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Biomedical subjects

J M Collins

Publications and source records attributed to J M Collins.

At least 145 records · Page 8Linked to original sources
PubMed1983

Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol.

Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.

Administration, Oral↗
PubMed1983

Test dose for predicting high-dose methotrexate infusions.

Eighteen evaluable patients were studied to determine whether individual methotrexate (MTX) kinetics, determined by test-dose bolus injection, could be used to predict plasma drug concentrations during and after high-dose infusion. Small nontoxic doses of MTX (10 mg/m2) was given to patients who were followed for 12 to 24 hr and the kinetic data were used to predict subsequent kinetic behavior of moderate- and high-dose methotrexate infusions (150 to 1500 mg/m2 over 12 to 18 hr). After test-dose injection, MTX clearance varied from 36 to 138 ml/min/m2 and decreased with advancing age (r = -0.49, P less than 0.05). MTX clearance varied from 24 to 100 ml/min/m2 after high-doses. Although there was a trend to decreasing clearance with advancing age, this was not as clear as with the test dose (r = -0.42, P greater than 0.05). There was no correlation between MTX clearance and creatinine clearance in this group of patients in whom creatinine clearance varied from 32 to 63 ml/min/m2. When the kinetic parameters derived from the test-dose data were used, accurate predictions could be made of the infusion plateau (r = 0.89, P less than 0.001) and 24-hr (r = 0.92, P less than 0.001) MTX concentrations after high-dose infusions. Our results indicate that test-dose MTX kinetics may serve as a guide to dose modification of MTX infusions in some high-risk patients.

Adult↗
PubMed1983

Differentiation of promyelocytic (HL-60) cells into mature granulocytes: mitochondrial-specific rhodamine 123 fluorescence.

Rhodamine 123, a fluorescent dye which binds as a result of the transmembrane potential, was used to stain the mitochondria of HL-60 cells, a cell line established from human promelocytic leukemia cells. The DMSO-induced differentiation of promyelocytic cells into mature granulocytes caused a fourfold decrease in fluorescence intensity that paralleled the disappearance of S-phase and G2M cells. This suggests that upon myeloid differentiation whereby the cells enter an irreversible quiescent state, the mitochondrial mass of the cells has decreased. This suggestion is corroborated by electron microscopy, which shows a decrease in the number of mitochondria, and by decreases in total mitochondrial protein and cytochrome oxidase activity. The respiratory rate of isolated mitochondria did not change, suggesting that the transmembrane potential remained the same. Undifferentiated cells in exponential phase of growth exhibit an intracellular heterogeneity of fluorescence intensity. This heterogeneity appears to have a cell age basis, as late S/G2M cells, obtained by centrifugal elutriation, yielded twice the fluorescence intensity of early G1 cells.

Cell Differentiation↗
PubMed1983

Distributed model for drug delivery to CSF and brain tissue.

Measurements of drug concentration in cerebrospinal fluid (CSF) provide the most accessible index of drug delivery to the brain. Our perception of the blood-brain barrier has been largely shaped by these measurements. A crucial question for the interpretation of these data is the nature of the relationships between drug concentration in CSF and the drug concentration profile in brain tissue. A distributed model for the delivery of drugs via plasma to brain tissue and CSF is presented, and the relationships between capillary exchange, tissue diffusion, and CSF turnover rate are explored. The effects of blood-brain barrier disruption on tissue and CSF concentrations are also simulated.

Animals↗
PubMed1983

Pharmacology of intraperitoneal chemotherapy.

In this review of the pharmacology and clinical application of intraperitoneal drug administration, we have tried to acquaint the reader with the current state of the art. At this juncture it is important to outline briefly some of the major remaining questions. First, as we have discussed, the analysis of tumor penetration is at present poorly formulated and needs more detailed analysis. Second, the current catheter arrangements are adequate but certainly not ideal. Third, there is need for Phase I and pharmacologic data on additional drugs to provide greater flexibility in terms of combination chemotherapy. Finally, and most importantly, there is a need for a series of careful randomized clinical trials to be done which will assess the clinical value of this form of treatment in the situations listed in Table 3.

