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PubMed1985

Uptake of gamma-aminobutyric acid by human blood platelets: comparison with CNS uptake.

Human blood platelets show a sodium and temperature dependent uptake of gamma-aminobutyric acid (GABA) and other neuroactive amino acids. The most potent inhibitors tested of platelet GABA uptake were taurine and beta-alanine, while nipecotic acid and cis-3-aminocyclohexanecarboxylic acid were relatively weak inhibitors. These results suggest GABA is transported by a beta-amino acid uptake process in human platelets. Thus, platelet GABA uptake may more closely resemble glial rather than neuronal uptake.

Amino Acids↗
PubMed1983

Role of the ventromedial nucleus of the thalamus in motor behaviour--I. Effects of focal injections of drugs.

An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits gamma-aminobutyrate metabolism, raised gamma-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting gamma-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane carboxylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the gamma-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis- 1,3-aminocyclohexane carboxylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial muscimol. Treating one ventromedial thalamus with muscimol greatly intensified any pre-existing posture directed towards that side, and vice versa. These data suggest that the ventromedial nucleus is not involved with the expression of stereotyped behaviours, but can profoundly influence posture and locomotion, especially in the presence of some other motor stimulus. The recovery of circus movements in rats with impaired ventromedial nucleus function implies this nucleus is not essential for the execution of circling in these models.

Amino Acids↗
PubMed2001

Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin.

BACKGROUND: Cilomilast is an orally active, selective phosphodiesterase 4 inhibitor currently in clinical development for the treatment of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study was to examine the tolerability and steady-state pharmacokinetics of cilomilast and digoxin when coadministered at standard therapeutic doses in healthy adults. METHODS: In an initial, open-label phase, healthy young adults received cilomilast 15 mg BID for 5 days. After a 7-day washout period, subjects entered a double-blind, crossover phase during which they received oral digoxin (375 microg once daily) for 2 consecutive 14-day periods with no intervening washout period. Cilomilast 15 mg BID or placebo was coadministered during the first 14-day period. Subjects then crossed over to the alternative treatment for the second 14-day period. Blood and urine samples were collected at appropriate times for evaluation of digoxin and cilomilast steady-state pharmacokinetic parameters. The size of the study was sufficient to achieve 90% power to correctly exclude an effect of cilomilast. RESULTS: Twelve of the 16 subjects enrolled completed the study. There were 4 withdrawals--1 due to noncompliance, 1 due to a positive drug screening, and 2 due to adverse events. At steady state, cilomilast 15 mg BID had no significant effect on the steady-state pharmacokinetic parameters of digoxin, with 90% CIs for both primary end points--area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval and minimum plasma concentration--completely contained within the specified interval for equivalence (0.80-1.25). A mean reduction in maximum observed plasma concentration of digoxin of 11% was observed during coadministration with cilomilast, and time to maximum concentration was delayed by a median of 1 hour, suggesting a small reduction in the rate of digoxin absorption. Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics. The most frequently reported adverse event was headache. CONCLUSIONS: Cilomilast 15 mg BID had no clinically significant effect on steady-state AUC or on predose trough plasma concentrations of digoxin (375 microg once daily). The steady-state pharmacokinetics of cilomilast 15 mg BID were similar whether administered alone or with digoxin at steady state (375 microg once daily).

Adolescent↗
PubMed1998

3-Amino-5-hydroxybenzoic acid synthase, the terminal enzyme in the formation of the precursor of mC7N units in rifamycin and related antibiotics.

The biosynthesis of ansamycin antibiotics, like rifamycin B, involves formation of 3-amino-5-hydroxybenzoic acid (AHBA) by a novel variant of the shikimate pathway. AHBA then serves as the starter unit for the assembly of a polyketide which eventually links back to the amino group of AHBA to form the macrolactam ring. The terminal enzyme of AHBA formation, which catalyzes the aromatization of 5-deoxy-5-amino-3-dehydroshikimic acid, has been purified to homogeneity from Amycolatopsis mediterranei, the encoding gene has been cloned, sequenced, and overexpressed in Escherichia coli. The recombinant enzyme, a (His)6 fusion protein, as well as the native one, are dimers containing one molecule of pyridoxal phosphate per subunit. Mechanistic studies showed that the enzyme-bound pyridoxal phosphate forms a Schiff's base with the amino group of 5-deoxy-5-amino-3-dehydroshikimic acid and catalyzes both an alpha, beta-dehydration and a stereospecific 1,4-enolization of the substrate. Inactivation of the gene encoding AHBA synthase in the A. mediterranei genome results in loss of rifamycin formation; production of the antibiotic is restored when the mutant is supplemented with AHBA.

