Biomedical subjects

G S Shen

Publications and source records attributed to G S Shen.

7 recordsLinked to original sources

PubMed2000

A self-complementary, self-assembling microsphere system: application for intravenous delivery of the antiepileptic and neuroprotectant compound felbamate.

Felbamate (FBM) is a novel antiepileptic drug (AED) and neuroprotectant (NP) compound that interacts with strychnine-insensitive (SI) glycine receptors in brain (IC(50) = 374 microM). FBM concentrations required to interact with SI glycine receptors are consistent with brain levels following oral and intraperitoneal administration of AED and NP doses. Because of the solubility limits of FBM, an intravenous (iv) form has not been developed. Nevertheless, an iv form could be important for the treatment of disorders such as status epilepticus and neuronal damage due to hypoxic/ischemic events. Substituted diketopiperazines precipitate in acid to form microspherical particles of uniform size ( approximately 2 microm). The microsphere system entraps drugs on precipitation and dissolves near physiological pH to release the drug cargo. Therefore, microspheres were used to produce an iv formulation of FBM. Mice were administered the FBM/microsphere (20-60 mg/kg FBM) and tested for protection against tonic extension seizures using maximal electroshock. The FBM/microsphere was effective in a time- and dose-dependent manner following iv administration. The median effective dose (ED(50)) for protection against MES seizures at 30 min was 27.2 mg/kg [95% confidence interval (CI) = 20.8-33.4, slope = 6.5]. The ED(50) for minimal motor impairment at 30 min was 167 mg/kg (95% CI = 155-177, slope = 28.1). Thus, the feasibility of encapsulating FBM or similar aqueous insoluble compounds in a microsphere system with delivery by the iv route for treatment of epilepsy and various central nervous system disorders has been clearly demonstrated. Studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals.

Animals↗

PubMed1999

NMR solution structure of alpha-conotoxin ImI and comparison to other conotoxins specific for neuronal nicotinic acetylcholine receptors.

Alpha-Conotoxins, peptides produced by predatory species of Conus marine snails, are potent antagonists of nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels involved in synaptic transmission. We determined the NMR solution structure of the smallest known alpha-conotoxin, ImI, a 12 amino acid peptide that binds specifically to neuronal alpha7-containing nAChRs in mammals. Calculation of the structure was based on a total of 80 upper distance constraints and 31 dihedral angle constraints resulting in 20 representative conformers with an average pairwise rmsd of 0.44 A from the mean structure for the backbone atoms N, Calpha, and C' of residues 2-11. The structure of ImI is characterized by two compact loops, defined by two disulfide bridges, which form distinct subdomains separated by a deep cleft. Two short 310-helical regions in the first loop are followed by a C-terminal beta-turn in the second. The two disulfide bridges and Ala 9 form a rigid hydrophobic core, orienting the other amino acid side chains toward the surface. Comparison of the three-dimensional structure of ImI to those of the larger, 16 amino acid alpha-conotoxins PnIA, PnIB, MII, and EpI-also specific for neuronal nAChRs-reveals remarkable similarity in local backbone conformations and relative solvent-accessible surface areas. The core scaffold is conserved in all five conotoxins, whereas the residues in solvent-exposed positions are highly variable. The second helical region, and the specific amino acids that the helix exposes to solvent, may be particularly important for binding and selectivity. This comparative analysis provides a three-dimensional structural basis for interpretation of mutagenesis data and structure-activity relationships for ImI as well other neuronal alpha-conotoxins.

Amino Acid Sequence↗

PubMed1994

Flow dependence of metoprolol elimination in isolated perfused rat liver.

The effect of blood flow rates on hepatic elimination of metoprolol (Met) was studied in a recirculating isolated perfused rat liver system with a constant infusion of Met into the reservoir. This design ensures that, at a steady state, the elimination rate of Met is a constant. The results showed that at flow rates of 10, 20, and 30 ml.min-1, the concentrations of Met entering the liver (Cin) were 7.6, 5.0, and 3.4 micrograms.ml-1 and the concentrations leaving the liver (Cout) were 1.2, 2.0, and 2.7 micrograms.ml-1, while the logarithmic average concentrations in hepatocytes (C) were 3.4, 3.2, and 3.0 micrograms.ml-1, respectively. It is concluded that the hepatic elimination of Met is flow-dependent, which is in accordance with the 'parallel tube' model.

Animals↗

PubMed1993

Effect of dose of metoprolol on its elimination by isolated perfused rat liver in vitro.

The effects of dose of metoprolol (Met) on hepatic elimination was studied in isolated rat liver perfused at a flow of 25 ml.min-1. The results showed that Met was eliminated by rat liver in accordance with one-compartment model. Linear kinetic eliminating processes (apparent first-order kinetics) were found in doses of Met 0.2, 0.5, 1.0, and 2.0 mg, T1/2 were 8.3, 8.8, 9.6, and 10.6 min and the clearance rate were 11.7, 11.8, 9.6, and 8.6 ml.min-1, respectively. Nonlinear eliminating processes were found in doses of Met 4, 8, and 12 mg. Vm and Km were 0.98, 1.05, and 0.94 microgram/min-1.ml-1 and 15.6, 16.9, and 14.6 micrograms.ml-1, respectively. It is concluded that hepatic Met elimination is independent on lower doses, but rested upon high doses.

Animals↗

PubMed1989

[Inhibitory action of intracerebroventricular injections of norepinephrine and clonidine on ventricular extrasystoles induced by stimulating hypothalamus in rabbits].

The effects of bilateral intracerebroventricular (icv) injections of norepinephrine (NE) and clonidine on hypothalamic stimulation-induced ventricular extrasystoles (VE) were investigated in alpha-chloralose and urethane anaesthetized rabbits. NE and clonidine reduced the number of HVE. The effects of NE were antagonized by pretreatment with phentolamine and yohimbine, but unaffected by pretreatment with prazosin. Pretreatment with yohimbine could also abolish the effects of clonidine. It is concluded that the effects of reduction in VE induced by NE and clonidine may be mediated by activating central alpha 2-adrenoceptors rather than alpha 1-adrenoceptors.

Animals↗

PubMed1989

[Inhibitory effects of gamma-aminobutyric acid and diazepam on ventricular arrhythmias induced by hypothalamic electric stimulation].

The experiments were carried out on rabbits with ventricular arrhythmias (VA) induced by hypothalamic electric stimulation. The effects of GABA or diazepam (Dz) and picrotoxin on VA were observed. After GABA 0.25, 0.5, 1 mg/rabbit were injected into cerebral ventricle (icv) or cisterna magna (icm), the VA was dose-dependently reduced, the similar effect was seen after Dz 0.1 mg was injected into subarachnoid cavity (sac) or icm. The effect was not induced by GABA sac or Dz icv. Picrotoxin 20 micrograms icv or 30 micrograms icm obviously increased VA, and this effect was partly antagonized by pretreatment with GABA 0.5 mg icv or icm and Dz 0.1 mg icm. The results suggest that central GABAergic system plays an important role in development of arrhythmias, and that increasing activity in this system may inhibit VA.

Animals↗

PubMed1981

Prostaglandin E and F2 alpha levels in plasma and amniotic fluid during mid-trimester abortion induced by trichosanthin.

This paper gives a brief account concerning the estimation of PGE and PGF2 alpha concentrations in both plasma and amniotic fluid by radioimmunoassay in mid-trimester abortion induced by Trichosanthin. The significant change in amniotic fluids as compared with that in plasma is brought out for discussion as an aid to the study of mechanism of abortion by Trichosanthin.

Abortifacient Agents, Nonsteroidal↗