Search PubMed⌕ Search

Biomedical subjects

A Gillespie

Publications and source records attributed to A Gillespie.

At least 55 records · Page 3Linked to original sources
PubMed1990

Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule.

Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.

Adolescent↗
PubMed1990

A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors.

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was greater than 95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing's sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.

Adolescent↗
PubMed1989

Phase I trial and pharmacokinetic evaluation of fazarabine in children.

A phase I trial of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 16 children with refractory malignancies. Dose-limiting toxicity consisting of reversible granulocytopenia and thrombocytopenia was observed in 4 of 4 solid tumor patients treated at the starting dose of 20 mg/m2/h. Subsequent patients were treated at a dose of 15 mg/m2/h which was determined to be the maximum tolerated dose. Moderate nausea and vomiting were the only other toxicities observed. Plasma steady-state concentrations of fazarabine were attained by 2-4 h in all patients and were 1.8 and 2.5 microM at the 15- and 20-mg/m2/h doses, respectively. The total body clearance of fazarabine was 571 and 550 ml/min/m2 at the 15- and 20-mg/m2/h doses, respectively. In three of four patients evaluated, fazarabine was detectable in the cerebrospinal fluid (CSF). Steady-state CSF concentrations ranged from 0.29 to 0.74 microM in these three individuals and the steady-state CSF:plasma ratios ranged from 0.22-0.25. Both the plasma and CSF steady-state concentrations were within the 0.1 to 1 microM range reported to be cytotoxic in vitro against the Molt-4 human T-lymphoblastic leukemia cell line. Based on the above, the optimal dose for phase II trials of fazarabine administered as a 24-h infusion is 15 mg/m2/h (360 mg/m2/day).

Antimetabolites, Antineoplastic↗
PubMed1989

Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa.

A Phase I trial of thiotepa (TT) administered as an i.v. bolus was performed in 19 children with refractory malignancies. The starting dose was 25 mg/m2 with escalations to 50, 65, and 75 mg/m2. Seven additional patients were treated with 8-h infusions at 50 or 65 mg/m2. The maximum tolerated bolus dose was 65 mg/m2. Reversible myelosuppression was the dose-limiting toxicity. The plasma and cerebrospinal fluid (CSF) pharmacokinetic parameters of TT and its major active metabolite tepa (TP) were also evaluated. When the bolus or infusion methods of TT administration were compared, there was little difference observed in any pharmacokinetic parameter for either TT or TP. The plasma disappearance of TT was rapid and biphasic with half-lives of 0.14 to 0.32 and 1.34 to 2.0 h. Dose-dependent pharmacokinetics was demonstrated by steadily declining plasma clearance with increasing TT dose. Clearance values declined from 28.6 liters/m2/h at the 25-mg/m2 dose to 11.9 liters/m2/h at the 75-mg/m2 dose. The half-life of TP was longer than that of TT and ranged between 4.3 and 5.6 h. There was evidence of the saturation of TP production. TT and TP both exhibited excellent penetration into the CSF, producing lumbar and ventricular concentrations which were nearly identical to simultaneous plasma concentrations. In one patient with a Rickham reservoir, the CSF:plasma area under the (concentration x time) curve ratios for TT and TP were 1.01 and 0.95, respectively. The above data indicate that TT can be safely administered to pediatric patients at doses higher than conventionally used. The favorable CSF penetration of TT and TP suggests that Phase II studies of TT be considered in patients with central nervous system tumors.

Adolescent↗
PubMed1989

Muscle cell potassium, RNA and hydration in pregnancy and pre-eclampsia.

