Three-dimensional stochastic cooling in the relativistic heavy ion collider.

Three-dimensional stochastic cooling of 100 GeV/nucleon gold beams has been achieved in the Relativistic Heavy Ion Collider (RHIC). We discuss the physics and technology of the cooling systems and present results with a beam. A factor of 2 increase in luminosity was achieved and another factor of 2 is expected.

Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule.

Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.

Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly.

Topotecan (SK&F 104864, hycamptamine, NSC 609699) is believed to exert its cytotoxic effects through inhibition of topoisomerase I, the activity of which recovers rapidly on removal of the drug in vitro. In vivo studies show that the activity of topotecan is schedule dependent, favoring repeated doses. Early human studies showed that topotecan (the active lactone) had a short half-life in plasma. To prolong drug exposure, we administered topotecan as a 24-h i.v. infusion and repeated it weekly. We treated 32 patients with doses of 1.0-2.0 mg/m2. Median performance status was 1, and all but four patients had received prior chemotherapy. Dose-limiting neutropenia occurred at doses > or = 1.75 mg/m2; nadirs were observed after 1-3 doses. The recommended phase II dose is 1.5 mg/m2/week. One patient with metastatic colon cancer had a partial response. Both plasma topotecan (lactone) and total topotecan (measured by converting the hydroxyacid form to the lactone by acidification of the sample) were measured by high-performance liquid chromatography in 21 patients. During infusion, mean topotecan plasma steady-state concentrations ranged from 4.7-11.4 nM. Plasma elimination was best fit to a one-compartment model with a mean t1/2 of 3.5 h. The mean total body clearance was 388 ml/min/m2. Concentrations of the inactive form approximated those of the lactone throughout. No evidence for dose-dependent pharmacokinetics was observed in this dose range. Pharmacodynamic analysis, using the sigmoid Emax model, revealed that the pharmacokinetic parameters of both lactone and total drug were positively correlated with bone marrow toxicity. Total drug steady-state plasma concentration provided a good estimate of neutropenia, suggesting a simple, easily monitored, pharmacokinetic parameter for adaptive dosing using this schedule. Phase II evaluation of this weekly schedule is indicated in solid tumors.

Relationship between platinum-DNA adduct formation and removal and cisplatin cytotoxicity in cisplatin-sensitive and -resistant human ovarian cancer cells.

We examined several aspects of platinum-DNA adduct formation and repair in cisplatin-sensitive and -resistant human ovarian cancer cell lines. The formation of cisplatin-interstrand crosslinks (ICLs) was measured in five DNA sequences by renaturing agarose gel electrophoresis. There were considerable differences (up to 4-fold) in ICL levels in these DNA sequences following a 4-h incubation with cisplatin; however, the pattern of ICL formation did not depend on whether the region was transcriptionally active or gene encoding. Incubation of purified DNA with cisplatin yielded an ICL pattern with considerably less variability between the regions examined. Cisplatin ICL and total DNA platination levels were significantly higher (up to 20- and 40-fold, respectively) in cisplatin-resistant cell lines as compared to the parental, cisplatin-sensitive cell line at equivalent levels of cisplatin cytotoxicity. Under cisplatin exposure conditions which yielded similar initial levels of sequence-specific ICLs, the cisplatin-resistant cells removed up to 2.5 times more ICLs by 12-h posttreatment than the parental cell line. Increased removal of the individual platinum-deoxyribonucleosides of platinum-DNA adducts was also observed in the highly resistant C200 cell line as determined by high performance liquid chromatography separation and quantitation by atomic absorption spectrometry. These results indicate that DNA repair contributes significantly to cisplatin resistance and that increased DNA-damage tolerance may also be a component of the resistance phenotype in this model system.

Pharmacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose.

The dithiolethione oltipraz (OPZ) has activity as a chemopreventive agent in animal models and is in early clinical trials. OPZ undergoes metabolism by molecular rearrangement to yield a pyrrolopyrazine derivative, M3, which we have previously shown to be inactive in the induction of detoxication genes. M3 is metabolized further: at least 10 possible conjugates have been described in three species. We developed a new high-performance liquid chromatography method to simultaneously measure plasma concentrations of OPZ and of M3. This method was applied to serial plasma samples in a Phase I clinical trial, in which OPZ was administered at single doses varying from 125 to 1000 mg/m2. OPZ and M3 concentration-time profiles were highly variable among individuals, and the occurrence of secondary concentration peaks suggested substantial enterohepatic cycling. Absorption was rapid, and the mean time to peak was 2.2 h. Maximum plasma concentration values were proportional to the dose. Harmonic mean half-lives at these doses ranged from 9.3-22.7 h. There were indications of dose-dependent pharmacokinetic properties because apparent clearance and volume of distribution at steady state increased with dose, although these changes were not statistically significant as a result of high interpatient variability. Accordingly, there were less than proportional increases in the OPZ and M3 area under the curve and maximum plasma values. Interpretation of OPZ and M3 disposition is confounded by the unknown bioavailability factor; however, the most likely inferences are that bioavailability of OPZ decreases with increasing dose and that metabolism to M3 is saturable.

Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel.

