Biomedical subjects

F Ji

Publications and source records attributed to F Ji.

At least 19 recordsLinked to original sources

PubMed2006

Overexpression of RhoA is associated with poor prognosis in hepatocellular carcinoma.

AIMS: The aim of this study was to investigate the relationship between RhoA expression and clinic pathological parameters of hepatocellular carcinoma (HCC), and to evaluate the prognostic value of RhoA for HCC patients. METHODS: Three methods, including reverse transcription and polymerase chain reaction, Western blot and immunohistochemical staining were employed to detect RhoA expression in 128 HCC specimens. The correlation between RhoA expression and clinicopathologic outcome, and prognostic value of RhoA for HCC patients were analyzed. RESULTS: HCC tissues revealed significantly higher levels of both RhoA mRNA and protein than pericarcinomatous liver tissues (PCLT) (P=0.001). The mRNA and protein expression levels of RhoA in HCC tissues showed strongly positive correlation (correlation coefficient=0.712, P=0.01). There was significant correlation among RhoA mRNA and protein overexpression, and venous invasion (P=0.009 and P=0.040, respectively) and cell differentiation (P=0.021 and P=0.017). HCC patients with RhoA-positive expression showed a significantly poor prognosis than those with RhoA-negative expression (P=0.039). CONCLUSIONS: Our data strongly suggested that increased RhoA expression in HCC correlated with venous invasion and cell differentiation of HCC, overexpression of RhoA indicated a poor prognosis in HCC patients.

Adult↗

PubMed2006

Effect of manganese source on manganese absorption by the intestine of broilers.

Two experiments were conducted to investigate the effect of Mn source on Mn absorption by the intestine of broilers. In Experiment 1, the effect of Mn source, including MnSO(4), 2 Mn-amino acid chelates (Mn-Gly and Mn-Met) synthesized in our laboratory, 3 Mn-amino acid complexes with different complex strengths (Mn-Met E, Mn-AA A, and Mn-AA B), and 2 mixtures of MnSO(4) with Gly or Met, on Mn absorption was assessed with ligated loops of different small intestinal segments of broilers. In Experiment 2, the absorption of Mn from MnSO(4), Mn-AA A, and Mn-AA B was compared with intact broilers fed ad libitum. The criterion used for comparison was the Mn content of hepatic portal vein plasma. The absorption of Mn was higher (P < 0.0002) by ligated ileal loops than by duodenal and jejunal ones. Met supplementation increased (P < 0.03) the absorption of Mn as MnSO(4). The absorption of Mn as Mn-AA A and Mn-AA B with moderate and strong complex strengths, respectively, were higher (P < 0.05) than those of Mn as MnSO(4) and Mn-Met E with weak complex strength. On d 7 and 9 of Experiment 2, the Mn content of portal vein plasma was higher (P < 0.03) for Mn-AA B with strong complex strength than for MnSO(4). On d 9, Mn content in plasma was higher (P < 0.01) for Mn-AA B with strong complex strength than for Mn-AA A with a moderate one. The results from this study confirm that the ileum was the main site of Mn absorption for broilers, and Met was more effective in facilitating Mn absorption than Gly as a ligand. Organic Mn was more efficiently absorbed than inorganic Mn (MnSO(4)); the absorption of organic Mn with moderate and strong complex strengths was greater than that of the organic Mn, which was weak, and the absorption of organic Mn with strong complex strength was greater than that of the organic Mn with a moderate strength.

Analysis of Variance↗

PubMed2006

Effects of manganese source and calcium on manganese uptake by in vitro everted gut sacs of broilers' intestinal segments.

