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PubMed2005

Effect of the ATP-sensitive potassium channel opener ZM226600 on cystometric parameters in rats with ligature-intact, partial urethral obstruction.

The activity of a recent K(ATP) channel opener, the N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (ZM226600) was investigated on a female rat model of overactive bladder with outlet obstruction. Both ZM226600 and pinacidil instilled into the bladder (10(-7) M, 30 min) or following systemic administration (10, 100 nmol/kg e.v.) almost completely abolished bladder overactivity and improved residual volume and frequency of micturition. However, pinacidil affected arterial pressure. Oxybutynin instilled into the bladder (10(-7), 10(-6), 10(-5) M, 30 min) decreased detrusor overactivity by about 16%, 25% and 46% respectively, but also blocked micturition reflexes at highest doses tested. Oxybutynin reduced detrusor overactivity by about 50% and 80%, after systemic administration (10, 100 nmol/kg e.v.), but also blocked micturition reflexes at the highest dose tested. In conclusion, ZM226600 is more active than oxybutynin in reducing bladder overactivity, and it is devoid of vascular side effects observed with pinacidil. Its short duration of action (about 1 h) is probably the main problem to solve, in order to consider this compound a valid alternative to antimuscarinics in the therapy of bladder overactivity.

Adenosine Triphosphate↗
PubMed2006

Pharmacological characterization of urinary bladder smooth muscle contractility following partial bladder outlet obstruction in pigs.

Partial bladder outlet obstruction of the pig is considered as a valuable preclinical model for evaluating the profile of compounds for the treatment of bladder overactivity. In this study, we characterized the pharmacological properties of isolated bladder smooth muscle from pigs following partial outlet obstruction and its sensitivity to potassium channel openers. Bladder strips from obstructed animals showed significantly lower maximal efficacy (E(max)) and sensitivity to stimulation by ATP and carbachol, but not to those evoked by serotonin, compared to age-matched controls. Tissue strips from obstructed animals also showed a 2.5-fold increase in the potency and significantly reduced maximum response following K+ depolarization. With respect to spontaneous activity, bladder strips from control strips demonstrated little spontaneous phasic activity at all preloads examined. In contrast, bladder strips from obstructed animals showed large preload-dependent increases in spontaneous phasic activity at preload values of 16-32 g. The potencies of K(ATP) channel openers to relax carbachol-evoked contractions showed a good 1:1 correlation (r(2)=0.90) between obstructed and control bladder strips. These studies demonstrate that obstructed pig bladders show enhanced spontaneous phasic activity especially at elevated preloads, which may underlie unstable myogenic bladder contractions reported in cystometrographic measurements in vivo. The impaired responses to electrical field stimulation could be attributed to reduced efficacies and/or lower sensitivities of muscarinic and purinergic signaling pathways. K(ATP) channel sensitivities remain essentially unimpaired in the obstructed bladder and could be effectively modulated by openers with potential for the treatment of overactive bladder secondary to outlet obstruction.

Adenosine Triphosphate↗
PubMed2005

The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration.

Aqueous solubility, apparent partition coefficient (logPapp) and catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibiting potency of entacapone and tolcapone were compared in vitro. Both drugs (at 10 and 100 microM) were also delivered directly into rat striatum via a microdialysis probe. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations were measured to evaluate the inhibition of striatal COMT in vivo. Although entacapone had 15-fold better aqueous solubility than tolcapone at pH 7.4, also tolcapone had sufficient aqueous solubility to remain in solution at 100 microM. The logPapp of tolcapone was higher than that reported for entacapone in the pH range from 5.0 to 7.4. Entacapone and tolcapone inhibited equally rat striatal COMT in vitro with Ki values of 1.86 and 2.50 nM, respectively. Both drugs had similar outflow from the microdialysis probe in vitro. Perfusion of 100 microM entacapone increased significantly extracellular DOPAC levels compared to the control group. Both entacapone and tolcapone (at 10 and 100 microM) decreased significantly HVA levels, but entacapone was significantly more effective than tolcapone at 100 microM. In conclusion, entacapone and tolcapone are equally potent COMT inhibitors against rat striatal COMT in vitro. After local intrastriatal administration, entacapone appeared to inhibit COMT faster and more effectively than the more lipophilic tolcapone. Thus, intrastriatal administration led to opposite results compared to those reported in the brain after systemic administration. The present results also suggest that the local distribution of entacapone and tolcapone differ when the drugs are delivered directly into the brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗
PubMed2003

3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-diones, a new group of antimycobacterial compounds against potentially pathogenic strains.

