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PubMed1990

Excitatory amino acid antagonists and memory: effect of drugs acting at N-methyl-D-aspartate receptors in learning and memory tasks.

The role of N-methyl-D-aspartate (NMDA) receptors in memory processes was examined using a Y-shaped maze and a step-through passive avoidance task in mice. In the Y-maze, the total number of arm entries, which represents locomotor activity and alternation behaviour, thought to reflect working memory, were measured. Competitive NMDA antagonists, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylate) and CPP (3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphate), impaired spontaneous alternation at doses which reduced locomotion of mice. N-Methyl-D-aspartate prevented the impairment of alternation and decrease of locomotor activity produced by CGS 19755 and CPP. These results suggest that NMDA-dependent processes are involved in the mechanisms of working memory. In contrast, the non-competitive NMDA antagonist, MK 801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) dramatically enhanced the total number of arm entries, while reducing alternation behaviour, N-Methyl-D-aspartate had no effect on MK 801-induced enhancement of locomotor activity and impairment of alternation. In the passive avoidance task, mice were trained to avoid entry into the dark compartment. At doses which impaired working memory in the alternation task, CPP, CGS 19755 and MK-801 reduced acquisition, when administered before training. N-Methyl-D-aspartate antagonized the effect of CPP, CGS 19755 and MK-801. Neither CPP nor MK-801 affected retention, when administered immediately after training or before testing retention. N-Methyl-D-aspartate had no effect on retention with high-intensity shock, but facilitated retention with low-intensity shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacological characterization of LY233053: a structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action.

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid], the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity. The relatively short duration of action of LY233053 may make this compound particularly advantageous as a neuroprotective agent in the treatment of acute conditions such as cerebral ischemia.

Administration, Oral↗
PubMed2000

Effect of argatroban on trinitrobenzene sulfonic acid-induced colitis.

BACKGROUND: Recent studies have suggested that heparin is effective for treatment of inflammatory bowel disease (IBD) and its various effects (in addition to the anticoagulant effect). We evaluated the effects of argatroban as an antithrombin drug on trinitrobenzene sulfonic acid (TNB)-induced colitis, an established model of IBD. METHODS: Rats were randomly assigned to four groups in which mini-osmotic pumps containing saline (TNB-S), argatroban (TNB-A), or 100 U/kg heparin (TNB-H) were intraperitoneally implanted. Three days after the pumps were implanted, TNB was infused via the anus, and colitis was induced. After 5 days, prothrombin time (PT), activated partial prothrombin time (APTT), antithrombin III (AT-III), platelet, fibrinogen, colonic wet weight, macroscopic damage score, histological score, mucosal myeloperoxidase activity and mucosal leukotrien B4 (LTB4) levels were compared among the four groups. RESULTS: The APTT was prolonged in the heparin treatment group but only slightly prolonged in the argatroban treatment group. The platelet count and the fibrinogen level were higher in the TNB-S group than in the healthy control group and the AT-III level was slightly lower in the TNB-S group than in the healthy control group and lower still in the TNB-H group. CONCLUSIONS: The colonic wet weight was similar among the four groups while the macroscopic damage score, histological score, mucosal myeloperoxidase activity and the mucosal LTB4 level were significantly decreased in the TNB-A and TNB-H groups. Argatroban, as well as heparin may be effective for treatment of TNB-induced colitis.

Analysis of Variance↗
PubMed1990

Comparative effects of aspirin, a synthetic thrombin inhibitor and a monoclonal antiplatelet glycoprotein IIb/IIIa antibody on coronary artery reperfusion, reocclusion and bleeding with recombinant tissue-type plasminogen activator in a canine preparation.