Three experiments were conducted with everted gut sacs to investigate the effects of Mn source and Ca on Mn absorption in different intestinal segments of broilers. In Experiment 1, the Mn uptake by everted sacs of duodenum, jejunum, and ileum after different incubation times was compared to determine an optimum incubation time. In Experiment 2, 8 different Mn sources, including MnSO4, organic Mn sources (Mn-amino acid chelates, Mn-amino acids complexes with different complex strength), and mixtures of MnSO4 with Gly or Met were used to assess the effect of Mn source on Mn uptake. In Experiment 3, the effect of Ca in media on the uptake of Mn from MnSO4 and Mn-amino acids complexes was investigated. The uptake percentages of Mn by everted ileal sacs were significantly higher than those by duodenal and jejunal sacs. The uptake of Mn as Mn-Met chelate was significantly higher than that of Mn as Mn-Gly chelate. The uptake percentages of Mn as Mn-amino acid complex with moderate complex strength (Mn-AA A) and Mn-amino acid complex with strong complex strength (Mn-AA B) were significantly higher than that of Mn as MnSO4. The uptake of Mn as Mn-AA B by jejunal sacs was significantly higher than that of Mn as Mn-AA A in media containing high level of Ca. The uptake percentages of Mn at high Ca level were significantly higher than those at normal level. The results indicate that when incubated in vitro, ileum was the main site of Mn absorption for broilers. The absorption of Mn as organic sources were higher than that of Mn as inorganic Mn. The absorption of Mn as Mn-AA B with strong complex strength by jejunal sacs was higher than that of Mn as Mn-AA A with moderate complex strength in media containing high level of Ca. As a ligand, Met was more effective in facilitating Mn absorption than Gly. Furthermore, the transportation of Mn through intestinal cells was enhanced by adding Ca as CaCl2 to the buffer solutions.

Animal Feed↗

PubMed2006

Characterization of mammary gland development in pregnant gilts.

The purpose of this study was to quantify mammary gland (MG) growth during pregnancy in gilts and to determine the effect of anatomical location on gland growth. Size, composition, and histomorphology of MG were determined during gestation in 29 primigravid gilts. Gilts were allotted randomly to 6 slaughter groups: d 45 (n = 6), 60 (n = 4), 75 (n = 5), 90 (n = 4), 102 (n = 5), and 112 (n = 5) of gestation. Mammary glands were obtained at slaughter, and skin and extraneous fat pad were removed to obtain parenchymal MG tissue. Mammary glands were further separated into individual MG, and their locations were recorded. Individual MG were weighed and bisected in an approximate midsagittal section to measure cross-sectional area. Mammary glands were ground individually and pooled according to anatomical region: the first and second pairs of MG = anterior MG; the third, fourth, and fifth pairs of MG = middle MG; the sixth, seventh, and eighth pairs of MG = posterior MG. Contents of DM, CP, ether extract, and crude ash were measured. Wet weight, DM, CP, and ash content of total and individual MG increased (P < 0.01) between d 45 and 112 of gestation. Cross-sectional area of individual MG increased (P < 0.01) as gestation progressed. Percentage of CP and ash increased (P < 0.01), whereas percentage of ether extract decreased (P < 0.01) as gestation progressed. This inverse relationship between percentages of CP and ether extract (r = -0.999; P < 0.0001) was consistent with the histological shift from primarily an adipose tissue in early gestation to one containing extensive lobuloalveolar tissue in late gestation. Wet weight of middle MG was greater (P < 0.05) than that of posterior MG at d 102 and 112 of gestation, and amount of CP in middle MG was greater (P < 0.05) than that in anterior and posterior MG at d 102 and 112 of gestation, indicating that middle MG grow faster than other MG during late gestation. Rates of wet weight gain and protein accretion were accelerated (P < 0.01) after d 74 and 75 of gestation, respectively, indicating the importance of MG growth during the last trimester of gestation. The increase in rate of protein accretion after d 75 indicates a greater protein requirement for MG growth during later gestation.

Animals↗

PubMed2006

Effects of dietary humic substances on pig growth performance, carcass characteristics, and ammonia emission.

