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Biomedical subjects

J M Collins

Publications and source records attributed to J M Collins.

At least 163 records · Page 9Linked to original sources
PubMed1981

Inert gas exchange of subcutaneous and intraperitoneal gas pockets in piglets.

Subcutaneous and peritoneal tissue conductances for inert gases were measured in anesthetized Yorkshire piglets. Conductance spanned at least a 50-fold range in both subcutaneous and peritoneal tissues and showed the order: sulfur hexafluoride less than helium, neon less than ethylene less than nitrous oxide. Determination of conductance by measurement of composition changes within the gas space rather than the rate of pocket disappearance was particularly advantageous for the study of rapidly absorbed gases. Also, the simultaneous breathing of several inert gases substantially reduced interindividual variation by use of a reference gas. This study contains the first description of peritoneal gas exchange, including an estimate of effective peritoneal blood flow under conditions similar to laparoscopy. The critical role of diffusivity for discrimination between film and penetration models is discussed. More definitive modeling requires in vitro determination of tissue gas solubility and diffusivity.

Absorption↗
PubMed1981

Flow cytometric monitoring of R 3327 rat prostate carcinoma.

The R 3327 G tumor responds to estrogen in early stages, but relapses when estrogen therapy is continued beyond 50 days postimplantation. Measurement of DNA content per cell by flow cytometric analysis revealed two populations of cells in the tumors with ploidies of 2 c and 3.2 c. The proportion of aneuploid cells (3.2 c), determined from the flow cytometric DNA distributions, correlated well with tumor weight and age in control and estrogen treated animals. The simple parameter of per cent aneuploid cells thus adequately reflected the responsive and unresponsive states of tumors under hormonal therapy.

Aneuploidy↗
PubMed1981

Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans.

Intrahepatic tumor is a major problem in clinical oncology. While direct intravascular infusions provide high local drug concentrations and variable rates of tumor response, they are limited by technical considerations and complications. In this study, we have tested whether high portal venous and hepatic arterial concentrations of 5-fluorouracil (5-FUra) can be achieved by administering drug via peritoneal dialysis. Four patients with metastatic colon carcinoma had a Tenckhoff catheter surgically implanted. During dialysis therapy with 4 mM 5-FUra, simultaneous samples of peritoneal fluid and of portal venous, hepatic venous, and peripheral venous, and arterial blood were obtained, and 5-FUra concentrations were determined. Mean peak portal vein drug concentrations were 60 microM and exceeded the measured concentrations in the other vessels. Total drug exposures as measured by concentration x time (mM x min) during Exchange 1 were: portal, 3.8 +/- 0.65; hepatic vein, 0.97 +/- 0.44; peripheral vein, 0.90 +/- 0.32; and arterial, 1.1 +/- 0.26. During Exchange 7, total drug exposures were: portal, 6.3 +/- 1.4; hepatic vein, 2.5 +/- 1.3; peripheral vein, 2.3 +/- 1.1; and arterial, 2.7 +/- .85. The fraction of i.p. drug that exited the peritoneal cavity through the portal venous system ranged from 0.29 to 1.0. This variation resulted in part from uncertainty in estimating portal blood flow and gastrointestinal drug elimination. Calculated hepatic extraction was 67% (range, 0.23 to 0.89). Extrahepatic metabolism was demonstrated. Measured 5-FUra concentrations compared favorably to values predicted by a pharmacokinetic model for 5-FUra. Dialysis therapy (i.p.) with 5-FUra provides a means of achieving high drug concentrations for treating both i.p. and intrahepatic tumor. Further clinical testing of this route of administration is warranted.

Adult↗
PubMed1981

Nonlinear pharmacokinetics of misonidazole and desmethylmisonidazole in the isolated perfused rat liver.

Dose-dependent elimination of misonidazole (MISO) and its metabolite desmethylmisonidazole (DESMISO) were investigated in the isolated perfused rat liver and saturation kinetics were observed for both compounds. The simplest model which accurately described the DESMISO clearance from the perfusate consisted of a saturable elimination pathway (Vmax 3 = 32 nmol/min, Km3 = 11 micro M) in parallel with a first-order pathway [CL5 (clearance) = 0.21 ml/min]. A similar model was constructed for MISO (Vmax2 = 110 nmol/min, Km2 = 10 micro M, CL4 = 0.36 ml/min), but required an additional saturable pathway (Vmax1 = 226 nmol/min, Km1 = 1850 micro M) to characterize the generation of DESMISO, as suggested by in vitro microsomal studies. A good correlation was demonstrated between DESMISO perfusate concentrations (generated during the course of MISO perfusion) and simulations based on the MISO model which included the microsomal data. The MISO and DESMISO models demonstrate that the relative contributions of the different pathways for MISO and DESMISO elimination are strongly concentration-dependent and that the MISO leads to DESMISO pathway is a minor route. A qualitative similarity in saturation kinetics was observed in the disappearance curves for both MISO and DESMISO from the liver perfusate. MISO In combination with an excess of DESMISO resulted in a marked decrease in the clearance rate of MISO from the liver perfusate. This observation suggest that MISO and DESMISO are metabolized along similar pathways.