The comparative effects of intravenous aspirin, the synthetic thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8- quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (Argatroban) and F(ab')2 fragments of monoclonal antibody 7E3 against platelet glycoprotein IIb/IIIa (7E3-F[ab']2) on thrombolysis, reocclusion and bleeding associated with 0.45 mg/kg body weight bolus injections of recombinant tissue-type plasminogen activator (rt-PA) were studied in a canine coronary artery thrombosis model. Coronary patency was monitored for 2 h both by flow probe and by coronary angiography. Four groups were studied: Group I = pretreated with 17 mg/kg intravenous aspirin (n = 6), Group II = pretreated with 200 micrograms/kg per min intravenous Argatroban for 60 min (n = 5), Group III = pretreated with aspirin and Argatroban (n = 5) and Group IV = pretreated with 0.8 mg/kg intravenous 7E3-F(ab')2 (n = 5). In Group I, reflow occurred in four of six dogs, but did not persist; reflow was induced in Group II in four of five dogs, persisting in one; in Group III, reflow occurred in all five dogs, persisting in four; in Group IV reflow was achieved in four of five dogs, persisting in two. The frequency of persistent reflow in Group III was significantly higher than in the combined Groups I and II (p = 0.012), whereas the time to reflow was significantly shorter in the groups receiving Argatroban than in the aspirin group (median 25 versus 55 min, p = 0.04). There were no significant differences between Groups III and IV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Tissue distribution of two NMDA receptor antagonists, [3H]CGS 19755 and [3H]MK-801, after intrathecal injection in mice.

The tissue distribution of [3H]cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (NK-801) was investigated after a single IT injection into lumbar spinal cord of mice. The level of radioactivity was analyzed in the lumbar, thoracic, and cervical spinal cord, brainstem, frontal cortex, liver, lungs, kidneys, stomach, intestine, spleen, heart, and blood from 5 min up to 6 h after injection. Within the CNS, [3H]CGS 19755 redistributed slowly from the site of injection toward the brainstem and cortex, peaking in the cortex 3-4 h after IT injection. At no time, however, did the relative level per gram of tissue in the frontal cortex exceed 10% of the relative level in the lumbar region of the spinal cord. The highest peripheral level of [3H]CGS 19755 was found in the kidneys. [3H]MK-801 redistributed rapidly from the spinal cord injection site to the peripheral organs. The highest peripheral levels of [3H]MK-801 were found in the lungs and liver, where the radioactivity peaked at 10 and 30-60 min, respectively, after injection. The relative levels of [3H]CGS 19755 were consistently higher in CNS tissues (except for the first 15 min in the frontal cortex) and blood than the corresponding levels of [3H]MK-801. The opposite relationship was true in the liver, lungs, kidneys, stomach, intestine, spleen, and heart. The effect on the response latency in the hot-plate test was quantified in the same animals immediately prior to sacrifice for the distribution study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Characterization of [3H]CGS 19755 binding sites in the rat spinal cord.

[3H]Cis-4-phosphonomethyl-2-piperidine carboxylic acid ([3H]CGS 19755) was used to investigate the pharmacology and characteristics of the N-methyl-D-aspartate (NMDA) receptor recognition site from Triton X-100-treated membranes of rat spinal cord and cerebral cortex. The association of [3H]CGS 19755 was biphasic in both spinal cord and cerebral cortical membranes reaching a maximum after 5 min of incubation then decreasing to a steady level after an additional 10 min, suggesting that a proportion of the binding is unstable. The dissociation of the stable binding component was biphasic with rate constants at 4 degrees C of 1.55 and 0.020 min-1 for the spinal cord and 1.48 and 0.051 min-1 for the cerebral cortex. These multiple sites could not be captured in the saturation studies which were best fitted to a one-site model using non-linear regression analysis. Depending on the time of incubation with [3H]CGS 19755, KD and Bmax values differed; 9.9-26.1 nM and 25-96 fmol/mg protein vs 14.0-26.5 nM and 449-900 fmol/mg protein for spinal cord and cerebral cortex, respectively. The rank order of potency of inhibiting [3H]CGS 19755 binding was similar in both tissues: L-glutamate > CGS 19755 = CPP > NMDA. The specific NMDA agonist cis-2,4-methanoglutamate potently inhibited [3H]CGS 19755 binding as did MDL 100,925, although the latter was one order of magnitude less potent in the spinal cord than in the brain. The Hill coefficients were significantly lower than unity. In both tissues, AMPA, kainate and glycine competed poorly with [3H]CGS 19755.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacologic blockade of inner retina.