A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones and depends on the partition coefficients and electronic indexes.

Anti-Bacterial Agents↗
PubMed2006

In vitro permeation of repellent DEET and sunscreen oxybenzone across three artificial membranes.

DEET and oxybenzone are two essential active ingredients in repellent and sunscreen products. We performed a series of in vitro diffusion studies to evaluate the transmembrane permeation of DEET and oxybenzone across three artificial membranes, low-density polyethylene (LDPE), low fouling composite (LFC) and mixed cellulose esters (MCE), from concurrent use of commercial repellent and sunscreen preparations. Permeation of DEET and oxybenzone across the test membranes was synergistically increased when both the repellent and the sunscreen formulations were applied simultaneously. Different application sequences and formulation types also resulted in variable permeation profiles of DEET and oxybenzone. Compared to biological piglet epidermis under the identical experimental conditions, transmembrane permeation of DEET was suppressed in LDPE and LFC membranes, but enhanced in MCE membrane; transmembrane permeation of oxybenzone was reduced in LFC membrane, but increased in LDPE and MCE membranes. Permeability coefficients of DEET and oxybenzone in all three artificial membranes were significantly different from those in piglet skin. It was concluded that the permeation profiles of the compounds were dependent upon physicochemical characteristics of the membranes and the formulations.

Animals↗
PubMed2004

Aspergillus fumigatus CY018, an endophytic fungus in Cynodon dactylon as a versatile producer of new and bioactive metabolites.

Aspergillus fumigatus CY018 was recognized as an endophytic fungus for the first time in the leaf of Cynodon dactylon. By bioassay-guided fractionation, the EtOAc extract of a solid-matrix steady culture of this fungus afforded two new metabolites, named asperfumoid (1) and asperfumin (2), together with six known bioactive compounds including monomethylsulochrin, fumigaclavine C, fumitremorgin C, physcion, helvolic acid and 5alpha,8alpha-epidioxy-ergosta-6,22-diene-3beta-ol as well as other four known compounds ergosta-4,22-diene-3beta-ol, ergosterol, cyclo(Ala-Leu) and cyclo(Ala-Ile). Through detailed spectroscopic analyses including HRESI-MS, homo- and hetero-nuclear correlation NMR experiments (HMQC, COSY, NOESY and HMBC), the structures of asperfumoid and asperfumin were established to be spiro-(3-hydroxyl-2,6-dimethoxyl-2,5-diene-4-cyclohexone-(1,3')-5'-methoxyl-7'-methyl-(1'H, 2'H, 4'H)-quinoline-2',4'-dione) and 5-hydroxyl-2-(6-hydroxyl-2-methoxyl-4-methylbenzoyl)-3,6-dimethoxyl-benzoic methyl ester, respectively. All of the 12 isolates were subjected to in vitro bioactive assays against three human pathogenic fungi Candida albicans, Tricophyton rubrum and Aspergillus niger. As a result, asperfumoid, fumigaclavine C, fumitremorgin C, physcion and helvolic acid were shown to inhibit C. albicans with MICs of 75.0, 31.5, 62.5, 125.0 and 31.5 microg/mL, respectively.

Antifungal Agents↗
PubMed2005

Simultaneous analysis of insect repellent DEET, sunscreen oxybenzone and five relevant metabolites by reversed-phase HPLC with UV detection: application to an in vivo study in a piglet model.

N,N-Diethyl-m-toluamide (DEET) and oxybenzone are two essential active ingredients in insect repellent and sunscreen preparations. We developed and validated a simple, sensitive, and selective HPLC assay to simultaneously measure DEET, oxybenzone and five primary metabolites of DEET and oxybenzone in biological samples including plasma, urine and skin strips. The compounds were separated on a reversed-phase C18 column using three-stage gradient steps with methanol and water. DEET and two relevant metabolites were detected at 254 nm, while oxybenzone and three relevant metabolites were detected at 289 nm. The limit of detection was 0.6 ng for DEET and 0.5 ng for oxybenzone, respectively. The developed method was further applied to analyze various biological samples from an in vivo animal study that evaluated concurrent use of commercially available insect repellent and sunscreen preparations.

