Superspin glass state in a diluted nanoparticle system stabilized by interparticle interactions mediated by an antiferromagnetic matrix.

In nanoparticle systems consisting of two magnetic materials (bi-magnetic nanoparticles or nanoparticles embedded in a magnetic matrix), there is a constantly growing interest in the investigation of the interplay between interparticle interactions and the nanoparticle-matrix interface exchange coupling, because of its enormous impact on a number of technological applications. The understanding of the mechanisms of such interplay is a great challenge, as it would allow controlling equilibrium and non-equilibrium magnetization dynamics of exchange coupled nanoparticles systems and finely tuning their anisotropy. Here, we provide evidence that this interplay leads to a collective superspin glass (SSG) behavior in a system of diluted ferromagnetic (FM) nanoparticles embedded in an antiferromagnetic (AFM) matrix (5% volume fraction of Co particles in Mn film matrix). We have developed a novel mesoscopic model to study the influence of interparticle interaction on the exchange bias (EB) and the dynamical behavior of assemblies of FM nanoparticles embedded in a granular AFM matrix. Our mesoscopic model is based on reducing the amount of simulated spins to the minimum number necessary to describe the magnetic structure of the system and introducing the adequate exchange parameters between the different spins. The model replicates remarkably well the observed static and dynamical SSG properties as well as the EB behavior. In addition, the proposed model well explains the role of the significant Co/Mn alloying and of the granularity of the matrix in mediating interparticle interactions through exchange and dipole-dipole coupling between the uncompensated moments of its grains and the exchange interaction at the Co/Mn interface.

Superparamagnetic blocking and superspin-glass freezing in ultra small δ-(Fe(0.67)Mn(0.33))OOH particles.

The magnetic properties of ultra-small (~2 nm) δ-(Fe(0.67)Mn(0.33))OOH nanoparticles prepared by a microemulsion technique have been investigated by magnetization and ac susceptibility measurements at variable frequency. The results provide evidence of two different magnetic regimes whose onset is identified by two maxima in the zero-field-cooled susceptibility: a large one, centered at ~150 K (T(mh)), and a narrow one at ~30 K (T(ml)). The two temperatures exhibit a different frequency dependence: T(mh) follows a Vogel-Fulcher law τ = τ(0)exp[(E(a)/k(B))/(T-T(0))], indicating a blocking of weakly interacting nanoparticle moments, whereas T(ml) follows a power law τ = τ(0)(T(g)/T(mν)-T(g))(α), suggesting a collective freezing of nanoparticle moments (superspin-glass state). This picture is coherent with the field dependence of T(ml) and T(mh) and with the temperature dependence of the coercivity, strongly increasing below 30 K.

Role of diffusion-weighted magnetic resonance imaging in prostate cancer evaluation.

PURPOSE: The authors analysed the role of diffusion-weighted imaging (DWI) as an additional tool in magnetic resonance (MR) evaluation of prostate cancer. MATERIALS AND METHODS: Forty-one patients with suspected prostate cancer underwent MR imaging (1.5 Tesla). A DWI sequence was added to the standard morphological protocol, with a maximum b value of 1,000 s/mm(2). Diffusion maps were obtained, and the apparent diffusion coefficient (ADC) was calculated by drawing a region of interest (ROI) over healthy tissue and areas suspicious for malignancy. Histology was considered the gold standard. RESULTS: The areas correctly classified by MR imaging (42/51) had a low signal intensity on T2-weighted imaging and low ADC value (0.99 ± 0.15 mm(2)/s; p<0.01) compared with the healthy peripheral zone (PZ) (1.73 ± 0.27 mm(2)/s; p<0.01). Nine areas classified as suspicious for malignancy on T2-weighted sequences showed high ADC (1.44 ± 0.06 mm(2)/s; p<0.01) and were confirmed to be disease free by subsequent histological examination. The accuracy of morphofunctional MR imaging was 81.6% compared with 73.7% of the morphological analysis alone. CONCLUSIONS: The addition of DWI to the standard protocol increases the overall diagnostic performance of MR imaging in detecting prostatic cancer. Thus, DWI can help the clinician determine the most appropriate management strategy for the patient.

Extracellular ATP hydrolysis in Caco-2 human intestinal cell line.