PURPOSE: To determine whether anterior ischemic optic neuropathy and compressive optic neuropathy in humans alter the photopic flash ERG and to investigate the cellular origins of the waves that are affected by pharmacologic agents in primates. METHODS: Photopic flash ERGs were recorded differentially, with DTL electrodes, between the two eyes of 22 patients with diagnosed optic neuropathy (n = 17, anterior ischemic optic neuropathy [AION]; n = 5, compressive optic neuropathy) and 25 age-matched control subjects and in 17 eyes of 13 monkeys (Macaca mulatta). The stimulus consisted of brief (<5 ms) red (lambda(max) = 660 nm) Ganzfeld flashes (energy range, 0.5-2.0 log td-s) delivered on a rod-saturating blue background of 3.7 log sc td (lambda(max) = 460 nm). An eye of the patient with ischemic changes at the disc was classified as symptomatic if it showed visual field defects with a mean deviation (MD) of P < 2%. Recordings in macaque monkeys were made before and after inner retinal blockade with tetrodotoxin (TTX) (1.2-2.1 microM; n = 7), TTX+N-methyl-d-aspartate (NMDA; 1.4-6.4 mM; n = 7), and cis-2, 3 piperidine dicarboxylic acid (PDA; 3.3-3.8 mM; n = 3). RESULTS: The PhNR amplitude was significantly reduced in both symptomatic (P = 3.4 x 10(-8)) and asymptomatic (P = 0.036) eyes of patients with AION or compressive optic neuropathy (P = 0.0054) compared with control subjects. The PhNR amplitude in the symptomatic eye showed a moderate correlation with field defects (P < 0.05) similar to previous findings in open-angle glaucoma. The a-wave also was reduced significantly in the symptomatic eye (P = 0.0002) of patients with AION. The i-wave, a positive wave on the trailing edge of the b-wave peaking around 50 ms, became more prominent in eyes in which the PhNR was significantly reduced. In monkeys, the PhNR was eliminated by TTX. The a-wave at the peak and later times was reduced by TTX, further reduced by NMDA, and eliminated after PDA in response to the red stimuli. PDA also eliminated the i-wave. CONCLUSIONS: PhNR amplitude is significantly reduced in eyes with open-angle glaucoma, AION, and compressive optic neuropathy. Experiments in primates indicate that this reduction reflects loss of a spike-driven contribution to the photopic ERG. There also are small spike-driven contributions to the a-wave elicited by full-field red stimuli. The i-wave, which becomes more prominent when the PhNR is reduced, has origins in the off-pathway distal to the ganglion cells.

Adult↗
PubMed1990

Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition.

The effect of heparin and of the synthetic competitive thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfon yl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (argatroban) on platelet-rich arterial thrombosis was studied in a rabbit model, consisting of a 4-6-mm everted ("inside-out") femoral arterial segment. Intravenous injection of heparin (200 units/kg) failed to prevent occlusion within 60 minutes in all 10 rabbits, whereas intravenous argatroban infusion at a rate of 100 or 200 micrograms/kg/min for 60 minutes, which prolonged the thrombin time more than fourfold, prevented thrombosis in nine of 13 rabbits (p = 0.002 vs. i.v. heparin). Intra-arterial infusion of 200 units/kg heparin over 60 minutes prevented occlusion in six of nine rabbits (p = 0.003 vs. i.v. heparin), whereas intra-arterial argatroban at a rate of 100 micrograms/kg/min for 60 minutes prevented thrombosis in all 10 rabbits (p = 0.00001 vs. i.v. heparin). Patency of femoral arterial segments was maintained after the end of the intra-arterial heparin and intravenous or intra-arterial argatroban infusion for up to 3 hours despite normalization of the thrombin time and partial thromboplastin time. Pathologic examination of the graft revealed that the inverted adventitial surface was covered by layers of platelets without platelet aggregation or fibrin deposition. These findings indicate that thrombin plays an important role in platelet-rich arterial thrombosis, and that the thrombogenic stimulus is rapidly attenuated by short-term infusion of the synthetic thrombin inhibitor. Selective thrombin inhibition can constitute an alternative approach to the prevention of arterial occlusion after angioplasty or thrombolytic therapy in patients with unstable coronary syndromes.