Thirty four pregnant women from 26 to 38 weeks gestation and 24 pregnant women with pre-eclampsia gave samples of muscle (rectus abdominis) at caesarean section. Muscle samples were analysed for H2O, K+, Mg2+ and Na+. Cell extracellular H2O was partitioned by the use of the Cl- space. Also protein, nucleic acids and Zn2+ were determined. From 26 to 38 weeks gestation the concentration of K+ per litre of cell water ([Ki]) slowly declined. The slope was significant. Points for patients with pre-eclampsia fell below the line and analysis of covariance showed that the two populations were different (P less than 0.001). Patients A-J were regarded clinically as severe pre-eclamptics. Points for these patients, in general, fell between 1 and 2 SDs below the normal line. Since other cations per litre of muscle cell water did not change, questions are raised. is the cation gap filled by amino acids or does vascular spasm cause a leakage of K+ from muscle cells? Does hypotonicity eventually develop leading to water intoxication? The low oncotic pressure in pre-eclampsia (shown here), the negative free water clearance could all favour increased cell hydration (some evidence for this is presented here towards term). Assessment of available information concerning creatinine excretion during normal pregnancy and K40, K42 studies together with our own rodent studies leads us to believe that a significant increase in muscle mass occurs, but such may not be the case in pre-eclampsia since the reduction in RNA and Zn2+ concentrations in muscle would suggest excessive protein degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗
PubMed1987

Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells.

Myeloma cells destroy bone by producing an osteoclast-stimulating factor that has chemical and biological characteristics similar to the bone-resorbing activity present in the supernatants of activated leukocyte cultures. Recently, a number of bone-resorbing leukocyte cytokines have been identified, including interleukin-1, lymphotoxin, and tumor necrosis factor. We have examined the products of human myeloma cells for the presence of these bone-resorbing cytokines. In a tumor cell line derived from a patient who had myeloma with osteolytic bone lesions and hypercalcemia, we found that the myeloma cells induced bone-resorbing activity and cytotoxic activity in vitro. Most of the bone-resorbing activity and all cytotoxic activity were suppressed by neutralizing antibodies to lymphotoxin. The myeloma cells expressed both lymphotoxin and tumor necrosis factor mRNA, but no tumor necrosis factor could be detected in the cell-culture medium. Interleukin-1 mRNA was not detected in the myeloma cells, and biologic activity of interleukin-1 was not measurable in the medium harvested from the cultured cells. The bone-resorbing activity induced by recombinant tumor necrosis factor and recombinant interleukin-1 was not affected by treatment with the lymphotoxin antibodies. When lymphotoxin was infused subcutaneously into normal mice (10 micrograms per day for three days), their plasma calcium levels increased. We also evaluated four established cell lines derived from three other patients with myeloma, and found a similar pattern of lymphotoxin expression in each. It appears that production of the bone-resorbing cytokine lymphotoxin is related to osteoclastic bone destruction and hypercalcemia in patients with myeloma.

Animals↗
PubMed1985

Muscle cell growth and the distribution of water and electrolyte in human pregnancy.

Ten normal pregnant women had muscle composition analyses (rectus abdominis) carried out at 39-40 weeks of pregnancy. Water, chloride (Cl), chloride space (ECV), non-chloride space (ICW), potassium (K), sodium (Na), magnesium (Mg) and zinc (Zn) determinations were carried out. Analyses for DNA (cell number), protein: DNA ratio (cell size), RNA and collagen were also performed. Similar analyses were performed on uterine muscle and placentae before and after perfusion with Earle's solution. Data from pregnant patients were compared with similar estimations carried out on rectus abdominis samples from 13 non-pregnant subjects undergoing gynaecological procedures. Muscle tissue and predicted muscle mass (MM) (which constitutes 40% of body weight) demonstrated that the gain in body K was due to the products of conception, that ICW decreased per unit weight in muscle (8%), ECV increased (41%) without a radical change in muscle water content (2%). Overall a 6 l gain in ECV and a 2 l gain in ICW can be accounted for during pregnancy. The results of this study indicate that added hydration excluding the products of conception (placenta, infant, uterus) is mainly extracellular. Intracellular Na concentration decreases (50%) and it is speculated that the cation gap is made up by H+ in the presence of extracellular alkalosis. Muscle cells diminish in size but cell number per gram is constant. Zinc content (Zn/DNA) decreases. Previous experimental work suggests that MM increases by about 10% during pregnancy and this information has been included in considerations but it remains to be shown to what extent total muscle cell numbers increase and as to whether such increased muscle growth remains following pregnancy.

