Pharmacokinetic characteristics of the novel anticancer agent CPT-11 and its active metabolite in plasma and lung lymph fluid following intravenous administration to sheep

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11, 100286-90-6) is one of the most promising novel anticancer agents, especially for lung cancer. 7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolic of CPT-11, has much stronger cytotoxicity than CPT-11. The present study was designed to evaluate the distribution and behavior of CPT-11 and SN-38 in lung lymph circulation following intravenous infusion. Awake sheep with chronically instrumented lung lymph fistulas were prepared. The concentrations of CPT-11 and SN-38 in plasma and lung lymph fluid were measured after intravenous infusion of 100 mg/body of CPT-11 for 90 min. SN-38 constantly showed higher lymph to plasma concentration ratios than those of CPT-11, and the % area under the curve (AUC) ratio of SN-38/CPT-11 in lymph fluid was significantly higher than that in plasma. These data indicated that SN-38 distributed in lung tissue moved more easily into lung lymph fluid than CPT-11, and might be more rapidly metabolized in lung tissue than plasma. CPT-11 may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.     

A case of polymyalgia rheumatica with swelling and pitting edema of the distal lower extremities

We report a case of an 82-year-old woman with polymyalgia rheumatica (PMR) associated with swelling and pitting edema of the lower extremities. The patient had been previously admitted because of PMR in 1990, but there was no history of swollen extremities. In July 1996, at another hospital, she was again diagnosed as having PMR on the basis of pain in the neck, shoulders and lower back. Administration of prednisolone was followed by improvement of the symptoms. Four months later, similar pain recurred and swelling of the lower extremities was noted. On admission, the erythrocyte sedimentation rate was 86 mm/h, and C-reactive protein was 15.5 mg/dl. Reviewing the previous treatment, it was ascertained that her clinical deterioration was due to premature reduction of the steroid dosage. The cause of the swelling of the lower extremities was unlikely to be heart, liver, kidney or endocrine disease. Prednisolone was increased from 2.5 mg to 10 mg daily with marked improvement in all the symptoms including the swelling and pitting edema. In 1996, a study reported distal extremity swelling with pitting edema as a manifestation of PMR, which mostly developed concurrently with proximal symptoms or during relapses of PMR. The swelling responded poorly to non-steroidal antiinflammatory drugs but promptly to corticosteroids. The distal swelling was reported to be tenosynovitis and synovitis of the surrounding structures. The present case appears similar to that report. More studies of PMR need to be done.     

A High-Methionine Diet for One-Week Induces a High Accumulation of Methionine in the Cerebrospinal Fluid and Confers Bipolar Disorder-like Behavior in Mice

Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or a diet containing 16 graded Met doses (1.2×–13×). High-Met diets for one-week induced a dose-dependent decrease in body weight and an increase in serum Met levels with a 2.55 mM peak (versus basal 53 µM) on the 12×Met diet. Total homocysteine (Hcy) levels were also upregulated while concentrations of other amino acids were almost maintained in serum. Similarly, levels of Met and Hcy (but not the other amino acids) were highly elevated in the cerebrospinal fluids of mice on the 10×Met diet; the Met levels were much higher than Hcy and the others. In a series of behavioral tests, mice on the 10×Met diet displayed increased anxiety and decreased traveled distances in an open-field test, increased activity to escape from water soaking and tail hanging, and normal learning/memory activity in a Y-maze test, which were reflections of negative/positive symptoms and normal cognitive function, respectively. These results indicate that high-Met ad libitum feeding even for a week can induce bipolar disorder-like disease models in mice.     

Interference from irrelevant features on visual discrimination by macaques (Macaca fuscata): A behavioral analogue of the human Stroop effect.

To study the operation of selective attention in a conflict situation with automatic processes, we trained 4 Japanese macaques; (Macaca fuscata) extensively on a manual go/no-go task. The monkey had to discriminate either the color, shape, motion direction, or location of a visual stimulus. In each trial, the behavioral meaning of the relevant feature (go or no-go) could either be congruent or incongruent with irrelevant features of the same stimulus. Reaction times were slowed, and error rates increased when irrelevant stimulus features were incongruent with the required response. The effects were obtained when the monkey attended to the color, shape, or motion direction, but not when it attended to the location of the stimulus. The effects were cumulative so that the interference from 1 incongruent feature was smaller than that from 2 incongruent features. We propose that the present paradigm provides a behavioral analogue of the human Stroop effect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pt diffusion in B2-type ordered NiAl intermetallic compound and its diffusion mechanisms