In a clinical trial of paclitaxel (Taxol) and carboplatin in combination, the severity of thrombocytopenia was less than would be expected with an equivalent dose of carboplatin alone. To determine whether a pharmacokinetic interaction was responsible for this observation, the effect of pretreatment with Taxol on the pharmacokinetics of carboplatin was examined in 11 patients. Each patient was randomized to one of two treatment groups that determined the order of drug treatments. The treatments were carboplatin as a 30-min infusion alone or immediately following 175 mg/m2 Taxol administered as a 3-h i.v. infusion. The treatments were separated by 1 week. The carboplatin dose was chosen to produce a target area under the concentration-time curve (AUC) of 3.75 mg-min/ml according to a previously published formula (A. H. Calvert et al., J. Clin Oncol., 7: 1748-1756, 1989). The mean administered dose of carboplatin was 338 mg. Serial blood samples were collected over 24 h and analyzed for total and free platinum, and, in some patients, Taxol. The pharmacokinetics of carboplatin (i.e., total clearance and volume of distribution at steady state), was not significantly affected by pretreatment with Taxol. Total clearances of carboplatin were 67.2 +/- 28.8 ml/min and 64.6 +/- 27.9 ml/min in the absence and presence of Taxol, respectively (P = 0.56). The AUC of free carboplatin (3.45 mg-min/ml) obtained in the absence of Taxol was not significantly different from that measured in the presence of Taxol (3.27 mg-min/ml). The AUC of carboplatin in both the absence and presence of Taxol agreed with the projected target AUC of 3.75 mg-min/ml. In conclusion, the application of an individualized dosing strategy is valid for the calculation of the carboplatin dose in this combination. The pharmacokinetics of carboplatin is not altered by pretreatment with Taxol at a standard dose, and a pharmacokinetic interaction is not responsible for the altered toxicity of the combination.

Saturable entry of leukemia inhibitory factor from blood to the central nervous system.

Leukemia inhibitory factor (LIF) is a neurotrophic cytokine now under clinical investigation for its effects on the CNS. We studied its passage across the blood-brain barrier (BBB) from blood to brain and spinal cord. Although a large amount of LIF was reversibly associated with the cerebral vasculature, intact LIF did reach brain parenchyma. Multiple-time regression analysis showed ready access of LIF to the CNS at a rate much faster than that of the vascular marker albumin. Excess LIF inhibited the entry of 125I-LIF after administration i.v. or by in-situ perfusion in blood-free buffer. Efflux of LIF from brain to blood was slower than reabsorption by CSF bulk flow, indicating that LIF tended to be retained in the brain. Although ciliary neurotrophic factor (CNTF) and LIF bind to the same receptor complex, CNTF did not cross-inhibit the entry of LIF into the CNS. A monoclonal antibody to LIF, however, abolished the entry of LIF. Our results show that peripherally administered LIF readily enters the brain and spinal cord by a saturable transport system across the BBB that may have biological implications.

Saturable entry of ciliary neurotrophic factor into brain.

Ciliary neurotrophic factor (CNTF), like tumor necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), is a cytokine with neurotrophic properties. Since all three cytokines are found in the periphery as well as brain, and since TNF and GM-CSF cross the blood-brain barrier (BBB) by a saturable mechanism, we investigated whether CNTF also saturably enters the brain from the blood. We found that CNTF crosses the BBB rapidly, with a rate of entry (Ki) of 4.60 (+/-0.78) x 10(-4) ml/g min, considerably faster than that of the 99mTc-albumin control. The Ki was reduced more than 3-fold by addition of excess unlabeled CNTF. The results indicate that CNTF is saturably transported across the BBB from blood to brain.

A homogenization sampling procedure for calculating trabecular bone effective stiffness and tissue level stress.

A homogenization sampling procedure is introduced which allows computation of effective trabecular bone stiffness and individual trabecula level stress based on precise models of trabecular bone architecture. Three-dimensional digitized images of 53 trabecular bone specimens with a resolution of 50 microns per voxel were directly converted into three-dimensional finite element meshes by making each voxel an 8-node isoparametric brick element. Owing to the large mesh of 8000 elements, an element-by-element preconditioned conjugate gradient (EBEPCG) program was written to solve the local homogenization finite element equations. Predicted effective stiffness measures correlated well with experimental results (R2 > 0.73). The predicted effective stiffness tended to under estimate the experimental values. Average absolute errors in effective stiffness estimates ranged between 31 and 38% for the sampling procedure compared to a range 49-150% for a regression fit to volume fraction squared. Trabecula level stress ranged between -200 and +300 times that predicted by analyzing trabecular bone as a continuum. Both tensile and compressive tissue stresses were engendered by a continuum compressive stress. Trabecula level strain energy density (SED) ranged between 0 and 100 times the continuum SED value for two trabecular specimens. In conclusion, the homogenization sampling procedure consistently predicted the influence of trabecular bone architecture on effective stiffness. It can also provide trabecular tissue stress and strain estimates for arbitrary global loading of whole bones. Tissue stresses and strains showed large variations compared to corresponding continuum level quantities.

The genus Speleocola lipovsky (Acari: Trombiculidae) with descriptions of two new species from Venezuela.

Speleocola Lipovsky 1952 is redescribed. New species S. clangula off Rhipidomys sp., Venezuela, and S. nolae off Peropteryx kappleri, Venezuela, are described. A key to the 5 included species is given.

Keys to the genera of chiggers of the western hemisphere (acarina: trombiculidae).

Synotpic keys to the 87 genera of chiggers in the Western Hemisphere (Nearctic and Neotropical regions) as well as illustrations to the terminology employed, are presented.