Antineoplastic Agents↗
PubMed1983

A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240).

Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.

Adult↗
PubMed1983

Phase II and pharmacokinetic study of aziridinylbenzoquinone [2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone, diaziquone, NSC 182986] in high-grade gliomas.

2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (AZQ; Diaziquone, NSC 182986) is a rationally designed antitumor drug possessing sufficient lipid solubility to allow penetration into the central nervous system. Thirty-one patients with high-grade glioma and progressive disease following radiation, with or without previous chemotherapy, have been treated with 144 cycles of drug, consisting of 20 mg/sq m given as an i.v. infusion on Days 1 and 8 of a 28-day cycle. Responses were measured by serial computer tomography scanning. Of the 28 evaluable patients, 6 (21%) had limited improvement (10 to 40% reduction in tumor size) on computer tomography scan, 10 (36%) had disease stabilization, and 12 (43%) had progressive disease. The drug was well tolerated clinically, with little acute toxicity. The major toxicity was myelosuppression, which appeared cumulative, using this dose regimen. AZQ was measurable in both tumor tissue and tumor cyst fluid in patients on therapy. Plasma samples taken during the period of infusion confirm that 50% or more of the total AZQ exposure occurs during the infusion period. AZQ behaves as intended by design and demonstrates activity in this poor-prognosis group of patients.

Adult↗
PubMed1983

Pharmacokinetics of the hypoxic radiosensitizers misonidazole and demethylmisonidazole after intraperitoneal administration in humans.

The hypoxic radiosensitizers misonidazole or demethylmisonidazole were administered i.p. in a 2-liter volume to 6 patients affected by advanced ovarian carcinoma, and the pharmacokinetic course of the two drugs was studied. The clearance of misonidazole and demethylmisonidazole from the peritoneal fluid was 19.1 and 12.4 ml/min, respectively. At 3 hr after drug administration, both radiosensitizers had peritoneal fluid concentrations more than 8 times larger than in the plasma. The concentration x time exposure in the peritoneal fluid was 3.2 times larger than in plasma for misonidazole and 7.6 times for demethylmisonidazole. The advantage of i.p. delivery compared with systemic delivery decreases with distance from the peritoneal surface, but the advantage may be maintained for up to 1 mm or 100 cell layers. These differences between the two routes of administration provide a rational basis for the expectation that a substantial increase of the therapeutic benefits of misonidazole and demethylmisonidazole in potentiating radiation therapy or chemotherapy can be expected in treating tumors confined to the i.p. space.

Female↗
PubMed1983

Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols.

The plasma pharmacokinetics of Adriamycin and adriamycinol following a 15-min infusion of 75 mg/sq m of Adriamycin were studied in ten patients previously untreated with Adriamycin. The disappearance kinetics of Adriamycin could adequately be described by a biexponential equation with an initial half-life of 8-min and a terminal half-life of 30 hr. The major drug exposure (area under the concentration-time curve) occurs during the terminal phase where drug concentrations are generally less than 10(-7) M (0.05 micrograms/ml). An improvement in the high-performance liquid chromatography sensitivity facilitated the determination of the terminal phase. The plasma kinetics of adriamycinol, the major and only known active metabolite of Adriamycin, show a rapid initial increase in plasma concentration followed by a slow decline which parallels that of Adriamycin during the terminal phase. The relative drug exposure of adriamycinol to Adriamycin was approximately 50%. The relationship between the measured plasma drug levels and free drug available for distribution into tissues was studied by comparing the plasma binding characteristics of Adriamycin and adriamycinol. A constant 20 to 25% of the total plasma concentrations of both Adriamycin and adriamycinol was freely diffusible over the whole range of observed concentrations, 20 nM to 2 microM. Thus, the free drug exposure (area under the concentration-time curve) of tumor and host tissues in vivo can be determined from these plasma measurements, since the free drug exposures in plasma and in extracellular fluid are equivalent. These results can also serve as a guide for the design of clinically relevant in vitro studies of Adriamycin and adriamycinol. The pharmacokinetic parameters determined in this study have been used to simulate plasma concentration-time courses for a variety of Adriamycin treatment schedules. Alternatives are suggested which reduce peak plasma Adriamycin concentration while antitumor area under the concentration-time curve is maintained.