Five experiments were conducted to test the effects of various dietary humic substances (HS; HS1, 2, 3, and 4, each with different fulvic and humic acid contents) on pig growth, carcass characteristics, and ammonia emission from manure. In Exp. 1, 120 pigs were allotted to 3 dietary treatments without HS (control) or with HS1 at 0.5 and 1.0% (8 pens/treatment and 5 pigs/pen) and fed diets, based on a 5-phase feeding program, from weaning (d 21.3 +/- 0.3 of age) to 60 kg of BW. In Exp. 2 and 3, 384 pigs (192 for each experiment) were allotted to 3 dietary treatments without HS, with HS1, or with HS2 (0.5%) for Exp. 2 and without HS, or with HS3 or HS4 (0.5%) for Exp. 3 (8 pens/treatment and 8 pigs/pen in each experiment). Pigs were fed diets, based on a 6-phase feeding program, from weaning (25.4 +/-0.2 and 23.6 +/-0.3 d of age for Exp. 2 and 3, respectively) to 110 kg of BW. In Exp. 4, 96 pigs were weaned at 22.1 +/-0.2 d of age and allotted to 2 treatments without or with HS1 at 0.5% (6 pens/treatment and 8 pigs/pen), and in Exp. 5 96 pigs were weaned at 20.9 +/-0.3 d of age and allotted to 3 treatments without HS, or with HS3 or HS4 (0.5%; 4 pens/treatment and 8 pigs/pen). Pigs were fed the diets for at least 2 wk before they were moved to an environmental chamber to measure aerial ammonia and hydrogen sulfide for 48 h at 5-min intervals. In Exp. 1, pigs fed diets with HS1 at 0.5% had greater (P < 0.05) ADG during phase 3 and greater (P < 0.05) G:F during phases 3 and 5 than control pigs. In Exp. 2, pigs fed diets with HS1 or HS2 at 0.5% had greater (P < 0.05) ADG and G:F than control pigs during the entire feeding period, whereas in Exp. 3 HS3 or HS4 did not improve pig growth performance. Ammonia emission from manure was reduced by 18 or 16% when pigs were fed diets with HS1 (P = 0.067) or HS4 (P = 0.054), respectively. The results of this study indicate that the effects of dietary HS are variable but may improve growth performance of pigs and reduce ammonia emission from manure. Further research is needed to clarify these effects and the mechanisms by which HS may cause them.

Ammonia↗

PubMed2006

Pharmacological effects of some newly developed soft anticholinergics and a receptor-binding QSAR study.

Receptor-binding studies using cloned human muscarinic receptors (M1-M4 subtypes) were performed on newly synthesized soft anticholinergics (F-828, F-838, SGM, SGE, SA-A) that are isosteric/ isoelectronic analogs of glycopyrrolate. The receptor binding pK(i) values of the new soft drugs were in the 5.5-9.5 range; with the majority being in the 7.0-8.5 range. As previously observed for similar structures, the pK(i) values tended to decrease with increasing molecular size, and with the introduction of three structural indicator variables, a QSAR equation accounting for close to 75% of the variability could be established. Confirming the known stereospecificity of these receptors, pure 2R isomers were found more active than the corresponding isomeric mixtures. In agreement with soft drug design principles, acid metabolites (SA-A) were found considerably less active than their parent esters. The more active, 2R isomer of SA-A showed some muscarinic subtype selectivity (M3/M2), which was not observed for the parent compounds of this zwitterionic metabolite. Guinea pig ileum assay pA2 values have also been determined, and they were found to be in good agreement with the pK(i), values obtained from the binding study (r2 = 0.72). SGM and SGE caused pupil-dilation in rabbit eyes, but their mydriatic effects lasted considerably shorter than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that they are locally active and safe, with a low potential to cause systemic side effects.

Algorithms↗

PubMed2005

Effects of dietary supplementation with copper sulfate or tribasic copper chloride on broiler performance, relative copper bioavailability, and oxidation stability of vitamin E in feed.