Extracellular nucleotides and nucleosides activate signaling pathways that play major roles in the physiology and pathophysiology of the gastrointestinal tract. Ectonucleotidases hydrolyze extracellular nucleotides and thus regulate ligand exposure to purinergic receptors. In this study, we investigated the expression, localization and activities of ectonucleotidases using Caco-2 cells, a model of human intestinal epithelial cells. In addition, by studying ATP release and the rates of extracellular ATP (eATP) hydrolysis, we analyzed the contribution of these processes to the regulation of eATP in these cells. Results show that Caco-2 cells regulate the metabolism of eATP and by-products by ecto-nucleoside triphosphate diphosphohydrolase-1 and -2, a neutral ecto-phosphatase and ecto-5'-nucleotidase. All these ectoenzymes were kinetically characterized using intact cells, and their presence confirmed by denatured and native gels, western blot and cytoimmunofluorescence techniques. In addition, regulation of eATP was studied by monitoring the dynamic balance between intracellular ATP release and ectoATPase activity. Following mechanical and hypotonic stimuli, Caco-2 cells triggered a strong but transient release of intracellular ATP, with almost no energy cost, leading to a steep increase of eATP concentration, which was later reduced by ectoATPase activity. A data-driven algorithm allowed quantifying and predicting the rates of ATP release and ATP consumption contributing to the dynamic accumulation of ATP at the cell surface.

Thermal hysteresis of Morin transition in hematite particles.

Rhombohedral shaped, single crystal hematite particles with narrow size distribution (D(TEM) = 93 +/- 2 nm) were prepared by hydrolysis of iron chloride and polymerisation in water. The results of field dependent magnetization measurements at different warming-cooling rates and ac susceptibility measurements at varying frequencies are reported and discussed. Thermal hysteresis (DeltaT(M)) associated with the Morin transition and field dependence of the Morin temperature (T(M)) are observed in warming-cooling cycles (DeltaT(M) = 25 and 13 K for H = 0.1 and 3 T, respectively) due to the first order phase transition. A frequency dependence of ac susceptibility is observed above T(M), as a result of the relaxation of the magnetic moment of hematite particles in the weak-ferromagnetic phase.

Natural flavonoids inhibit the plasma membrane Ca2+-ATPase.

Research on flavonoids from plant sources has recently sparked increasing interest because of their beneficial health properties. Different studies have shown that flavonoids change the intracellular Ca2+ homeostasis linked to alterations in the function of mitochondria, Ca2+ channels and Ca2+ pumps. These findings hint at plasma membrane Ca2+-ATPase (PMCA) involvement, as it transports Ca2+ actively to the extracellular medium coupled to ATP hydrolysis, thus maintaining ion cellular homeostasis. The present study aims to investigate the effect of several natural flavonoids on PMCA both in isolated protein systems and in living cells, and to establish the relationship between flavonoid structure and inhibitory activity on PMCA. Our results show that natural flavonoids inhibited purified and membranous PMCA with different effectiveness: quercetin and gossypin were the most potent and their inhibition mechanisms seem to be different, as quercetin does not prevent ATP binding whereas gossypin does. Moreover, PMCA activity was inhibited in human embryonic kidney cells which transiently overexpress PMCA, suggesting that the effects observed on isolated systems could occur in a complex structure like a living cell. In conclusion, this work reveals a novel molecular mechanism through which flavonoids inhibit PMCA, which leads to Ca2+ homeostasis and signaling alterations in the cell.

Regulation of extracellular ATP of human erythrocytes treated with α-hemolysin. Effects of cell volume, morphology, rheology and hemolysis.

Alpha-hemolysin (HlyA) of uropathogenic strains of Escherichia coli irreversibly binds to human erythrocytes (RBCs) and triggers activation of ATP release and metabolic changes ultimately leading to hemolysis. We studied the regulation of extracellular ATP (ATPe) of RBCs exposed to HlyA. Luminometry was used to assess ATP release and ATPe hydrolysis, whereas changes in cell volume and morphology were determined by electrical impedance, ektacytometry and aggregometry. Exposure of RBCs to HlyA induced a strong increase of [ATPe] (3-36-fold) and hemolysis (1-44-fold), partially compensated by [ATPe] hydrolysis by ectoATPases and intracellular ATPases released by dead cells. Carbenoxolone, a pannexin 1 inhibitor, partially inhibited ATP release (43-67%). The un-acylated toxin ProHlyA and the deletion analog HlyA∆914-936 were unable to induce ATP release or hemolysis. For HlyA treated RBCs, a data driven mathematical model showed that simultaneous lytic and non-lytic release mainly governed ATPe kinetics, while ATPe hydrolysis became important after prolonged toxin exposure. HlyA induced a 1.5-fold swelling, while blocking this swelling reduced ATP release by 77%. Blocking ATPe activation of purinergic P2X receptors reduced swelling by 60-80%. HlyA-RBCs showed an acute 1.3-2.2-fold increase of Ca2+i, increased crenation and externalization of phosphatidylserine. Perfusion of HlyA-RBCs through adhesion platforms showed strong adhesion to activated HMEC cells, followed by rapid detachment. HlyA exposed RBCs exhibited increased sphericity under osmotic stress, reduced elongation under shear stress, and very low aggregation in viscous media. Overall results showed that HlyA-RBCs displayed activated ATP release, high but weak adhesivity, low deformability and aggregability and high sphericity.