Acetylcysteine↗
PubMed1982

Nuclease S1 sensitive sites in parental deoxyribonucleic acid of cold-and temperature-sensitive mammalian cells.

Temperature-sensitive mutants of 3T3 cells (H6-15) express the transformed phenotype at 33 degrees C and the normal phenotype at 39 degrees C. Cold-sensitive mutants of Chinese hamster ovary cells (cs4-D3) express the transformed phenotype at 39 degrees C and the normal phenotype, along with a G1 block, at 33 degrees C. When either cell type is under conditions such that it is normal and in a G0 state, the number of S1-sensitive sites in purified DNA, labeled in parental chains only, is zero. When the normal cells are stimulated by 10% serum, the number of S1 sites per 10(5) base pairs increases slightly, to 0.7 in cs4-D3 and 1.1 in H6-15. Under conditions permitting the expression of the transformed phenotype, but not proliferation, the maximum number of S1 sites per 10(5) base pairs is 5 in cs4-D3 and 44 in H6-15. When the stationary transformed cells are stimulated by 10% serum, the number of S1 sites per 10(5) base pairs increases to 6 in cs4-D3 and 43 in H6-15. Furthermore, the DNA from the stimulated transformed H6-15 cells contains at least twice as many S1 sites as the total number of breaks (nicks plus gaps), raising the possibility of the acquisition of stable looped or cruciform structures as the cells are stimulated.

Animals↗
PubMed1982

Contribution of lungs to total body clearance: linear and nonlinear effects.

The contribution of the lungs to the total body clearance of drugs is examined in a framework that emphasizes their anatomical position. For intravenous administration, the lung is the only organ other than blood that can account for a total body clearance in excess of the cardiac output. Systemic arterial drug concentration and tissue drug exposure are inversely proportional to total body clearance. Although the role of the lung has been overshadowed by that of the liver, several examples are presented to demonstrate that relatively small amount of pulmonary activity can produce a large reduction in systemic arterial drug concentration. For oral administration, first-pass elimination by the liver and lungs in series results in a synergistic increase in total body clearance. Nonlinear effects caused by saturation of elimination pathways are also examined. Increased emphasis on experimental investigation of the pulmonary contribution is warranted, especially for drugs with high apparent clearance.

Animals↗
PubMed1982

Concentration-dependent disappearance of fluorouracil from peritoneal fluid in the rat: experimental observations and distributed modeling.

The rate of disappearance of fluorouracil from peritoneal fluid has been experimentally measured and mathematically modeled. The experimental data were obtained following the instillation of 50 ml of dialysis fluid which contained an initial fluorouracil concentration ranging from 24 microM to 12 mM. The rate of disappearance was strongly dependent upon concentration. A distributed model has been formulated which incorporates concepts of diffusion with saturable metabolism and nonsaturable capillary uptake in the tissue surrounding the peritoneal fluid. This model successfully describes the experimental observations and also suggests that the effective penetration depth into tissue is highly dependent upon concentration.

Animals↗
PubMed1982

Changes in the plasma membrane of yeast observed by spin label electron spin resonance and caused by photodynamic attack.

Spin label electron spin resonance (ESR) was used to characterize the response of lipid regions of the plasma membrane of yeast to photodynamic attack. Following photodynamic attack, the structure of these lipid regions changed resulting in the disappearance of an apparent order-disorder phase transition as well as impeding the diffusion of the steric acid based spin label 12NS into and across the plasma membrane. We propose that singlet molecular oxygen reacting with unsaturated carbon bonds in the fatty acyl chains of lipid surrounding channel proteins leads to an increase in the order of the lipid array and/or a change in the channel protein's conformation and is the cause of the lethal effect of externally sensitized photodynamic action.

Cell Membrane↗
PubMed1982

Diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone, plasma and cerebrospinal fluid kinetics.