Diffusion of platinum element which increase protectivity of NiAl layer for hot corrosion and oxidation of Ni-base superalloys was investigated in NiAl compound with compositions of 43.7–51.9 at% Al at 1373–1673 K by the diffusion couple method. The diffusion coefficients, D_Pt, exhibit a large concentration dependence of valley type-shape; the D_Pt has the minimum value quite near the stoichiometric composition and it increases with deviation from the stoichiometry. On the other hand, the activation energy, Q, shows the maximum value near the stoichiometry. Q slightly decreases with Ni composition in Ni-rich side, while it decrease dramatically with Al composition in Al-rich side. Diffusion of platinum element in NiAl occurs mainly by the Triple defect mechanism at stoichiometry, by the anti-site atom bridge mechanism in considerably off-stoichiometry in Ni-rich side and by the next nearest neighbor-jump mechanism with constitutional Ni vacancies in quite off-stoichiometry in Al-rich side.     

Role of physiologic concentrations of stem cell factor in leukemic type growth of myelodysplastic CD34+ cells

Extrapolation of animal data to assess pharmacokinetic parameters in humans is an important tool in drug development. Allometric scaling has many proponents, and many different approaches and techniques have been proposed to optimise the prediction of pharmacokinetic parameters from animals to humans. The allometric approach is based on the power function Y = aWb, where the bodyweight of the species is plotted against the pharmacokinetic parameter of interest on a log-log scale. Clearance, volume of distribution and elimination half-life are the 3 most frequently extrapolated pharmacokinetic parameters. Clearance is not predicted very well (error between predicted and observed clearance > 30%) using the basic allometric equation in most cases. Thus, several other approaches have been proposed. An early approach was the concept of neoteny, where the clearance is predicted on the basis of species bodyweight and maximum life-span potential. A second approach uses a 2-term power equation based on brain and body weight to predict the intrinsic clearance of drugs that are primarily eliminated by phase I oxidative metabolism. Most recently, the use of the product of brain weight and clearance has been proposed. A literature review reveals different degrees of success of improved prediction with the different methods for various drugs. In a comparative study, the determining factor in selecting a method for prediction of clearance was found to be the value of the exponent. Integration of in vitro data into in vivo clearance to improve the predictive performance of clearance has also been suggested. Although there are proponents of using body surface area instead of bodyweight, no advantage has been noted in this approach. It has also been noted that the unbound clearance of a drug cannot be predicted any better than the total body clearance (CL). In general, there is a good correlation between bodyweight and volume of the central compartment (Vc); hence, Vc does not face the same complications as CL. The relationship between elimination half-life (t 1/2 beta) and bodyweight across species results in poor correlation, most probably because of the hybrid nature of this parameter. When a reasonable prediction of CL and Vc is made, t 1/2 beta may be predicted from the equation t 1/2 beta = 0.693 Vc/CL.     

Permanent Strength of Metals: A Case Study on FCC Metals Processed by Severe Plastic Deformation

Metallurgical and Materials Transactions A - The present study emphasizes the importance of the direct evaluation of the athermal strength of structural materials, which is the time-independent...     

Investigation of pre- and post-dryout heat transfer of steam-water two-phase flow in a rod bundle

Pre- and post-dryout heat transfer experiments were performed for steam-water two-phase flow in a 5 × 5 rod bundle under conditions of total mass fluxes from 80 to 320 kg/m²s, inlet qualities from 0.1 to 0.8, heat fluxes from 3 to 26 W/cm² and a pressure of 3 MPa. Heater rod surface temperatures or heat transfer coefficients predicted by several correlations were compared with experimental data with emphasis on the applicability of the correlations to the present experimental conditions which were pertinent to thermal-hydraulic conditions during a LOCA in a nuclear reactor. The Chen and Biorge et al. correlations underestimated heat transfer coefficients in the pre-dryout region. The Varone-Rohsenow prediction which accounted for the thermal nonequilibrium effect, calculated heater rod surface temperatures relatively well in the post-dryout region over the whole region of the present experimental conditions. The Dittus-Boelter and Groeneveld correlations predicted heater rod surface temperatures relatively well in the post-dryout region under high total mass flux conditions, but underestimated considerably under low total mass flux conditions.     

Migration rate of lenticular voids in UO2 under the influence of temperature gradient

The migration rate of lenticular voids in uranium dioxide was measured in convection with an analysis of structural changes behavior in the irradiated fuel. The lenticular voids were fabricated in the interface of two thin discs of high density UO₂ by contacting and subsequently resintering the polished faces of the discs. The specimen was heated under the influence of a temperature gradient of 3000–5000°C/cm for 1–9 h, using an induction furnace. The migration rates were measured on the micrographs of the specimen after heating, and the results obtained showed good agreement with the theoretical values derived from Sens' model.