Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats

Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (K_i) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.     

Electrospun P(LLA-CL) nanofiber: a biomimetic extracellular matrix for smooth muscle cell and endothelial cell proliferation

Poly(L-lactide-co-epsilon-caprolactone) [P(LLA-CL)] with L-lactide to epsilon-caprolactone ratio of 75 to 25 has been electrospun into nanofibers. The relationship between electrospinning parameters and fiber diameter has been investigated. The fiber diameter decreased with decreasing polymer concentration and with increasing electrospinning voltage. The X-ray diffractometer and differential scanning colorimeter results suggested that the electrospun nanofibers developed highly oriented structure in CL-unit sequences during the electrospinning process. The biocompatibility of the nanofiber scaffold has been investigated by culturing cells on the nanofiber scaffold. Both smooth muscle cell and endothelial cell adhered and proliferated well on the P(LLA-CL) nanofiber scaffolds.     

Autochthonous Dengue Fever,Tokyo, Japan, 2014

After 70 years with no confirmed autochthonous cases of dengue fever in Japan, 19 cases were reported during August–September 2014. Dengue virus serotype 1 was detected in 18 patients. Phylogenetic analysis of the envelope protein genome sequence from 3 patients revealed 100% identity with the strain from the first patient (2014) in Japan.     

Rapid determination of viral RNA sequences in mosquitoes collected in the field

A method for rapid determination of viral RNA sequences (RDV) was applied to homogenates of Aedes aegypti collected in Thailand in an area in which dengue fever (dengue hemorrhagic fever) is endemic, using the mosquito cell line C6/36. Nucleic acid sequences of dengue virus type 4 and cell fusing agent virus were detected. This RDV method has the potential to become a standard method for detection of both known and newly emerging, unknown mosquito-borne viruses.     

Excellent performance of aromatic polyguanamines induced by multiple hydrogen bondable tetraazacalix[2]arene[2]-triazine ring in their main chain

A series of poly(guanamine) (c-PG)s containing tetraazacalix[2]arene[2]-triazine (mPDA₂CyC₂) were successfully prepared by solution polycondensation of mPDA₂CyC₂ with various aromatic diamines in an aprotic organic solvent with a lithium chloride additive (5 wt%) at 150 °C for 6 hours. The number-average molecular weights (M_n)s of these c-PG polymers reached up to 31 500, with a relatively broad molecular weight distribution (M_w/M_n) of 5.3. They showed good solubility in aprotic organic solvents, such as N-methylpyrrolidone and N,N-dimethylacetamide at a concentration of 2 mg mL⁻¹. The glass transition temperatures (T_g) of the c-PG polymers were in the range 359 °C–392 °C, approximately 160 °C higher than those of counterpart polymers (i.e., with no aza-calixarene-based PG (l-PG)). The coefficients of thermal expansion (CTEs) of the c-PG polymers were 29.7–48.1 ppm K⁻¹ (at 100 °C–150 °C), much lower than those of l-PG samples, i.e., 59.1–85.1 ppm K⁻¹. Transparent and almost colorless c-PG films were successfully prepared by a solution casting method, showing maximum tensile strength (σ_S), modulus (E_γ), and elongation at break (E_b) values of 151 MPa, 6.3 GPa, and 4.4%, respectively, for the c-PG polymer from mPDA₂CyC₂ and 4,4′-oxydianiline monomers. The corresponding l-PG film exhibited σ_S, E_γ, and E_b values of just 76 MPa, 5.4 GPa, and 1.6%, respectively. These outstanding thermal and mechanical properties of the c-PG polymers can be attributed to their multiple hydrogen bonding interaction between mPDA₂CyC₂ residues in the polymer backbone. This interaction was identified by infrared spectroscopy measurements at the broad absorption band around 3000–3400 cm⁻¹.

Poly(guanamine)s containing tetraazacalix[2]arene[2]triazine ring within the polymer main-chain show outstanding thermal and mechanical properties arisen from the multiple-hydrogen bond.     

Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine

The effect of the intake of 200 g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0-24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0-24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0-24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p < 0.05). The finding that the ratios of Cmax and AUC0-24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0-24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.     

Limits to gene flow in a cosmopolitan marine planktonic diatom

The role of geographic isolation in marine microbial speciation is hotly debated because of the high dispersal potential and large population sizes of planktonic microorganisms and the apparent lack of strong dispersal barriers in the open sea. Here, we show that gene flow between distant populations of the globally distributed, bloom-forming diatom species Pseudo-nitzschia pungens (clade I) is limited and follows a strong isolation by distance pattern. Furthermore, phylogenetic analysis implies that under appropriate geographic and environmental circumstances, like the pronounced climatic changes in the Pleistocene, population structuring may lead to speciation and hence may play an important role in diversification of marine planktonic microorganisms. A better understanding of the factors that control population structuring is thus essential to reveal the role of allopatric speciation in marine microorganisms.     

Prothiofos metabolites in human poisoning.

CASE REPORT: A 63-year-old woman was admitted to a local hospital after the ingestion of 40% prothiofos preparation (Tokuthion) 370 mL. Gastric lavage was performed and cathartics, active charcoal, diuretics, atropine sulfate, and pralidoxime were administered. Serum cholinesterase activity was 1.3 IU/L (normal 200-460 IU/L). The patient's consciousness was gradually restored after 4 hours of charcoal hemoperfusion and she was discharged 5 days after admission with no sequelae. METHOD: Plasma and urine prothiofos and metabolites were detected by gas chromatography-flame photometry and gas chromatography-mass spectrometry. Two despropyl metabolites were synthesized for identification and estimation. RESULTS: The main metabolites were identified with authentic prothiofos and methyl esters of synthesized des-S-propyl prothiofos oxon (O-2,4-dichlorophenyl O-ethyl phosphate), despropyl prothiofos oxon (O-2,4-dichlorophenyl O-ethyl phospholothiolate), and des-S-propyl prothiofos (O-2,4-dichlorophenyl O-ethyl phosphorothioate). Despropyl prothiofos (O-2,4-dichlorophenyl O-ethyl phosphorodithioate) was also identified in plasma. Large amounts of the hydrolyzed product, 2,4-dichlorophenol and its conjugate were also found. The metabolic pattern of prothiofos in humans appears to be different from that in rats.     

Surface engineering of electrospun polyethylene terephthalate (PET) nanofibers towards development of a new material for blood vessel engineering

Non-woven polyethylene terephthalate nanofiber mats (PET NFM) were prepared by electrospinning technology and were surface modified to mimic the fibrous proteins in native extracellular matrix towards constructing a biocompatible surface for endothelial cells (ECs). The electrospun PET NFM was first treated in formaldehyde to yield hydroxyl groups on the surface, followed by the grafting polymerization of methacrylic acid (MAA) initiated by Ce(IV). Finally, the PMAA-grafted PET NFM was grafted with gelatin using water-soluble carbodiimide as coupling agent. Plane PET film was also surface modified and characterized for basic understanding of the surface modification process. The grafting of PMAA and gelatin on PET surface was confirmed by XPS spectroscopy and quantitatively analyzed by colorimetric methods. ECs were cultured on the original and gelatin-modified PET NFM and the cell morphology, proliferation and viability were studied. Three characteristic surface makers expressed by ECs were studied using immuno-florescent microscopy. The gelatin grafting method can obviously improve the spreading and proliferation of the ECs on the PET NFM, and moreover, can preserve the EC's phenotype.