Animals↗
PubMed2007

Effect of ophthalmic solution components on acrylic intraocular lenses.

PURPOSE: To investigate the effect of ophthalmic solution components on the surface of acrylic intraocular lenses (IOLs). SETTING: Department of Opthalmology, Showa University School of Medicine. METHODS: Measurement of the contact angles of ophthalmic solutions on 3 acrylic IOLs was performed. The solutions were diclofenac sodium (Diclod), bromfenac sodium (Bronuck), betamethasone phosphate (Rinderon), dibekacin sulfate (Panimycin), polysorbate 80 (Tween 20), benzalkonium chloride, chlorobutanol, methylparahydroxybenzoate, and propylparahydroxybenzoate. The IOLs were incubated at 35 degrees C for 2 weeks in undiluted ophthalmic solutions and in 1:10 dilutions of ophthalmic solution components. The IOLs were sectioned and observed by scanning electron microscopy. RESULTS: The contact angle of Diclod and Bronuck solutions was the smallest. The contact angle of Rinderon and Panimycin was similar to that of distilled water. Scanning electron microscopy examination of IOLs incubated in ophthalmic solution components showed intralenticular changes. The IOLs immersed in ophthalmic solutions did not show any change, even after extended incubation. CONCLUSION: The chemical components of ophthalmic solutions, such as surfactants and solvents, permeate acrylic IOLs, suggesting the potential for long-term adverse effects of eyedrops in pseudophakic eyes.

Acrylic Resins↗
PubMed2006

Removal of chromium from aqueous solution using cellulose acetate and sulfonated poly(ether ether ketone) blend ultrafiltration membranes.

A process for purifying aqueous solutions containing heavy and toxic metals such as chromium has been investigated. Chromium salts are largely used in various industries including leather-manufacturing industry. Ultrafiltration processes are largely being applied for macromolecular and heavy metal ion separation from aqueous streams. Cellulose acetate and sulfonated poly(ether ether ketone) blend ultrafiltration membranes were prepared by precipitation phase inversion technique in 100/0, 90/10, 80/20 and 70/30% polymer blend compositions and subjected to the rejection of chromium at different concentrations such as 200, 400, 600, 800 and 1000 ppm with a water-soluble macroligand (polyvinylalcohol). Factors affecting the percentage rejection and permeate flux such as pH, concentration of solute, concentration of PVA, transmembrane pressure and composition of blend membranes were investigated. It was found that percentage rejection improved at a pH 6 and a macroligand concentration of 2 wt.%. The transmembrane pressure and concentration of solute also have an effect on the separation and product rate efficiencies of the blend membranes.

Alcohols↗
PubMed2026

Fused Deposition Modeling (FDM) of polyether-ether-ketone (PEEK) dental implants: A systematic review of the effect of printing parameters on mechanical behaviour and surface quality.

PURPOSE: This systematic review evaluated how FDM printing parameters influence mechanical behaviour and surface characteristics of 3D-printed PEEK and identified parameter combinations linked to the most favourable mechanical performance and surface quality. MATERIALS AND METHODS: An electronic search was conducted in: MEDLINE (Ovid), PubMed, Embase, Web of Science, Scopus, and Compendex (last update: January 2025). Studies that evaluated the effect of FDM printing parameters on mechanical and surface properties of PEEK were included. Outcomes comprised compressive, tensile, and flexural strengths, elastic modulus, fracture toughness, surface hardness, roughness, and wettability. RESULTS: Of 4005 reports screened, 54 manuscripts were included. 92.6% (n = 50) of articles showed low risk-of-bias, while 7.4% (n = 4) showed medium risk-of-bias. Tensile strength was the most investigated mechanical parameter (78%), followed by elastic modulus (41%), flexural strength (30%), compressive strength (20%), and fracture toughness (6%). Surface roughness was the most evaluated surface property (30%), followed by hardness (17%) and wettability (6%). Across studies, higher printing temperatures, lower printing speed, thinner layer thickness, and maximum infill ratio in a horizontal printing orientation were associated with higher strengths, less warpage, increased accuracy, and improved surface quality. CONCLUSION: Specific combinations of FDM printing parameters can significantly improve the mechanical and surface properties of PEEK. However, it is difficult to meet all the optimal conditions simultaneously. Thus, balancing between different parameters must be considered in practical production.