Cell Division↗
PubMed1979

Effects of the prostaglandins on the uterus. Prostaglandins and uterine contractility.

The effect of intravenous and intrauterine administration of PGE1 or PGE2 and PGF2 alpha as well as oral administration of PGE2 on the sensitivity and reactivity of the nonpregnant human uterus was studied. With the use of the flaccid microballoon technique or a micro transducer catheter, uterine recordings were made at frequent intervals throughout the menstrual cycle. Independently of the route of administration and of the phase of the cycle, treatment with PGF2 alpha invariably resulted in stimulation of uterine motility. A high sensitivity to PGF2 alpha was noted during the late secretory phase both in normal and dysmenorrheic women. A marked decrease in sensitivity to both PGE2 and PGF2 alpha administered by the intrauterine route was observed in the periovulatory phase. Inhibition of uterine contractility by PGE2 following both intrauterine and oral administration was noted during active menstrual bleeding in normal as well as in dysmenorrheic women. These findings suggest that endogenous prostaglandins may play a role in the regulation of the normal uterine motility during the menstrual cycle and that the main reason for the abnormal contractility pattern seen in dysmenorrheic women during menstrual bleeding is an increased PGF2 alpha/PGE2 ratio.

Administration, Oral↗
PubMed1978

Antepartum stress cardiotocography using buccal oxytocin.

The use of buccal pitocin in the performance of stressed antenatal cardiotocography was studied. Sixty-three tests were performed on 40 patients. All the patients were followed through labour and delivery. The results were evaluated and compared with those where an intravenous oxytocin infusion was used. Buccal pitocin produced comparable uterine contractions to those obtained by intravenous oxytocin, with similar test results. The avoidance of venepuncture and infusion was a positive advantage of this method of applying the stress.

Administration, Oral↗
PubMed1977

Adenoepidermoid and adenosquamous carcinoma of the uterus. A clinicopathologic study of 118 cases.

A series of 118 cases of adenoepidermoid carcinoma and adenosquamous tumors of the uterus is presented. The results indicate that cervical tumors are frequently occult and are often not diagnosed until late in the course of the disease. Stage for stage, the five-year survival rate is poorer than the usual results for cervical malignancy. Endometrial tumors also had a poor five-year survival rate, with a high incidence of myometrial extension. The incidence of myometrial invasion and survival figures were similar to those for poorly differentiated endometrial cancer.

Adenocarcinoma↗
PubMed1972

Oxytocin release by infused prostaglandin.

Plasma oxytocin levels were measured serially in 22 women receiving prostaglandin E(2) or F(2alpha) intravenously for the induction of labour. Oxytocin was detected in the plasma of 19 of the 22 women; positive levels were found in 60 (43%) of 139 plasma samples, an incidence similar to that in the late first stage of spontaneous labour. Oxytocin was found in the maternal plasma even when the fetus was dead, and in the plasma of two men receiving prostaglandin infusions. This indicates that prostaglandins stimulate the pituitary directly and suggests that this mechanism may play a part in the oxytocic action of infused prostaglandins.

Female↗
PubMed1972

Prostaglandin-oxytocin enhancement and potentiation and their clinical applications.

The pharmacological phenomena of enhancement and potentiation of uterine response occur respectively when combinations of some prostaglandins and oxytocin are given serially and simultaneously to a patient. Employing these phenomena allows small doses of the drugs to achieve the same effects as a large dose given alone. In a pilot study of the use of the combination of prostaglandin and oxytocin for the induction of mid-trimester abortion seven of nine women were aborted within 48 hours. Side effects attributable to prostaglandin were eliminated or reduced in severity.

Abortion, Induced↗