Actinobacteria↗
PubMed2000

Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain.

BACKGROUND: Systemic administration of gabapentin was shown previously to attenuate mechanical allodynia in a rat model of postoperative pain. Because intrathecal administration of gabapentin is effective in other hypersensitivity states, the authors tested its effect in the postoperative model, its interaction with another antiallodynic agent (clonidine), and a possible mechanism of gabapentin action (entry into sites of action via an L-amino acid transporter). METHODS: Male Sprague-Dawley rats were anesthetized with halothane, and an incision of the plantaris muscle of right hind paw induced punctate mechanical allodynia. Withdrawal threshold to von Frey filament application near the incision site was determined before and 2 h after surgery. Then, an intrathecal injection was performed and thresholds were determined every 30 min for 3 h thereafter. RESULTS: Paw incision induced a mechanical hypersensitivity (mechanical threshold > 25 g before incision and < 5 g after). Intrathecal gabapentin dose-dependently (10-100 microg) reduced mechanical allodynia. Intrathecal injection of an inhibitor of L-amino acid transporters or a competitor for this transporter, L-leucine, did not reverse the intrathecal effect of gabapentin. The ED50 of intrathecal gabapentin, clonidine, and their combination were 51, 31, and 9 microg, respectively, and isobolographic analysis showed synergy between gabapentin and clonidine. CONCLUSIONS: Intrathecal gabapentin is effective against tactile allodynia that occurs after paw incision, and interacts synergistically with clonidine. Unlike results in vitro, gabapentin does not obligatorily need to enter cells via the L-amino acid transporter mechanism to achieve its effects in vivo.

Acetates↗
PubMed2004

Interaction between anticonvulsants and human placental carnitine transporter.

PURPOSE: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. METHODS: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. RESULTS: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. CONCLUSIONS: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.

Acetates↗
PubMed1988

Differential inhibition of various deoxyribonucleic acid polymerases by Evans blue and aurintricarboxylic acid.

The inhibitory effects of two anionic compounds, Evans blue and aurintricarboxylic acid (ATA), on various kinds of polynucleotide-synthesizing enzymes were examined. Under the assay conditions, optimized for each enzyme species, both these compounds strongly inhibited the activities of the purified human DNA polymerases alpha, beta, gamma, and DNA primase as well as those of DNA polymerase I and RNA polymerase from Escherichia coli and Rauscher leukemia virus reverse transcriptase. ATA was particularly effective in inhibiting retroviral reverse transcriptase and cellular DNA polymerase alpha. Evans blue, which is a structural analogue of suramin, exerted its inhibitory action largely by competing with the template.primer for the same binding site of the enzyme. On the other hand, ATA inhibited most, if not all, of these enzyme activities noncompetitively with respect to either the template.primers or nucleoside 5'-triphosphate substrates. The inhibition constants for ATA were, in general, smaller than those for Evans blue.

Animals↗
PubMed1986

Uptake of gamma-aminobutyric acid and glycine by synaptosomes from postmortem human brain.

Synaptosomes prepared from frozen postmortem human brain accumulated the neurotransmitter gamma-aminobutyric acid (GABA) and the conformationally restricted GABA analogue cis-3-aminocyclohexanecarboxylic acid (ACHC) by a sodium-dependent, temperature-sensitive, high-affinity transport process into an osmotically sensitive compartment. This transport process could be inhibited by GABA analogues (ACHC, 2,4-diaminobutyric acid, nipecotic acid, arecaidine, guvacine) that have been shown in studies on other species to be relatively selective for neuronal rather than glial uptake systems, whereas the glial uptake inhibitor beta-alanine was ineffective. Synaptosomes prepared from frozen post-mortem human medulla and spinal cord, but not cerebral cortex, took up the neurotransmitter glycine by a sodium-dependent high-affinity transport process. The kinetic parameters for the high-affinity uptake of GABA, ACHC, and glycine were Km = 10 +/- 3, 49 +/- 19, and 35 +/- 19 microM; and Vmax = 98 +/- 15, 84 +/- 25, and 5.5 +/- 2.5 nmol/min/100 mg protein, respectively. These results demonstrate the feasibility of using human CNS preparations for studying GABA and glycine uptake, and suggest that such studies may be useful neurochemical markers for transmitter-specific presynaptic terminals in health and disease.