Benzophenones↗
PubMed2004

Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells.

Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors used as adjuncts to levodopa in the treatment of Parkinson's disease (PD). The use of tolcapone has been limited by its hepatotoxicity, the cause of which remains uncertain. Tolcapone compound is an uncoupler of mitochondrial respiration in isolated mitochondria and this action may be relevant to its effect on liver function. We have examined the actions of COMT inhibitors on cultured cells, comparing them with those of the classical uncoupler carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), in order to provide insight into their mechanism of potential toxicity. Tolcapone and FCCP were shown to be toxic to human neuroblastoma SH-SY5Y cells and caused a profound reduction in ATP synthesis. Entacapone was not toxic to SH-SY5Y. Tolcapone and FCCP were shown to be equally toxic to cells depleted of mtDNA and thus devoid of a functional respiratory chain. This study demonstrates that tolcapone markedly inhibits ATP synthesis in cultured cells mirroring the effects of a classical uncoupler. However its toxicity may also involve a mechanism independent of its effects upon oxidative phosphorylation.

Benzophenones↗
PubMed2004

Treatment of multilevel cervical fusion with cages.

BACKGROUND: Multilevel cervical discectomy usually requires plate and screw fixation for maintaining the spinal curvature, and increasing the graft fusion rate. However, the use of plate and screw fixation may cause a few complications, such as screw breakage, screw pullout, esophagus perforation, and cord or nerve root injury. In this study, we try to use cages to replace plate function in multilevel cervical fusion. METHODS: From January 1997 to June 2001, there were 180 consecutive cases of multilevel cervical degenerative disease. We randomized them into three groups: Group A (60 patients) underwent anterior discectomy and polyetheretherketone (PEEK) fusion, Group B (50 patients) underwent anterior discectomy, autogenous iliac crest graft (AICG) fusion and plate fixation, and Group C (70 patients) underwent anterior discectomy and AICG only. X-ray of cervical spine was taken every 3 months until fusion was complete. Spinal curvature was measured by lateral view of X-ray. The functional and working status were evaluated by Prolo scale. Blood loss and operation time were recorded, respectively. RESULTS: The total complication rates were 3.3%, 16%, and 54.3% in Groups A, B, and C respectively. The graft complications were evaluated by radiographic findings (graft collapse, nonunion, or dislodged graft). However, only 37.1% of patients (13/35) with graft complications had clinical symptoms (severe neck pain, radicular pain, or neurologic deficits). The fusion rate was better, and the time to fusion was sooner in Groups A and B than Group C, p < 0.001 (chi(2) test). PEEK cage is statistically better than plating group in total complications, p < 0.05. Graft collapse and nonunion were the major graft complications in Group C (AICG without plating). Screw pullout, and screw breakage were the main causes of plating complication. Blood loss was minimum in Group A, p < 0.05. Spinal lordosis increased by a mean of 4.61 +/- 2.93 mm and 1.68 +/- 5.02 mm in Groups A and B, respectively, but spinal kyphosis increased by a mean of -2.09 +/- 4.77 mm in Group C. Group A had a statistically better Prolo scale than Group C, p < 0.0001. CONCLUSIONS: Both PEEK cage without plating and AICG with plating are good methods for interbody fusion in multilevel cervical degenerative diseases. They increase spinal lordosis and graft fusion rate, and cause fewer surgical complications. However, PEEK cage is preferred in our study for multilevel fusion, because it has the fewest complication rates and the least amount of blood loss.

Adult↗
PubMed1997

Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) by sulfasalazine: a novel mechanism of anti-inflammatory activity.