Plasma and cerebrospinal fluid (CSF) kinetics of diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ), were evaluated after intravenous injection in patients with implanted Ommaya reservoirs. After a 30-min infusion plasma disappearance was very rapid, with a disposition half-life of 2 to 6 min and on elimination half-life of 25 to 35 min. Area under the concentration-time curve for CSF was 22% to 42% of the corresponding plasma area. Based upon total plasma AZQ concentration, volume of distribution for AZQ was 2.0 to 10.0 l/m2. Plasma binding of AZQ was 79% in one normal subject. When the effect of plasma binding is considered, distribution volumes are more plausible and it appears that free plasma AZQ is completely available to the CSF.

Adult↗
PubMed1982

Local and systemic toxicity resulting from large-volume ip administration of doxorubicin in the rat.

Doxorubicin was administered to rats in a simulated "belly bath" protocol. Fifty milliliters of various concentrations of drug solution was administered ip and was allowed to remain in situ for either 4 or 36 hours prior to removal. Animals were analyzed at 2, 14, and 60 days after treatment. Doses ranged from lethal (75 and 150 micrograms/ml for 4 hours; 12 and 24 micrograms/ml for 36 hours) to nontoxic (5 micrograms/ml for 4 hours). The most common lesion in surviving animals was chronic fibrosing peritonitis. Grossly, there were large volumes of peritoneal fluid in animals exposed to low concentrations (12 and 24 micrograms/ml) for 36 hours, but peritoneal adhesions were the most commonly observed finding when higher concentrations (20-150 micrograms/ml) were used for 4 hours. Commonly observed systemic toxic effects (bone marrow, gastrointestinal tract, and heart) were not seen in this study. Vehicle-treated control animals were negative for all histologic lesions and gross observations.

Animals↗
PubMed1981

Assembly of secondary intermediates during deoxyribonucleic acid replication in transformed human fibroblasts.

The elongation of replicative DNA was studied in transformed WI-38 cells (designated 2RA). Shear effects were avoided by use of an alkaline sucrose gradient sedimentation method whereby cells were lysed directly on top of gradients, at 4 degrees C in the dark. The earliest detected intermediate is a short (2 S) piece of DNA which is converted first to a 25 S piece and then to a 100 S piece, within 10 min. The 100 S piece is next converted to a 212 S, and a 370 S, and finally to a chromosomal DNA of about 450 S. This pattern is quite different from that previously reported by us for normal WI-38 cells, where there was a 50 S intermediate which was not quickly converted into a much larger size, but which gradually elongated, by addition of smaller pieces, to a larger size, of 100 S.; another difference was the time required for formation of the 100 S piece, i.e., 75 min (Rawles, J.W., Jr. and Collins, J.M. (1977) J. Biol. Chem. 252, 4762-4766).

Cell Line↗
PubMed1981

Elevated sialyltransferase activity in the intestinal lymph of colchicine-treated rats.

There is a marked increase in sialyltransferase activity (EC 2.4.99.1) in serum and a profound change in the endogenous acceptor property of sialyltransferase in the intestine of colchicine treated rats (Fraser, Ratnam, Collins and Mookerjea, (1980) J. Biol. Chem. 255, 6617-6625). To ascertain the contribution of intestine as a source of this elevated serum enzyme, sialyltransferase and other enzymes activities were measured in intestinal lymph before and after colchicine treatment. There was a 4-fold increase of the enzyme activity in lymph 3 h after treatment. The lymph flow rate, protein concentration and composition as measured by polyacrylamide gel electrophoresis were not affected. The kinetic properties of lymph sialyltransferase (protein and time dependence, pH optima and Km values for the substrate CMP-sialic acid) were essentially unchanged after treatment and were similar to the serum sialyltransferase. Alkaline phosphatase and lactic dehydrogenase activities remained unchanged. Although intestinal lymph sialyltransferase was increased by colchicine, enterectomy did not prevent the rise of serum sialyltransferase suggesting that the intestine is not a major source of the serum enzyme.

Animals↗