Animals↗
PubMed2000

Antithrombotic efficacy of RPR208566, a novel factor Xa inhibitor, in a rat model of carotid artery thrombosis.

Coagulation factor Xa is the sole enzyme responsible for activating the zymogen prothrombin to thrombin, resulting in fibrin generation, platelet activation, and subsequent thrombus formation. Our objective was to evaluate the antithrombotic efficacy of the novel factor Xa inhibitor, 2-(3-carbamimidoyl-benzyl)-3-[(3', 4'dimethoxy-biphenyl-4-carbonyl)-amino]-butyric acid methyl ester-trifluoroacetate (RPR208566), in a well-established rat model of arterial thrombosis, and to compare the results with those obtained with argatroban and heparin, direct and indirect inhibitors of thrombin, respectively. Thrombus formation was initiated by placing a filter paper saturated with FeCl(2) on the adventia of the carotid artery for 10 min. Time-to-occlusion was measured from initiation of injury until blood flow reached zero. Formed thrombi were removed and weighed 60 min after the placement of the filter paper. RPR208566, heparin, and argatroban dose-dependently increased time-to-occlusion and reduced thrombus mass. When administered at 500 microgram/kg+50 microgram/kg/min, RPR208566 prolonged time-to-occlusion to 56+/-4 min (vs. 18+/-2 min for vehicle) and reduced thrombus mass to 3.0+/-0.7 mg (vs. 7.3+/-0.6 mg for vehicle). The highest doses of argatroban (500 microgram/kg+50 microgram/kg/min) and heparin (300 U/kg+10 U/kg/min) increased time-to-occlusion to the maximum of 60 min and decreased thrombus mass to 5.5+/-0.8 and 2.6+/-0.3, respectively. The antithrombotic effects of heparin and argatroban at these doses were associated with increases in activated partial thromboplastin time of 5.6+/-0.9- and 2.9+/-0.3-fold over baseline, respectively. However, the highest dose of RPR208566 produced a modest 1.3+/-0.1-fold increase in activated partial thromboplastin time. These results indicate that factor Xa inhibition with compounds such as RPR208566 may be an attractive mechanism for novel antithrombotic drug therapy.

Amidines↗
PubMed1995

Correlation of CGS 19755 neuroprotection against in vitro excitotoxicity and focal cerebral ischemia.

The in vivo neuroprotective effect and brain levels of cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from feta mice were injured by exposure to 500 microM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 micro M, and against OGD the ED50 was 15.2 microM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 microM and 5 microM, respectively, at 1 h, 6 microM and 5 microM at 2 h, and 13 microM and 7 microM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection.

Animals↗
PubMed1993

Argatroban and inhibition of the vasomotor actions of thrombin.

We investigated the effects of the thrombin inhibitor, argatroban ((2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8- quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid) on the endothelium-derived relaxing factor-nitric oxide (EDRF-NO)-dependent relaxant, and the endothelial cell-independent constrictor actions of thrombin. Experiments were performed in isolated rings of canine coronary arteries. Argatroban inhibited thrombin-induced relaxation (range of thrombin activity 0.003-0.3 U/ml), with an ED50 of 0.3 microM. The ED50 value was not different from inhibition of thrombin amidolytic cleavage of the chromogenic substrate N-p-tosylgly-pro-arg-p-nitroanilide acetate (TOGSPAN 0.28 microM), but inhibition was highly selective. Argatroban did not block EDRF-NO-dependent relaxations to trypsin (0.003-0.3 U/ml; Emax -88.7 + 2.0% without vs. -88.1 +/- 2.7% with argatroban), acetylcholine (ACh 1 nM to 1 microM; Emax -90.5 +/- 4.7% and -88.6 +/- 3.1%, with and without argatroban, respectively), or the calcium ionophore A23187 (1 nM to 1 microM; Emax -98.5 +/- 1.2 vs. -99.4 +/- 0.6%). The inhibitory effects of argatroban on thrombin-induced constriction were then compared with those of the irreversible thrombin inhibitor D-phenylalanyl-L-prolyl L-arginine chloromethyl ketone (PPACK). The highest concentration of argatroban (10 microM) inhibited the vasoconstrictor effects of thrombin but did not completely block the effects (Emax 21.4 +/- 8.1% of KCl constriction without argatroban and Emax 14.0 +/- 5.2% of KCl-induced constriction with argatroban). In contrast, both a 10- and a 100-fold lower concentration of PPACK (0.1-1 microM) prevented the thrombin-induced increase in tension. Thrombin-induced constriction therefore appeared to disclose mechanistic differences between the two thrombin inhibitors. Thrombin vasomotor actions were inhibited by argatroban, however, and this may contribute significantly to the therapeutic effect of argatroban.