A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer.

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur-uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression (TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate (ORR) and overall survival (OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR (11%) and median OS (12.8 months) with twice daily administration were similar to that of thrice daily administration (12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

A randomized phase I trial of chronic oral etoposide with or without granulocyte-macrophage colony-stimulating factor in patients with advanced malignancies.

Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 micrograms/kg/day s.c. days 1-10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days -6 to -2). VP16 was begun at 25 mg/m2/day on level 1 and increased to 50 mg/m2/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm3 and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm3. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.

Photoelastic sphenoscopic analysis of crystals.

Birefringent crystals are at the basis of various devices used in many fields, from high energy physics to biomedical imaging for cancer detection. Since crystals are the main elements of those devices, a great attention is paid on their quality and properties. Here, we present a methodology for the photoelastic analysis of birefringent crystals, based on a modified polariscope. Polariscopes using conoscopic observation are used to evaluate crystals residual stresses in a precise but time consuming way; in our methodology, the light beam shape, which impinges on the crystal surface, has been changed from a solid cone (conoscopy) to a wedge (sphenoscopy). Since the polarized and coherent light is focused on a line rather than on a spot, this allows a faster analysis which leads to the observation, at a glance, of a spatial distribution of stress along a line. Three samples of lead tungstate crystals have been observed using this technique, and the obtained results are compared with the conoscopic observation. The samples have been tested both in unloaded condition and in a loaded configuration induced by means of a four points bending device, which allows to induce a known stress distribution in the crystal. The obtained results confirm, in a reliable manner, the sensitivity of the methodology to the crystal structure and stress.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

PURPOSE: To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS: Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION: The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies.

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m(2)/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl(S/F)) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl(S/F) was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration( )(median 16 v 9.5 microg/mL, P =. 0084) and area under the concentration-time curve (median 36 v 23 microg-h/mL, P =.0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m(2)/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

A photoelastic measurement system for residual stress analysis in scintillating crystals by conoscopic imaging.

The assessment of the stress state of scintillating crystals is an important issue for producers as well as users of such materials, because residual stress may arise during growth process. In this paper, a measurement system, based on the use of a photoelastic, conoscopic optical setup, is proposed for the assessment of stress state in scintillating crystals. Local stress values can be measured on the crystal in order to observe their spatial distribution. With the proposed system, it is possible to vary the dimensions of the inspected measurement volume. It has been validated with reference to a known stress state induced in a birefringent crystal sample and it has been tested for the case of loaded and unloaded samples, showing sub-millimetric spatial resolution and stress uncertainty ≤0.25 MPa. The proposed measurement system is a valid method for the inspection of scintillating crystals required by producers and users of such materials.

Peripheral neuropathy secondary to docetaxel (Taxotere)

Docetaxel (Taxotere), a semisynthetic analogue of the antitumor agent paclitaxel, inhibits tubulin depolymerization. Paclitaxel produces a peripheral neuropathy. This study delineates clinically and electrophysiologically the characteristics of a peripheral neuropathy due to docetaxel. In 186 patients receiving docetaxel in phase I and phase II protocols, we performed serial neurologic exams. As patients became symptomatic, quantitative sensory testing and nerve conduction studies were done. Twenty-one patients developed mild to moderate sensory neuropathy on taxotere at a wide range of cumulative doses (50 to 750 mg/m2) and dose levels (10 to 115 mg/m2). Ten of these patients also developed weakness of varying degree in proximal and distal extremities. Nine of the 21 patients had received neurotoxic chemotherapy before; 16 were treated with docetaxel at a dose level of 100 to 115 mg/m2. In summary, docetaxel produced a sensorimotor peripheral neuropathy in 11% of our patient population.

Overview of phase I trials of multitargeted antifolate (MTA, LY231514).

Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days. The maximum tolerated doses on these schedules were 4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting toxicity seen on all schedules was neutropenia, with a greater degree of reversible liver biochemistry disturbances observed on the daily x5 schedule. Given that toxicities were manageable and reversible, the antitumor activity exhibited, and the convenience of an every-21-day dosing schedule, this schedule was selected for phase II evaluation.

Diarrhea and enteric emerging viruses in HIV-infected patients.