Aged↗
PubMed1996

Comparison of the autoradiographic binding distribution of [3H]-gabapentin with excitatory amino acid receptor and amino acid uptake site distributions in rat brain.

1. Gabapentin is a novel anticonvulsant with an unknown mechanism of action. Recent homogenate binding studies with [3H]-gabapentin have suggested a structure-activity relationship similar to that shown for the amino acid transport system responsible for the uptake of large neutral amino acids (LNAA). 2. The autoradiographic binding distribution of [3H]-gabapentin in rat brain was compared with the distributions for excitatory amino acid receptor subtypes and the uptake sites for excitatory and large neutral amino acids in consecutive rat brain sections. 3. Densitometric measurement of the autoradiographic images followed by normalisation with respect to the hippocampus CA1 stratum radiatum, was carried out before comparison of each binding distribution with that of [3H]-gabapentin by linear regression analysis. The correlation coefficients observed showed no absolute correlation was observed between the binding distributions of [3H]-gabapentin and those of the excitatory amino acid receptor subtypes. The acidic and large neutral amino acid uptake site distributions demonstrated a much closer correlation to the [3H]-gabapentin binding site distribution. The correlation coefficients for D-[3H]-aspartate, L-[3H]-leucine and L-[3H]-isoleucine binding site distributions were 0.76, 0.90 and 0.88 respectively. 4. Concentration-dependent inhibition by unlabelled gabapentin of autoradiographic binding of L-[3H]-leucine and L-[3H]-isoleucine was observed, with non-specific binding levels being reached at concentrations between 10 and 100 microM. 5. Excitotoxic quinolinic acid lesion studies in rat brain caudate putamen and autoradiography were carried out for the amino acid uptake sites mentioned above. The resulting glial infiltration of the lesioned areas was visualized by autoradiography using the peripheral benzodiazepine receptor specific ligand [3H]-PK11195. A significant decrease in binding density in the lesioned area compared with sham-operated animals was observed for D-[3H]-aspartate, L-[3H]-leucine, L-[3H]-isoleucine and [3H]-gabapentin, whilst [3H]-PK11195 showed a significant increase in binding density indicative of glial infiltration into the lesioned area. These results suggest that the gabapentin binding site and the acidic and LNAA uptake site may be present on cell bodies of a neuronal population of cells. 6. From these studies it appears that [3H]-gabapentin, L-[3H]-leucine and L-[3H]-isoleucine bind to the same site in rat brain. The inhibition of [3H]-gabapentin binding by the LNAA uptake system-specific ligand, BCH, suggests that [3H]-gabapentin may label this uptake site, termed system-L. Conversely these ligands could be labelling a novel site that coincidentally has a similar structure-activity relationship to this uptake site. These results suggest a novel mechanistically relevant site of action for gabapentin and may enable further anti-epileptic agents of this type to be developed.

Acetates↗
PubMed2003

Effect of cilomilast (Ariflo) on TNF-alpha, IL-8, and GM-CSF release by airway cells of patients with COPD.

BACKGROUND: Inflammation in chronic obstructive pulmonary disease (COPD) is characterised by increased neutrophilic infiltration of the airways. Cilomilast, a novel selective phosphodiesterase 4 inhibitor in clinical development for COPD treatment, exerts anti-inflammatory effects. The ability of cilomilast to inhibit the release of neutrophil chemoattractants such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-8, and granulocyte-macrophage colony stimulating factor (GM-CSF) by bronchial epithelial cells and sputum cells isolated from 10 patients with COPD, 14 normal controls, and 10 smokers was investigated. METHODS: Bronchial epithelial cells obtained by bronchial brushing and sputum cells isolated from induced sputum samples were cultured for 24 hours in the presence or absence of cilomilast (1 micro M). After incubation the supernatants were harvested and the levels of mediators measured by ELISA. Chemotactic activity in supernatants was also measured using a Boyden chamber. RESULTS: TNF-alpha and IL-8 release by bronchial epithelial cells and sputum cells was higher in patients with COPD than in controls (p<0.0001) and smokers (p<0.0001). GM-CSF was only detectable in sputum cell supernatants and its level was higher in patients with COPD than in controls and smokers (p<0.0001, respectively). Cilomilast significantly reduced TNF-alpha release by bronchial epithelial cells and sputum cells (p=0.005) and GM-CSF release by sputum cells (p=0.003), whereas IL-8 release was not statistically inhibited. Supernatants of sputum cells and bronchial epithelial cells treated with cilomilast significantly decreased neutrophil chemotaxis (p<0.006 and p<0.008, respectively). CONCLUSIONS: Cilomilast inhibits the production of some neutrophil chemoattractants by airway cells. This drug may play a role in the resolution of neutrophilic inflammation associated with COPD and cigarette smoke.