Sulfasalazine is widely used in rheumatoid arthritis and inflammatory bowel diseases. The mechanisms of its activity have not been elucidated. In leukocytes, sulfasalazine and its analogue, CL 42A, inhibited the formation of leukotrienes and possibly of the second messenger compounds at the level of phospholipase C. Partial inhibition of interleukin-lbeta (IL-1beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) was also found. Since the synthesis of eicosanoids is induced by phospholipase A2 and since secretory phospholipase A2 (sPLA2) is proinflammatory, we investigated the impact of sulfasalazine and related compounds on mRNA, protein synthesis, and release of sPLA2 from osteoblasts. Sulfasalazine and CL 42A markedly inhibited extracellular release of sPLA2. The impact of sulfasalazine was evident at 50 microM (P < 0.001) and maximal at 400 microM, and that of CL 42A at 10 microM (P < 0.001) and 200 microM, respectively. Split products of sulfasalazine, 5-aminosalicylic acid (400 microM) and sulfapyridine (400 microM), had no impact. The effect of sulfasalazine and CL 42A was evident regardless of whether the cells were stimulated with IL-1beta/TNF-alpha, lipopolysaccharide/forskolin, or dibutyryl-cAMP. Sulfasalazine and CL 42A did not alter the level of sPLA2 mRNA. Exposure of stimulated fetal rat calvaria osteoblasts (FRCO) to sulfasalazine did not show accumulation of the intracellular sPLA2 protein as tested by western blot; however, enzymatic activity of PLA2 in disrupted cells was definitely increased. Thus, the impact is on the post-transcriptional release of sPLA2 rather than on the synthesis. There was also an increase in the extracellular release of prostaglandin E2 from FRCO exposed to sulfasalazine or to CL 42A. In contrast, sulfasalazine had no effect on the extracellular release of gelatinase from the cells or on mRNA of cytosolic PLA2 or cyclooxygenase 2. We conclude that the anti-inflammatory activity of sulfasalazine may be related, in part, to the selective inhibition of the extracellular release of proinflammatory sPLA2.

Anti-Inflammatory Agents↗
PubMed1998

Down-regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA levels and synthesis in syrian hamster C100 cells by the oxidosqualene cyclase inhibitor [4'-(6-allyl-ethyl-amino-hexyloxy)-2'-fluoro-phenyl]-(4-bromophenyl)-me thanone (Ro 48-8071): comparison to simvastatin.

In vivo inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7)--the enzyme which catalyzes the cyclization of monooxidosqualene to lanosterol--does not result in elevated 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) activity. This trait is attributed to increased levels of oxysterols, produced upon partial inhibition of OSC, that suppress HMGR and other sterol-responsive genes. The OSC inhibitor [4'-(6-allyl-ethyl-amino-hexyloxy)-2'-fluoro-phenyl]-(4-bromopheny l)-methanone (Ro 48-8071) was shown earlier to lower low-density lipoprotein (LDL) cholesterol in hamsters with no increase in hepatic HMGR, in contrast to simvastatin. To delineate the regulatory mechanism(s) by which Ro 48-8071 reduces cholesterol synthesis without raising HMGR levels, Syrian hamster C100 cells were incubated with either Ro 48-8071 or simvastatin, and their effects on cholesterol synthesis and LDL uptake, as well as on HMGR mRNA levels and rates of synthesis, were determined. Using RNase protection and radioimmunoprecipitation assays, we found that, in the absence of LDL in the culture medium, both HMGR mRNA levels and synthesis were reduced with concentrations of Ro 48-8071 inhibiting cholesterol synthesis by 50-75%, whereas LDL uptake was either reduced or unchanged. In contrast, simvastatin, at concentrations inhibiting cholesterol synthesis by the same 50-75%, increased both HMGR mRNA levels and synthesis, as well as LDL uptake. In the presence of LDL, HMGR mRNA levels and synthesis along with LDL uptake were little affected after incubation with Ro 48-8071. Still, simvastatin markedly increased both HMGR mRNA levels and synthesis in cells incubated in the presence of LDL, leaving LDL uptake unaffected. These data suggest that inhibition of OSC by Ro 48-8071 results in an indirect down-regulation of HMGR mRNA levels and synthesis.

Animals↗
PubMed1998

Effects of ZD6169, a KATP channel opener, on bladder hyperactivity and spinal c-fos expression evoked by bladder irritation in rats.