Animals↗
PubMed1990

Interactions between N-methyl-D-aspartate and CGS 19755 administered intramuscularly and intracerebroventricularly in pigeons.

Behavioral effects of N-methyl-D-aspartate (NMDA) and the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755) were studied in pigeons. NMDA decreased responding under a fixed-ratio schedule of food presentation and was 8000 times more potent administered intracerebroventricularly (i.c.v.) as compared to intramuscularly (i.m.). CGS 19755 was 870 times more potent in producing catalepsy when administered i.c.v.; however, the duration of catalepsy was similar by the two routes of administration. Administered i.m. CGS 19755 decreased response rates only at doses that also produced catalepsy; administered i.c.v. some doses of CGS 19755 decreased responding without producing other behavioral effects. Rate-decreasing effects of i.m. NMDA were attenuated by i.m. CGS 19755; however, when CGS 19755 was administered i.c.v., there was little or no antagonism of NMDA. Rate-decreasing effects of i.c.v. NMDA were not attenuated by i.m. or i.c.v. CGS 19755 up to doses that produced catalepsy or eliminated responding. The large difference in potency between i.m. and i.c.v. administration for NMDA and for CGS 19755, as well as the slower onset of catalepsy when CGS 19755 was administered i.m., suggests these compounds do not readily cross the blood-brain barrier when administered parenterally. The inability of CGS 19755 to attenuate the rate-decreasing effects of NMDA when CGS 19755 or NMDA was administered i.c.v. suggests NMDA might decrease responding by different mechanisms when administered i.m. or i.c.v. in pigeons. Together these results indicate antagonism of NMDA in this study, and perhaps in other studies, when both NMDA and CGS 19755 were administered parenterally, might result from a peripherally mediated interaction. Moreover, this agonist-antagonist interaction is not a simple, competitive antagonism.

Animals↗
PubMed2003

Regional variations in local contributions to the primate photopic flash ERG: revealed using the slow-sequence mfERG.

PURPOSE: To determine the variations with eccentricity of the primate photopic ERG and to separate contributions by different retinal cells by using intravitreal pharmacologic agents. METHODS: Slow-sequence multifocal (mf)ERGs were obtained from 19 anesthetized adult rhesus monkeys and 5 normal human subjects. Recordings in monkeys were obtained before and after injections of tetrodotoxin citrate (TTX) to block sodium-dependent spiking; TTX+N-methyl-D-aspartic acid (NMDA)+picrotoxin (PTX) or gamma-aminobutyric acid (GABA) to block all inner retinal activity; L-2 amino-4-phosphonobutyric acid (APB) to block the On-pathway; and cis-2, 3 piperidine dicarboxylic acid (PDA) to block the Off-pathway and the otherwise unblocked inner retinal activity. The stimulus consisted of 103 equal-sized hexagons within 17 degrees of the fovea; every 200 ms (15 frames), each hexagon had a 50% chance of remaining at 20 cd/m(2) or increasing briefly to 4.7 cd-s/m(2). Oscillatory potentials (OPs; 90-300 Hz) were extracted. RESULTS: The slow-sequence mfERG summed over the stimulated area looked similar to a standard photopic, full-field ERG, with a- and b-waves and OPs. OPs in the foveal and temporal retina were larger than in the nasal retina. This nasotemporal asymmetry was removed by TTX, and the OPs were eliminated, either by blocking inner retina activity or by blocking the On-pathway. The summed mfERG waveform, including OPs, was shaped mainly by the more peripheral retinal regions. The foveal b-wave peak occurred about 5 to 6 ms later than in the periphery, with the depolarizing peak of the On-pathway/bipolar contribution occurring earlier than the depolarizing peak of the Off contribution at all eccentricities. The a-wave was composed of a small photoreceptor contribution and postreceptoral portion originating from hyperpolarizing neurons. CONCLUSIONS: The variations in the primate photopic ERG with eccentricity are due to spike-driven oscillatory activity that is more prominent in central and temporal retina than in nasal retina and to the slower timing of all responses in the central, compared with the peripheral, retina. The full-field, photopic ERG most closely resembles the mfERG responses to stimulation of peripheral regions.