To evaluate the prevalence of enteric viruses and their possible association with diarrhea, 244 stool samples were collected from HIV-infected and uninfected patients with or without diarrhea (subgroups I-a, Ib, II-a, and II-b, respectively). Subjects were screened by polyacrylamide gel electrophoresis, latex agglutination, and enzyme immunoassays for rotaviruses, adenoviruses, picobirnaviruses, and astroviruses. Enteric viruses were found significantly more often in specimens from HIV patients (20%) than in specimens from uninfected HIV patients (0%) (p < 0.05). Picobirnavirus was detected in 14.63% of 82 HIV-infected patients with diarrhea, but it was detected neither in those without diarrhea (0%) (p < 0.05) nor in the groups of uninfected HIV subjects (0%) (p < 0.05). Nor could astrovirus (subgroups I-a [4.00%] versus subgroup I-b [5.26%],p > 0.05) or enteric adenovirus (subgroup I-a [1.22%] versus subgroup I-b [0%], p > 0.05) be linked to the diarrhea disorder in HIV-infected patients. Rotaviruses were not detected in any of the clinical subgroups studied. Enteric viruses were detected in 15 of 93 (16.13%) of the HIV-infected patients with CD4+ T cell count <200/microl and 3 of 19 (15.79%) of those HIV-infected individuals with a CD4+ T cell count 200-499/microl, showing no significant difference (p > 0.05). According to our data, unusual enteric viruses such as picobirnavirus, astrovirus, and enteric adenovirus occur in HIV-infected population in Córdoba, Argentina. However, only picobirnaviruses could be significantly associated with diarrhea in these patients.

Variation in lipid levels in morbidly obese patients operated with the LAP-BAND adjustable gastric banding system: effects of different levels of weight loss.

BACKGROUND: A moderate weight loss is known to improve the lipid levels in simple obesity. The extent of weight loss needed to achieve a clinically meaningful effect on lipid abnormalities in morbid obesity is little understood. We analyzed the effects of different levels of body weight loss on the lipid levels of morbidly obese patients operated with the LAP-BAND System. METHODS: 225 morbidly obese patients (172 F and 53 M) in which a complete lipid profile has been collected both before and 12-18 months after surgery were studied. The changes of the lipid profile were analyzed according to different levels of percent weight loss (%WL: <10%, 10-20%, 20-30%, >30%). RESULTS: Mean weight loss was 30.7+/-15.2 kg, corresponding to a 23.1+/-9.7% reduction of body weight. A large variability in the weight loss was observed. A significant difference in the change of the lipid parameters between the group with <10%WL and the group with 10-20%WL was observed for total-cholesterol (+10.0+/-17.2% vs -0.7+/-14.7%; p<0.05), for the LDL (+18.7+/-26.3% vs +3.1+/-22.9%; p<0.05), and for the triglycerides (+7.7+/-26.3% vs -21.9+/-25.4%; p<0.05). No further significant differences were found between the two groups with greater weight loss (20-30%WL and >30%WL) and the group with 10-20%WL, the only exception being the percent change in triglycerides levels, i.e. higher in the group with %WL >30 (-33.6+/-31.5% vs -21.9+/-25.4%; p<0.05). CONCLUSION: A moderate weight loss of 10-20% of initial body weight produced the maximal effects on the lipid levels in morbid obesity.

Unexpected absence of correlation between the genetic mechanisms regulating beta-carboline-induced seizures and anxiety manifested in an elevated plus-maze test.

Among the ligands of the benzodiazepine site, one can mention the benzodiazepines as agonists and some beta-carbolines (e.g. methyl-beta-carboline-3-carboxylate, abbreviated hereafter beta-CCM) as inverse agonists. Most benzodiazepines and beta-carbolines act on processes involved in memory, anxiety, and convulsions with opposite physiological effects. Since these molecules have influences on both anxiety and convulsions, we predicted that there would exist a genetic correlation between anxiety evaluated in an elevated plus-maze and susceptibility to beta-CCM-induced seizures. Using inbred strains of mice, the genetic correlation was estimated with the Hegmann and Possidente model. An absence of genetic correlation was found, showing that the mechanisms responsible for basal anxiety measured with the elevated plus-maze test and those leading to susceptibility to beta-CCM-induced seizures do not share the same genetic pathways.

A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation.

PURPOSE: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). METHODS: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m(2). The MTD of MTA was 600 mg/m(2), with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m(2) dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 microg/ml, 40.0 ml/min per m(2), 266 microg. h/ml, and 7.0 l/m(2), respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. CONCLUSIONS: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m(2). MTA is a promising new anticancer agent.