Animals↗
PubMed1981

High-volume intraperitoneal chemotherapy with methotrexate in patients with cancer.

The use of high-volume i.p. chemotherapy with methotrexate (7.5 to 50 microM methotrexate administered via peritoneal dialysis technique) was studied in four patients with ovarian cancer and one patient with malignant melanoma. All had tumor localized to the peritoneal cavity or liver. Methotrexate concentration in the peritoneum could be maintained 18- to 36-fold higher than corresponding plasma concentrations using this method, plasma levels remaining in the range of 0.2 to 3 microM. While local toxicity was generally limited and manageable, mild aseptic peritoneal irritation was commonly seen, and one episode of bacterial peritonitis did occur. Because of the concentration difference between peritoneum and the systemic circulation, systemic toxicity was moderate with only six of 29 treatment cycles resulting in myelosuppression. No definite therapeutic benefit was seen, but the tumors of four of five patients had demonstrated resistance to a methotrexate-containing chemotherapeutic regimen prior to this study. Further investigation of this novel treatment modality is warranted. In addition, this study provides the first measurement of peritoneal methotrexate clearance and the ratio of peritoneal in total body clearance.

Adenocarcinoma↗
PubMed1980

Different rates of DNA synthesis during the S phase of log phase HeLa S3, WI-38, and 2RA cells.

The amounts of DNA in individual cells of synchronized or log phase cultures can be determined from flow cytometry measurements of DNA:propidium fluorescence. We have used a model based on cell transit times through the cell cycle to obtain rates of DNA synthesis corresponding to different parts of the S phase of log phase cells. The five rates predicted by this method for log phase HeLa cells correlate well with those obtained by following the progression of highly synchronized HeLa cells through S phase. The absolute values of the rates can be expressed in channel number (proportional to fluorescent intensity), picograms of DNA, number of nucleotides, or molecular weight of DNA versus time, when the total cell cycle time is known, or in relative units, when it is not. The fastest rates for HeLa and 2RA cells are at the beginning and end of S phase, whereas WI-38 cells exhibited a gradual increase in rates from beginning to end of S phase. The determination of rates of DNA synthesis in log phase cultures, rather than synchronized ones, represents a substantial reduction in time, eliminates the possibility of induced metabolic artifacts as a result of the synchronization procedure, and permits the screening of many cell types that may not be amenable to precise synchronization.

Carcinoma↗
PubMed1980

Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes.

A two-compartment physiologic pharmacokinetic model has been developed for 5-fluorouracil (5FU). This model, which incorporates saturable whole body clearance, satisfactorily predicts disappearance kinetics after an intravenous bolus and steady-state levels during constant intravenous infusions. A half-saturating concentration (KM) of 15 microM was determined by comparison of model simulations with literature data. Both hepatic and extrahepatic elimination can be inferred for 5FU, but the exact anatomic or compartmental location of the clearance cannot be determined from the available clinical data. The effect of venous and arterial plasma sampling is discussed. This model has been extended to include intraperitoneal and oral administration of 5FU by the addition of peritoneal fluid and liver compartments.

Administration, Oral↗
PubMed1980

Variability of short-term cultures of HeLa S-3 cells: changes in DNA distributions and rates of DNA synthesis.

DNA distributions of HeLa S-3 cells in spinner culture exhibit significant time-dependent changes. The major differences appear to occur in the S-phase region. Significant changes in the rates of DNA synthesis in several S-phase subcompartments correlated well with the changes in the DNA distributions. It is proposed that fluctuations in these rates of DNA synthesis are a reflection of the inherent instability of these abnormal, heteroploid cells.

Cell Cycle↗
PubMed1980

Neocarzinostatin-induced DNA strand scission and subsequent cell cycle traverse in HeLa S3 cells.

HeLa cells were synchronized at the G1-S boundary by double thymidine block and treated for 1 hr with varying concentrations of the antibiotic anticancer protein neocarzinostatin (NCS). Cells were then released from the block and allowed to resume their cycle. Aliquots were removed at various times in order to monitor cell cycle progression and to assess repair of DNA strand breaks. Dose-dependent DNA strand breakage occurred at all concentrations of NCS tested down to 0.05 microgram/ml. Flow cytometry revealed that NCS-treated cells were delayed in entering S phase and that once in S phase their rate of progression through it was retarded significantly. At all concentrations of NCS tested, the majority of cells did not enter G2 by 12 hr. Untreated cells, on the other hand, completed mitosis by this time. NCS-treated cells had little ability to repair DNA breaks. There appeared to be a correlation between the initial number of NCS-induced DNA breaks and the delayed entry into the S phase but little correlation between the lack of strand scission repair and the retarded progress through S phase.