Adult↗
PubMed1978

Inhibition of cell-free protein synthesis by analogues of aurintricarboxylic acid.

Aurintricarboxylic acid is a potent inhibitor of cell-free protein synthesis by the post-mitochondrial supernatant of chick brain and the translation of mRNA by wheat germ lysate. Comparison of commercially available and chemically synthesized analogues of aurintricarboxylic acid indicates that the unique aurin triphenyl methane ring system and the carboxylic acid groups are both necessary for inhibition of cell-free protein synthesis in both systems.

Animals↗
PubMed2002

Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b.

Mutations in the gene of the hepatic glucose-6-phosphate transporter cause glycogen storage disease type 1b. In this disease, the altered glucose homeostasis and liver functions are accompanied by an impairment of neutrophils/monocytes. However, neither the existence of a microsomal glucose-6-phosphate transport, nor the connection between its defect and cell dysfunction has been demonstrated in neutrophils/monocytes. In this study we have characterized the microsomal glucose-6-phosphate transport of human neutrophils and differentiated HL-60 cells. The transport of glucose-6-phosphate was sensitive to the chlorogenic acid derivative S3483, N-ethylmaleimide, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, known inhibitors of the hepatic microsomal glucose-6-phosphate transporter. A glucose-6-phosphate uptake was also present in microsomes from undifferentiated HL-60 and Jurkat cells, but it was insensitive to S3483. The treatment with S3484 of intact human neutrophils and differentiated HL-60 cells mimicked some leukocyte defects of glycogen storage disease type 1b patients (ie, the drug inhibited phorbol myristate acetate-induced superoxide anion production and reduced the size of endoplasmic reticulum Ca(2+) stores). Importantly, the treatment with S3484 also resulted in apoptosis of human neutrophils and differentiated HL-60 cells, while undifferentiated HL-60 and Jurkat cells were unaffected by the drug. The proapoptotic effect of S3483 was prevented by the inhibition of nicotinamide adenine dinucleotide phosphate oxidase or by antioxidant treatment. These results suggest that microsomal glucose-6-phosphate transport has a role in the antioxidant protection of neutrophils, and that the genetic defect of the transporter leads to the impairment of cellular functions and apoptosis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2003

AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis.

AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), a phosphodiesterase 4 inhibitor, which is optimized for topical administration, was tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate (TDI). The allergic reaction was challenged by topical administration of TDI onto the mice ears. AWD 12-281 was tested for its anti-inflammatory potential by oral, intraperitoneal and topical administration. The phosphodiesterase 4 inhibitor, cilomilast (SB 207499), and/or the corticosteroid, diflorasone diacetate, were used as reference compounds. Given orally and intraperitoneally 2 h before as well as 5 and 24 h after TDI challenge, AWD 12-281 showed no, or only a transient inhibition of the allergen-induced ear swelling, whereas cilomilast significantly inhibited this ear swelling. Applied topically onto the ears before TDI challenge, AWD 12-281, cilomilast and diflorasone diacetate caused total inhibition of ear swelling 24 h after challenge, confirmed by a decrease of the pro-inflammatory cytokines interleukin-4, interleukin-6 and macrophage inhibitory protein-2. Administered topically after TDI challenge as therapeutic intervention, AWD 12-281 and diflorasone diacetate caused significant inhibition of ear swelling; cilomilast failed to do so. These results indicate that topically administered AWD 12-281 may be potent in the prevention and treatment of allergic/inflammatory skin diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

[Perfection of an experimental schedule for the quantitative evaluation of trans-abscissic acid by biological tests].

Using gas-liquid chromatography, we have studied the kinetics of the isomerization from trans-ABA to cis-ABA under the effect of short ultraviolet-light (254 nm). At first, for a given volume, the conditions required to reach 50% isomerization were determined. Then the method was adapted to the use of extracts. It is thus possible to estimate the amount of trans-ABA in extracts with a suitable biological test.

Abscisic Acid↗