An experiment was conducted using a total of 420, 1-d-old, Arbor Acres commercial male chicks to compare copper sulfate and tribasic copper chloride (TBCC) as sources of supplemental copper for broilers. Chicks were randomly allotted to 1 of 7 treatments for 6 replicates of 10 birds each and were fed a basal corn-soybean meal diet (11.45 mg/kg copper) supplemented with 0, 150, 300, or 450 mg/kg copper from copper sulfate or TBCC for 21 d. Chicks fed 450 mg/kg copper as copper sulfate had lower (P < 0.01) average daily feed intake and average daily gain than those consuming other diets. Feeding supplemental copper increased linearly (P < 0.0001) liver copper concentrations regardless of copper source. The slopes of regressions of log10 liver copper on different independent variables used in regressions differ (P < 0.05) between the 2 copper sources. Linear regression over nonzero dietary levels of log10 transformed liver copper concentration on added copper intake resulted in a slope ratio estimate of 109.0 +/- 3.4% (with a 95% confidence interval from 102.2 to 115.8) for bioavailability of copper from TBCC compared with 100 for that in copper sulfate. When the feeds were stored at room temperature for 10 or 21 d, the vitamin E content in the feed fortified with 300 mg/kg copper as TBCC was higher (P < 0.01) than that in the feed added with 300 mg/kg copper as CuSO4. The vitamin E contents in liver and plasma of broilers given TBCC were also higher (P < 0.01) than those of birds fed copper sulfate. The results from this study indicate that TBCC is a safer product and more available to broilers than copper sulfate, and it is chemically less active than copper sulfate in promoting the oxidation of vitamin E in feed.

Animal Feed↗

PubMed2005

Synthesis and pharmacological effects of new, N-substituted soft anticholinergics based on glycopyrrolate.

To reduce the possibility of systemic side-effects in locally administered anticholinergics, two new N-substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in vivo. Because stereospecificity is known to be important at muscarinic receptors, the new compounds SGM and SGE also have been prepared as their pure 2R isomers, 2R-SGM and 2R-SGE, by starting from optically pure (-)-cyclopentylmandelic acid, and the corresponding isomers were indeed found to be more active. The new soft glycopyrrolates were chemically more stable under acidic conditions, and the ethyl esters SGE were more stable than the methyl esters SGM. The new compounds were also found to be quite susceptible to extrahepatic metabolism, having half-lives of 20-30 min in rat plasma (in vitro), consistent with their soft nature. Binding studies at human muscarinic receptors (M(1)-M(4)) and guinea-pig ileum assays found 2R-SGM and 2R-SGE to have potencies somewhat less than, but close to, those of glycopyrrolate and N-methylscopolamine. They caused pupil dilation in rabbit eyes, but their mydriatic effects lasted for considerably less time than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that, in agreement with their soft nature, they are locally active, but safe and with a low potential to cause systemic side-effects.

Animals↗

PubMed2005

Changes in weight and composition in various tissues of pregnant gilts and their nutritional implications.

