the cerebrospinal fluid was poor. The results indicate that both renal excretion and metabolism are important for elimination of the drug.

Adult↗
PubMed1975

PTG, a new antineoplastic epipodyphyllotoxin.

The pharmacology of 4'-demethylepipodophyllotoxin 9-(4,6-0-thenylidene-beta-D-glucopyranoside) PTG, a new anticancer drug, is reported. Six patients with advanced cancer were treated with PTG (67 mg/m2 of body surface area intravenously) specifically labeled with tritium as the first dose of a weekly x 6 course. Recovery of drug in the urine was 44.49 +/- 8.2% of the administered dose in 72 hr, of which 78.7 +/- 5.1% was metabolite. Recovery in the feces was 0 to 10.05% in 4 patients. Plasma decay fitted the equation Cp = Ae(-alphat) + Be(-betat) + Ce(-gammat) by nonlinear least-squares regression. Mean values for the parameters (after infusion) were A 14.3 +/- 5.5, B 9.66 +/- 3.98, C 2.44 +/- 1.33 mug/ml; alpha 2.05 +/- 1.25, beta 0.26 +/- 0.15, gamma 0.038 +/- 0.016 hr(-1). Levels of drug in the cerebrospinal fluid (CSF) were less than 1% of plasma levels in 3 patients at 24 hr after treatment and 27% in 1 patient who had had brain surgery and brain radiotherapy. Four of 4 patients considered evaluable for toxicity (greater than 2 consecutive weekly doses) developed leukopenia (WBC les than 5,000/mm3). Mean nadir of WBC was 3,600/mm3. The most marked leukopenia (WBC, 2,300/mm3) was seen in the patient with the longest terminal phase plasma half-life (38.5 hr). Two of 5 patients evaluable for response received clinical benefit (1 laryngeal carcinoma, 1 histiocytic lymphoma). It is concluded that PTG has a long terminal phase half-life (11-38.5 hr), is largely metabolized, and does not penetrate the normal blood-brain barrier.

Adult↗