Adolescent↗
PubMed2002

Post-photoreceptoral activity dominates primate photopic 32-Hz ERG for sine-, square-, and pulsed stimuli.

PURPOSE: To evaluate the relative contributions of photoreceptors and postphotoreceptoral activity to the primate 32-Hz flicker electroretinogram (ERG) elicited by sine-wave, square-wave, and pulse stimuli. METHODS: Flicker 32-Hz ERGs were evoked from four adult rhesus (Macaca mulatta) monkeys using sine-wave, square-wave, and 4-ms pulse trains and xenon photostrobe flicker stimuli. All stimuli had time-averaged luminance of 2.11 log cd/m(2) and were presented on a 1.63-log cd/m(2) white background. Intravitreal injections of DL-2-amino-4-phosphonobutyric acid (APB) and cis-2,3-piperidinedicarboxylic acid (PDA) were given to block activity of ON- and OFF-bipolar cells, respectively. RESULTS: Flicker harmonic analysis showed that the fundamental frequency component provided nearly 75% of the sine-wave and square-wave ERGs versus 63% for 4-ms pulse stimuli and only 49% for strobe flicker. Strobe-flicker responses contained the greatest contribution from higher harmonic components. Removing the ON component with APB increased the fundamental component's amplitudes by more than 30% with sine-wave and square-wave ERGs but had a lesser effect on responses to 4-ms pulses and strobe flicker. When cone responses were isolated by synaptic blockade with APB+PDA, the fundamental component's amplitude was reduced to less than 20% of control for all four stimuli. Postsynaptic ON and OFF components were characterized by amplitude and phase vectors, and sine-wave and square-wave stimuli gave a large phase difference (138 degrees ) between ON and OFF components, which resulted in greater response self-cancellation than with the 4-ms pulse train (121 degrees phase difference) or for strobe flicker (118 degrees ). CONCLUSIONS: The major decrease in flicker responses after photoreceptor synaptic blockade implicates a major contribution from postphotoreceptoral activity to the fundamental flicker component, regardless of the stimulus type. Sine-wave and square-wave stimuli produced larger phase differences between ON- and OFF-pathway components, thereby causing more complete self-cancellation of postphotoreceptoral contributions and revealing slightly greater relative contribution directly from cone photoreceptors with these stimuli than with pulsed stimuli. The direct cone contribution was always small, however, and the clinical point is that 32-Hz flicker ERG amplitudes do not provide an unambiguous assessment of direct cone photoreceptor contribution with any of these stimuli.

Adaptation, Ocular↗
PubMed2004

Lessons from epidemiologic studies in clinical trials of traumatic brain injury.