The objectives of this study were to characterize the quantitative changes in various body tissues of high-lean type gilts during gestation and to determine the protein needs of pregnant gilts based on changes in tissue contents. Thirty-five gilts (158.2 +/- 8.3 kg) were housed in individual gestation crates with six unbred gilts randomly selected and slaughtered to provide data for d 0 of gestation. The remaining gilts were bred and assigned randomly to one of six slaughter groups: d 45, 60, 75, 90, 102, and 112. Gilts were fed 2 kg (as-fed basis) of gestation diet daily (3.1 Mcal/kg of ME and 0.56% lysine). Carcass soft tissue, bone, gastrointestinal tract, spleen, pancreas, kidney, liver, uterus, fetus, mammary gland, and the remaining viscera were separated and weighed. Carcass soft tissue, liver, remaining viscera, uterus, and gastrointestinal tract were ground, freeze-dried, and analyzed for composition. Body weights of the gilts increased quadratically (P < 0.001) during gestation. Weights of carcass soft tissue and uterus, including placenta, increased linearly (P < 0.001) during gestation. Weights of individual fetuses, fetal litters, individual mammary glands, and the entire mammary glands increased cubically (P < 0.001) during gestation. Crude protein in carcass soft tissue increased cubically (P < 0.01), whereas DM and ether extract (EE) in carcass soft tissue increased linearly (P < 0.01). The DM, CP, and EE in the entire mammary glands increased quadratically (P < 0.001) during gestation. The DM, CP, and EE in fetal litter increased cubically (P < 0.01) as gestation progressed. The accretion rates of the conceptus, fetal litter, individual fetus, individual mammary gland, and CP in fetal litter differed (P < 0.05) before and after d 70 of gestation. The CP daily gain from all maternal and fetal tissues was 40 and 103 g/d before and after d 70 of gestation, respectively, suggesting that pregnant gilts may require different quantities of dietary protein during gestation. Based on the maintenance requirement, maternal tissue gain, and conceptus gain, pregnant gilts require 6.8 and 15.3 g/d of true ileal-digestible lysine (or 147 and 330 g/d of true ileal-digestible protein) before and after d 70 of gestation, respectively, to support their true biological needs.

Animal Feed↗

PubMed2004

Growth and compositional changes of fetal tissues in pigs.

Three hundred twenty fetuses were obtained from 33 pregnant gilts (Camborough-22, Pig Improvement Co.) to determine rates of nutrient deposition in fetal tissues and to estimate nutrient requirements for fetal growth. Pregnant gilts were fed an equal amount of a gestation diet (2.0 kg/d; as-fed basis), and were slaughtered at d 0, 45, 60, 75, 90, 102, or 110 of gestation (n = 3 to 6 per day). Fetuses were dissected into carcass and individual tissues (including gastrointestinal tract, liver, lung, heart, kidney, spleen [> or = d 75]), and partial placental collection was made for chemical analysis. Fetal tissues were weighed and analyzed for DM, ash, CP, and crude fat. Regression equations were obtained to explain the weight and compositional changes of individual tissues during gestation. Weights of the fetus, carcass, gastrointestinal tract, liver, heart, lung, and kidney increased cubically (P < 0.001), whereas brain weight increased linearly (P < 0.001) as gestation progressed. Fetal protein and fat contents increased quadratically (P < 0.001) as gestation progressed (R2 = 0.906 and 0.904, respectively). Changes in fetal protein and fat contents fit a multiphasic regression that consisted of two linear equations (P < 0.001, R2 = 0.988 and P < 0.001, R2 = 0.983, respectively), indicating that protein and fat growth accelerated after d 69 of gestation. Fetal protein and fat accretions were 0.25 and 0.06 g/d (P < 0.001) before d 69 of gestation, and increased to 4.63 and 1.09 g/d (P < 0.001) after d 69 of gestation. Protein needs for tissue protein gains increased 19-fold after d 69 of gestation. Results of this study indicate that the growth of the fetus and fetal tissues occurs at different rates during gestation and support the practice of a two-phase feeding strategy (before and after approximately d 70 of gestation) for pregnant gilts.

Animal Feed↗

PubMed2002

Soft cannabinoid analogues as potential anti-glaucoma agents.

Cannabinoids are able to reduce elevated intraocular pressure; however, their use in glaucoma treatment is not approved due to severe systemic side effects. New cannabinoid derivatives have been designed based on a retrometabolic/soft drug approach; they were expected to have local effect, but not systemic side effects. Lead compounds and soft analogues were prepared using Pechmann condensation. In agreement with the SAR hypothesis used for the present soft drug design, all the compounds that were successfully synthesized had IOP lowering effect, but the common metabolite of soft analogues that was found to be inactive. Accordingly, when the soft analogue 8 was administered i.v., its biological effect lasted just for 15 minutes; nevertheless, when administered topically, its effect lasted significantly longer. Its metabolite, though, was inactive when applied either i.v. or topically. Thus, the designed soft analogues proved to be good candidates for topical control of glaucoma without producing systemic side effects. The preliminary i.v. experimental data could be successfully described by an indirect response PK/PD model.

