Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors

PURPOSE: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS: Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION: Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.     

Failure of ketoprofen and interferon combination therapy to improve interferon-resistant chronic hepatitis C

Previous studies have documented the effectiveness of magnetic resonance imaging for evaluating and following up the development of avascular necrosis of the femoral head. One of the limitations of this technique, however, is the distortion that is encountered with ferromagnetic screws. A traumatic fracture to the femoral head is a risk factor for avascular necrosis. The addition of internal fixation, which is often required in Pipkin-type fractures of the femoral head, creates significant image distortion on magnetic resonance scans used for postoperative follow-up. The artifact and field distortion present in magnetic resonance imaging when ferromagnetic screw fixation is used has been avoided at our institution by the use of titanium hardware. The authors, therefore, recommend the use of titanium screws in the fixation of Pipkin-type fractures in the hip joint.     

Arterial pulsation-dependent perivascular cerebrospinal fluid flow into the central canal in the sheep spinal cord

The impetus for the enlargement of syringes is unknown. The authors hypothesize that there is a flow of cerebrospinal fluid (CSF) from perivascular spaces into the central canal and that the flow is driven by arterial pulsations. Using horseradish peroxidase as a tracer, the CSF flow was studied in normal sheep, in sheep with damped arterial pulsations, and in sheep with lowered spinal subarachnoid pressure. The CSF flow from perivascular spaces into the central canal was demonstrated in the normal sheep, and two patterns of flow were identified: 1) from perivascular spaces in the central gray matter; and 2) from perivascular spaces in the ventral white commissure. Flow into the central canal was also observed in the sheep with lowered spinal subarachnoid pressure, but not in those with reduced arterial pulse pressure. This study provides evidence that CSF flow from perivascular spaces into the central canal is dependent on arterial pulsations. Arterial pulsation-driven CSF flow may be the impetus for the expansion of syringes.     

15N-NMR spectroscopy studies of ammonia transport and glutamine synthesis in the hyperammonemic rat brain

Ammonia transport and glutamine synthesis were studied in the hyperammonaemic rat brain in vivo using 15N-NMR spectroscopy at a plasma ammonia level of approximately 0.39 mM raised via an intravenous [15N]-ammonium acetate infusion. The initial slope of the time course of the summed cerebral 15N-labelled metabolites was used to determine the rate of ammonia net transport during hyperammonemia as 0.13 +/- 0.02 micromol/min/g (mean +/- SD; n = 5). Based on the total accumulation of glutamine and the 1:2 stoichiometric relationship between fluxes of four-carbon skeletons and nitrogen atoms, the rate of de novo glutamine synthesis through anaplerosis and subsequent glutamate dehydrogenase action was calculated to be 0.065 +/- 0.01 micromol/min/g. The rate of total glutamine synthesis was estimated to be 0.20 +/- 0.06 micromol/min/g (n = 5) by fitting the [5-15N]glutamine time course to a previously described model of glutamate-glutamine cycling between astrocytes and neurones. A large dilution was also observed in [2-15N]glutamine, which supports the glutamate-glutamine cycle as being an important pathway for neuronal glutamate repletion in vivo.     

In vitro selection for altered divalent metal specificity in the RNase P RNA

The ribozyme RNase P absolutely requires divalent metal ions for catalytic function. Multiple Mg2+ ions contribute to the optimal catalytic efficiency of RNase P, and it is likely that the tertiary structure of the ribozyme forms a specific metal-binding pocket for these ions within the active-site. To identify base moieties that contribute to catalytic metal-binding sites, we have used in vitro selection to isolate variants of the Escherichia coli RNase P RNA with altered specificities for divalent metal. RNase P RNA variants with increased activity in Ca2+ were enriched over 18 generations of selection for catalysis in the presence of Ca2+, which is normally disfavored relative to Mg2+. Although a wide spectrum of mutations was found in the generation-18 clones, only a single point mutation was common to all clones: a cytosine-to-uracil transition at position 70 (E. coli numbering) of RNase P. Analysis of the C70U point mutant in a wild-type background confirmed that the identity of the base at position 70 is the sole determinant of Ca2+ selectivity. It is noteworthy that C70 lies within the phylogenetically well conserved J3/4-P4-J2/4 region, previously implicated in Mg2+ binding. Our finding that a single base change is sufficient to alter the metal preference of RNase P is further evidence that the J3/4-P4-J2/4 domain forms a portion of the ribozyme's active site.     

Response decision processes in relational and overt aggression

Response decision processes of relationally and overtly aggressive children were assessed for both boys and girls. A hypothetical-situation instrument, adapted from past research, was used to assess children's evaluations of relationally aggressive and overtly aggressive responses to both relational and instrumental conflict situations for third-through sixth-grade children (n = 1,166). Findings revealed that both overtly aggressive boys and overtly aggressive girls evaluated overtly aggressive responses to instrumental conflict situations in relatively positive ways. Further, overtly aggressive girls, but not boys, evaluated overtly aggressive responses to relational conflict situations in relatively positive ways. Additionally, relationally aggressive boys evaluated relationally aggressive responses to instrumental conflict situations in relatively positive ways. Gender differences were also obtained. Boys evaluated overt aggression more positively, whereas girls evaluated relational aggression more positively. Implications of these findings for the role of gender, situation type, response type, and aggression type for our understanding of children's social information processing are discussed.