Lessions from epidemiological studies. The Clinical Trial Group for Neurosurgery of the University of California San Diego (UCSD) is involved in epidemiological studies and trials of new pharmacological agents in traumatic brain injury. A great number (> 10,000) of patients has been prospectively analyzed forming an integrated database for further purposes. The development of these databases is based on earlier work by the European Neurosurgeons Jennett and Braakmann and the US-Traumatic Coma Data Bank Study. These studies allowed for the development of sophisticated data collection instruments which were used in the international Tirilizad Trials which enrolled over 1,100 patients. A major observation from that trial was that pretreatment hypotension or hypoxia could be unbalanced even in a large two arm blinded study. Another issue of the tirilazad trial was the influence of gender affecting not only outcome but also drug metabolism. Similar experiences were gathered with the phase-III trial on the competitive NMDA-receptor antagonist selfotel, which interferes with the excitotoxic amino acid glutamate as mediator of secondary brain damage, as ischemia-induced neuronal degeneration. Unfortunately, the trial, already underway, had to be prematurely aborted, since concurrent stroke studies with enrollment of nonintubated patients on low-dose selfotel revealed an increased number of deaths and other adverse events. A retrospective analysis did not confirm that Selfotel was associated with an increased mortality in TBI, but there was also no evidence that the drug was efficacious. A problem here was that a major portion of patients did not have intracranial mass lesions (contusion, subdural haematoma) on CT, questioning whether these had a treatment responsive brain injury. Both studies on tirilazad or selfotel underscore the significance of well designed and conducted phase-I and -II trials to characterize the pharmacokinetics of the agent, to confirm availability of drug in the brain, and to identify a sufficient number of patients with lesions responding to the drug. A major issue is the blood-brain barrier permeability of the agent under study. Further, the phenomenon of secondary deterioration - neurological worsening - turned out as a powerful predictor of poor outcome. The findings and conclusions of both clinical trials (tirilazad, selfotel) were utilized for a subsequent patient study on CP101-606 in consultation with the Pfizer company, the US Brain Injury Consortium, and the San Diego Clinical Trial Group. The patient population was a priori selected towards responsiveness of the brain lesions to the treatment. The major conclusions are: I Development of therapeutic regimens targeted towards the mechanisms of brain injury. II Availability of adequate preclinical data. III Directing treatment towards an appropriate patient population. IV Central gathering and interpretation of the neuroradiological findings. V Monitoring of trial center performance. VI Stratification and pre-trial prognostic analysis for identification of subgroups.

Brain Injuries↗
PubMed2003

Effects of argatroban and heparin on thrombus formation and tissue plasminogen activator-induced thrombolysis in a microvascular thrombosis model.

Effects of (2R,4R)-4-methyl-1-[N(2)-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidine-carboxylic acid monohydrate (argatroban) and unfractionated heparin (UFH) were compared with respect to thrombus formation and tissue-type plasminogen activator (t-PA)-induced thrombolysis in a microvasculature thrombosis model. The antithrombotic activities of anticoagulants were evaluated with respect to the time required for the initiation of thrombus formation (T(i)) and the time required for the thrombus to stop blood flow (T(s)). The effects of anticoagulants administered with t-PA were evaluated by percent stenosis of the vessel and percent area of the thrombus. Argatroban (1-3 mg/kg/bolus) significantly prolonged T(i) and T(s) in a dose-dependent fashion compared to control. Argatroban (3 mg/kg/bolus) significantly prolonged both the T(i) and T(s) more effectively than UFH (100 anti-XaU (a-XaU)/kg/bolus), despite equivalent prolongation of the activated partial thromboplastin time (aPTT). Higher doses of UFH (300-500 a-XaU/kg) were required to significantly prolong T(i) and T(s), but at these doses, UFH caused over-prolongation of aPTT (>180 s), which might consequently cause bleeding complications. Argatroban (0.1-0.3 mg/kg/h) significantly accelerated thrombolysis by t-PA in both a dose- and time-dependent fashion. Although argatroban (0.1-0.2 mg/kg/h) did not significantly prolong the aPTT and bleeding time (BT) as compared with control, it significantly accelerated thrombolysis by t-PA at these doses of lower bleeding risk. Argatroban (0.3 mg/kg/h) significantly enhanced thrombolysis by t-PA, while UFH (12.5 anti-XaU/kg/h) attenuated it again, despite equivalent prolongation of the aPTT and BT. We conclude that argatroban seems to be a more efficient and safer anticoagulant than UFH for the prevention of thrombus formation and acceleration of t-PA-induced thrombolysis.

Animals↗
PubMed1990

In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator.