Cystometrographic recording and immunocytochemical techniques were used to examine the effects of ZD6169, an ATP-sensitive K+-channel opener, and capsaicin, an afferent neurotoxin, on urinary bladder hyperactivity and immediate early gene expression in the spinal cord induced by acetic acid (0.25%) irritation of the bladder. Chemical irritation of the bladder of the rat increased the frequency of voiding reflexes by 8 fold and increased c-fos expression in neurons in the dorsal commissure (DCM), sacral parasympathetic nucleus (SPN) as well as the medial and lateral dorsal horn (MDH, LDH) of L6 and S1 segments of the spinal cord. Pretreatment with ZD6169 (30 nM) for 1 h reduced the effect of acetic acid on voiding frequency as reflected by an increase in the intercontraction interval (ICI, 137+/-48% increase, P<0.05). ZD6169 also decreased the number of Fos positive neurons in the L6 spinal cord, in the DCM (62.1+/-7.1% decrease), SPN (48.8+/-7%), MDH (50+/-7.3%) and LDH regions (38. 8+/-10.5%). Similar reductions were noted in the S1 spinal cord: 65. 1+/-10.8% in DCM, 53.8+/-11% in SPN, 56+/-10.4% in MDH and 25.3+/-18. 1% in LDH. Capsaicin pretreatment (125 mg/kg, s.c., 4 days prior to the experiments) also reduced bladder hyperactivity (550% increase in ICI) and decreased the numbers of acetic acid-induced Fos positive neurons 78.8+/-6.3% in DCM, 73+/-7.8% in MDH, 59.2+/-16% in LDH and 45.2+/-17% in SPN of L6 segment of the spinal cord. These results suggest that ZD6169 can influence bladder hyperactivity by suppressing the firing of capsaicin-sensitive C-fiber bladder afferents which are known to modulate the micturition reflex.

Adenosine Triphosphate↗
PubMed1999

Effects of tolcapone upon soluble and membrane-bound brain and liver catechol-O-methyltransferase.

The present study was aimed to evaluate the sensitivity of soluble (S) and membrane bound (MB) catechol-O-methyltransferase (COMT) from rat brain and liver to inhibitors which interact with the enzyme as competitive (tropolone), non-competitive (S-adenosyl-l-homocysteine; SAHC) and tight-binding (tolcapone and 3,5-dinitrocatechol) inhibitors. COMT activity was evaluated by the ability to methylate adrenaline (0.1 to 2000 microM) to metanephrine in the presence of a saturating concentration of the methyl donor (S-adenosyl-l-methionine). When using a fixed amount of total protein (2 micrograms/ml), but variable concentrations of COMT, the inhibitory potency of tolcapone upon S- and MB-COMT activity in the brain was in the low nM range (IC50's of 2 and 3 nM, respectively), whereas in liver the IC50 values for tolcapone against liver MB- and S-COMT (IC50's of 123 and 795 nM, respectively) were markedly higher than those observed in the brain. By contrast, when inhibition studies were performed with a fixed concentration of COMT (15 nM), as determined by the Ackermann-Potter equation, tolcapone was found to be endowed with the same potency (in the low nM range) in inhibiting S- and MB-COMT from both brain and liver. As for tolcapone, 3,5-dinitrocatechol was more potent against MB- than against S-COMT when a fixed amount of total protein was used, but showed the same potency when a fixed concentration of COMT was used. Tropolone, a competitive inhibitor, was much less potent than tolcapone and 3,5-dinitrocatechol in inhibiting S- and MB-COMT from both brain and liver and its potency was found not to depend on enzyme concentration. SAHC, a non-competitive inhibitor, behaved similarly to tight-binding inhibitors when a fixed amount of total protein was used. By contrast, when a fixed amount of enzyme was used, SAHC was found to be endowed with the same potency against S- and MB-COMT from brain and liver. In the final series of experiments the inhibitory effect of tolcapone was examined under in vitro ex vivo conditions, using the same concentration of COMT (15 nM). One hour after its oral administration, tolcapone (0.3 to 30 mg/kg) was found to be much more potent against MB-COMT than against S-COMT. In the liver, 0.3 mg/kg tolcapone resulted in 82% inhibition of MB-COMT and 31% inhibition of S-COMT. In the brain, 3.0 mg/kg tolcapone inhibited 78% MB-COMT, whereas S-COMT activity was reduced by 38% only. In conclusion, the results reported here show that tolcapone is particularly potent in inhibiting MB-COMT from liver and brain under in vivo experimental conditions, though it does not discriminate between MB- and S-COMT under in vitro experimental conditions when using the same amount of enzyme in the assay.

Animals↗