Antibiotics, Antineoplastic↗
PubMed1980

Applications of light scatter to separation of stem cells.

A case is presented for light scatter as a potentially important discrimination parameter for electronic sorting of hemopoietic stem cells. Examples are presented of application of light scatter to sorting of primitive hemopoietic cells from bone marrow, thymus, and fetal yolk sac, using simple empirical approaches and a cell sorter equipped with a standard fixed-angle detector. Cells sorted in this way were ultrastructurally indistinguishable from stem cells observed in whole tissue sections or unfractionated suspensions and remained viable under culture conditions. Cells were further sorted into proliferative and nonproliferative stages whose morphologies were those expected for primitive and mature cells, respectively. Light scatter was a more specific marker for primitive thymocytes than binding of peanut agglutinin. Cells sorted from fetal yolk sac suspensions were ultrastructurally similar to candidate pluripotential stem cells of bone marrow. Therefore, where sorting rather than positive identification is the primary objective of flow analysis and histochemical correlations can be established after sorting, viable stem cells can be sorted from the simple hemopoietic tissues in high and verifiable purity. Sorting of pure stem cells from marrow will require an additional parameter for which an additional angle of light scatter may suffice.

Agglutination↗
PubMed1980

Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally.

A Phase I study was conducted of 5-fluorouracil administered i.p. in a 2-liter volume of 1.5% Inpersol. The drug was administered via Tenckhoff peritoneal dialysis catheters to ten patients with tumors confined to the i.p. space. Dialysis concentrations ranged from 5 micro M to mM. Complications of the dialysis procedure alone included mild abdominal discomfort and 2 cases of gram-negative bacterial peritonitis, both easily controlled with antibiotics. 5-Fluorouracil caused the same pattern of toxicity as when administered by other routes. There was no local or central nervous system toxicity. Dose-limiting toxicity included pancytopenia and mucositis at a dialysis concentration of 4.5 to 5 mM administered for eight consecutive 4-hr exchanges. There were two documented responses in eight evaluable patients. 5-Fluorouracil concentrations were measured by high-pressure liquid chromatography. Peritoneal fluid concentrations decline in a first-order fashion with a half-life of 1.6 hr. The mean permeability area product was 14 ml/min. A mean of 82% of drug was absorbed in 4 hr. Plasma levels rise over the first 30 to 45 min and decline in a nonlinear fashion. Plasma levels are substantially lower than are peritoneal fluid levels. Mean 4-hr peritoneal fluid concentration was 298 times the simultaneously measured plasma levels. Total body clearance ranged from 0.9 to 15 liters/min and declined with increasing dialysate concentration. We conclude the i.p. route is a relatively safe way to deliver high concentrations and large amounts of drug to the i.p. cavity with a significant pharmacological advantage over conventional routes of administration.

Colonic Neoplasms↗
PubMed1979

Separation of non-proliferating from proliferating thymic lymphocytes based on light scatter analysis.

Two populations of thymic lymphocytes from eight-week-old mice were separated based on the light scatter intensity they generated while passing through a flow cell analyser. The two populations were subsequently studied morphologically and analysed for the relative amount of DNA present in each cell. Cells having a low light scatter intensity had a high nuclear:cytoplasmic ratio, a heterochromatic nucleus, and a proliferative index (S + G2 + M) of only 23%. Cells with a high light scatter intensity had a low nuclear:cytoplasmic ratio, dispersed chromatin, frequently a uropod with budding microvilli and a proliferative index of 71%. The low light scatter cells resemble small cortical thymocytes or lymphocytes from the thoracic duct described by others. The highest light scatter cells resemble medium lymphocytes shown by others to be proliferative.

Animals↗
PubMed1979

Enantiomeric purity of naproxen by liquid chromatographic analysis of its diastereomeric octyl esters.

A sensitive and specific analytical method was developed to determine the enantiomeric purity of naproxen. A simple derivatization of naproxen with (S)-(+)-2-octanol proceeded quantitatively and gave a mixture of diastereomeric esters displaying baseline separation on liquid chromatography. The ratio of these esters was the same as the ratio of enantiomers present in naproxen samples assayed. Reproducibility of the method was excellent.

Chromatography, Liquid↗
PubMed1979

Separation of resting and proliferating granulocytic precursors.

We have obtained cells in various stages of granulocytic development by a combination of isopycnic separation and electronic cell sorting. Not only were immature cells (blast cells, promyelocytes and myelocytes) separated from mature cells (bands and polys), but the immature cells were separated into proliferating (S + G2 + M) and resting (Go/G1) compartments of the cell cycle. This permits the study of the morphological and biochemical changes associated with development apart from those changes associated with proliferation.

Animals↗