Administration, Topical↗

PubMed2002

Design, pharmacokinetic, and pharmacodynamic evaluation of soft anticholinergics based on tropyl alpha-phenylcyclopentylacetate.

Four new soft anticholinergic agents based on tropyl alpha-phenylcyclopentylacetate, 15a, 15b, 18a, and 18b, were designed and synthesized. Receptor binding studies on the cloned human muscarinic receptors indicated that the new soft anticholinergic agents possessed moderate potency as pKi ranged from 6.7 to 7.6. Mydriatic studies in rabbit eyes revealed that the duration of the action of the new soft anticholinergics (8.5-11.0 h) were shorter than that of atropine (about 24 h) under pharmacodynamic equivalent dose, and one of them, 18a, showed even shorter than that of tropicamide. In addition, after unilateral administration, significant dilation of pupil in the control eyes was observed with tropicamide and atropine but not with soft drugs, suggesting the systemic activity of soft drugs was minimal. With their soft nature, the new soft anticholinergics displayed much shorter protective effect against carbachol-induced bradycardia (about 30 min) than atropine (at least 60 min) in rats. In vitro and in vivo pharmacokinetic studies demonstrated that the soft anticholinergics were rapidly hydrolyzed into the corresponding inactive metabolites once they were introduced into the systemic circulation.

Algorithms↗

PubMed2002

Studies on a soft glycopyrrolate analog, SG-1.

A short-acting soft drug analog (SG-1) of glycopyrrolate (G) was developed by retrometabolic design in order to minimize systemic side effects and optimize the therapeutic index. SG-1,3-(1'-hydroxycyclopentyl)phenylacetoxy-1-methyl-1- methoxycarbonylpyrrolidinium bromide, was synthesized by: (a) esterification of phenylacetic acid with N-methyl-3-pyrrolidinol by DCC to obtain N-methyl-3-pyrrolidinyl phenylacetate; (b) reaction of lithium salt of above phenylacetates with cyclopentanone to obtain N-methyl-3-pyrrolidinyl 3-(1'-hydroxycyclopentyl)phenylacetate; and (c) quarternization with methyl bromoacetate in acetonitrile to give the designed product. To evaluate the pharmacological effect of SG-1, its mydriatic activity in rabbit eyes was compared to that of glycopyrrolate. At the pharmacodynamically equivalent doses (the lowest dose that induces the maximum response) of SG-1 (1%) and glycopyrrolate (0.1%), the mydriatic activities lasted for 5 and 100 h, respectively. Compared to glycopyrrolate, the intrinsic pupil dilation potency of SG-1 was lower (approximately 1/10th) but the duration of action was much shorter (< 1/20th) as SG-1 is susceptible to facile enzymatic hydrolysis/deactivation in the rabbit eyes. In vitro metabolism and stability investigations further supported this finding. In vitro half lives of SG-1 in rat plasma, blood, and 20% liver and lung tissue homogenates were 15.62, 53.86, 263.43, and 318.35 min, respectively. In human plasma and blood, half-lives were 19.93 and 88.32 min, respectively. SG-1 was relatively stable under acidic conditions (pH 5 and lower). SG-1 is a promising, clinically useful short acting anticholinergic.

Animals↗

PubMed2001

Receptor binding studies of soft anticholinergic agents.

Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pK(i) values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pK(i) s determined here and the pA 2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pK(i) (m1), pK(i) (m2), pK(i) (m3), and pK(i) (m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pK i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (O(e)), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r = 0.88) for the pK(i) (m3) values.

Animals↗

PubMed2000

A hypercycle theory of proliferation of viruses and resistance to the viruses of transgenic plant.