The effects of heparin and the synthetic competitive thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfon yl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (Argatroban) on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) was studied in groups of six or seven rabbits with arterial thrombosis. The model consisted of a whole-blood clot produced in a 1-cm isolated femoral arterial segment with superimposed endothelial damage and distal high-grade stenosis. rt-PA was injected as an intravenous bolus of 0.45 mg/kg body wt at 15-minute intervals until recanalization, or up to a maximum of four boluses. In seven rabbits given an intravenous injection of 17 mg/kg aspirin, rt-PA induced transient reflow in only one animal. In seven rabbits that received intravenous heparin (200 units/kg over 60 minutes), rt-PA administration produced reflow in five animals, which was persistent in two rabbits. Combined administration of aspirin and heparin in seven rabbits was associated with similar rt-PA-induced recanalization. rt-PA administration in six rabbits given intravenous Argatroban (100 micrograms/kg/min for 60 minutes) caused recanalization in five, with persistent patency in three. In six rabbits given aspirin and Argatroban, rt-PA caused recanalization in all, with persistent patency in five animals. Reflow occurred significantly more rapidly with Argatroban (14 +/- 7 minutes) than with heparin (35 +/- 11 minutes), reflow was obtained with fewer boluses of rt-PA in combination with Argatroban (median value of one bolus) than with heparin (median value, three boluses), and reocclusion after reflow was less frequent with Argatroban (0 of 11 versus 5 of 10 rabbits). Furthermore, the degree of thrombolysis determined by pathological analysis was significantly more extensive with Argatroban than with heparin, and patency persisted during a 3-hour observation period, despite elimination of Argatroban from the circulation. Thus, Argatroban, relative to heparin, enhances and sustains thrombolysis with rt-PA. It may offer promise as an adjunctive agent for thrombolytic therapy of arterial thrombosis.

Animals↗
PubMed1999

In vitro antiplatelet profile of FR171113, a novel non-peptide thrombin receptor antagonist.

Synthetic peptides (5 to 14 amino acids), identical in sequence to the new amino-terminus of the thrombin receptor generated following cleavage by thrombin, act as thrombin receptor agonist peptides. Whilst thrombin receptor antagonist peptides are known, non-peptide thrombin receptor antagonists have yet to be described. In the present study, we compared the antiplatelet effects of 3-(4-chlorophenyl)-2-(2,4-dichlorobenzoylimino)-5-(methoxycarbonyl methylene)-1,3-thiazolidin-4-one (FR171113), a novel non-peptide thrombin receptor antagonist, with the known thrombin receptor antagonist 3-mercapto-propionyl-Phe-Cha-Cha-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-OH (C186-65), and argatroban, a specific protease inhibitor of thrombin. FR171113 and C186-65 inhibited thrombin-induced platelet aggregation (IC(50)=0.29 microM and 15 microM, respectively) and Ser-Phe-Leu-Leu-Arg-Asn-NH(2) [a synthetic thrombin receptor agonist peptide (TRAP-6)] induced platelet aggregation (0.15 microM and 20 microM, respectively) in human washed platelets. Argatroban potently inhibited thrombin-induced platelet aggregation (IC(50)=3.5 nM), but did not inhibit TRAP-6-induced aggregation even at 100 microM. In contrast, these compounds did not show inhibitory effects on ADP- and collagen-induced aggregation in human platelet-rich plasma even at 100 microM. FR171113 caused a parallel shift to the right of the concentration-response curve describing aggregation induced by TRAP-6. The Schild plot of the data had a slope of -0.840 (r=0.98) and the pA(2) was 7.29. In protease activity studies using a chromogenic substrate, argatroban inhibited thrombin protease activity in a dose-dependent manner, whereas FR171113 and C186-65 were inactive, even at 100 microM. Additionally, only argatroban displayed dose-dependent prolongation of thrombin time, activated partial thromboplastin time and prothrombin time. FR171113 and C186-65 showed no effects, even at a concentration of 100 microM. These results suggest that FR171113 has a similar mode of action to C186-65, but with more potent antiplatelet activity. In conclusion, FR171113 is suggested to be the first example of a non-peptide thrombin receptor antagonist.

Arginine↗