A set of dynamical equations for the proliferation of two typical viruses TMV and PVY has been derived from the reaction equations describing their replication, assembly and translation. These equations can be seen as the generalization of hypercycle theory to the system. The quantitative explanation on the phenomena of proliferation of plant virus and the mechanism of resistance to the disease of transgenic plant is offered. The phenomenon of specific cessation of minus-strand RNA accumulation in the proliferation of TMV, the cross-protection of plant viruses and the mechanism of resistance to viruses of transgenic plant are discussed based on the computer simulation of the proliferation of viruses and the prediction of the secondary structure of the genomic RNA.

Computer Simulation↗

PubMed2000

Design, synthesis, and pharmacological evaluation of soft glycopyrrolate and its analog.

Glycopyrrolate is a quaternary anticholinergic drug. Like for other anticholinergics, the usefulness of this agent is limited by its side effects. In this study, based on the structure of glycopyrrolate, we designed a soft drug, methoxycarbonylphenyl-cyclopentylacetoxy-N,N-dimethyl-3-p yrrolidinium methyl sulfate (SG), and its analog, methoxycarbonylphenylcyclopentyl-acetoxyethyl-N,N,N-trimethylammon ium methyl sulfate (SGA). These soft drugs are expected to be locally active, but systemically inactive in order to increase therapeutic index. SG and SGA were synthesized by (i) carboxylation of methyl phenylcyclopentylacetate, (ii) esterification with N-methyl-3-pyrrolidinol (for SG) or 2-chloro-N,N-dimethylaminoethane (for SGA), and (iii) quarternization with dimethyl sulfate. Receptor binding studies demonstrate that SG has muscarinic subtype selectivity (m3/m2). Guinea pig ileum pA2 assay indicates that activity of SG is moderate, and SG is about ten times more potent than SGA. The in vivo characterization of SG and SGA, both in mydriasis tests and in prevention of carbachol induced bradycardia, supported its soft nature. Applying SG or SGA into rabbit eyes, the dilation of the contralateral (water-treated) pupils was not observed. Glycopyrrolate application, however, caused dilation of the contralateral pupil, indicating a systemic effect of this drug. Cardiac studies were carried out by evaluating the protective effect of soft anticholinergics against carbachol induced bradycardia. The results indicate that SG and SGA were as potent as atropine-MeBr in preventing carbachol induced bradycardia in the rat; however, their durations of action were significantly shorter. In conclusion, the newly synthesized SG and SGA showed soft nature in the body. They are anticholinergics with subtype selectivity and moderate potency, and can be used as topical antiperspirants.

Administration, Topical↗

PubMed2000

Soft cannabinoid analogues as potential anti-glaucoma agents.

Cannabinoids have intraocular pressure (IOP) lowering effects, thus, they have a therapeutic potential in the treatment of glaucoma. Unfortunately, in the same time, they show CNS and cardiovascular effects as well. Our aim was to develop a safer, cannabinoid type anti-glaucoma agent, a topically applied soft analogue, that has local, but no systemic effect. The lead compound chosen was a nitrogen-containing cannabinoid analogue that was shown to have IOP lowering activity. A full library of possible soft drugs was generated and the structures were ranked based on the closeness of calculated properties to those of the lead compound. The lead compound has been synthesized, and a preliminary pharmacological study was performed. The structure-activity relationship and pharmacological results indicate a good possibility for the development of a safe, soft anti-glaucoma agent.

Animals↗

PubMed1999

Development of the GABA system in organotypic culture of hippocampal and cerebellar slices from a 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient mice.

Mice lacking glutamic acid decarboxylase 67kDa (GAD67) are born with much reduced GABA contents but do not survive after birth. To estimate the subsequent development of GAD67-deficient neural tissue, the hippocampal and cerebellar slices were prepared while the mice were alive, and subjected to organotypic culture. Although GABA contents were initially less than 5%, they were markedly increased, and GABA-containing fiber networks were well developed during the culture, indicating that GAD65, the other GAD isoform, largely compensates for the lack of GAD67. Cerebellar Purkinje cells developed similarly in culture.

Animals↗