Domain-specific cognitive effects of tramiprosate in patients with mild to moderate Alzheimer's disease: ADAS-cog subscale results from the Alphase Study.

OBJECTIVES: Tramiprosate (homotaurine, ALZHEMEDTM) was recently investigated for its efficacy, safety and disease-modification effects in a Phase III clinical study in mild to moderate Alzheimer's disease (AD) patients (the Alphase study). The primary cognitive endpoint measure of that study was the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). To characterize potential cognitive benefits of tramiprosate, the present study describes exploratory analyses performed on scores obtained from the specific ADAS-cog subscales in order to determine whether specific domains of cognition may be differentially affected by tramiprosate, which would not have been evident from the measure's total score. DESIGN: Multi-center, double-blind, randomized, placebo-controlled study. SETTING: 67 investigative sites in the United States and Canada. PARTICIPANTS: A total of 1,052 patients were randomized. INTERVENTIONS: Patients were randomized to receive twice a day Placebo (n=353), tramiprosate 100 mg (n=352) and tramiprosate 150 mg (n=347). MEASUREMENTS: ADAS-cog assessments were conducted every three months over the 78-week study period. Exploratory analyses were performed by comparing ADAS-cog subscale scores between Placebo and each active treatment arm at each visit. RESULTS: The findings of this analysis revealed statistically significant differences or statistical trends in favour of tramiprosate on six ADAS-cog subscales, namely Following Commands, Language Comprehension, Ideational Praxis, Object Naming, Remembering Test Instructions, and Spoken Language Ability. Differences in favor of Placebo were only observed on the Constructional Praxis subscale. CONCLUSION: This exploratory analysis suggests that tramiprosate may have some benefit on memory, language and praxis skills in mild to moderate AD individuals. Future clinical studies of tramiprosate should include specialized neuropsychological tests to validate its effects within these cognitive domains.

Effect of tramiprosate in patients with mild-to-moderate Alzheimer's disease: exploratory analyses of the MRI sub-group of the Alphase study.

OBJECTIVES: The efficacy, safety and disease-modification of tramiprosate (homotaurine)were investigated in a recently completed large-scale Phase III clinical study in patients with mild to moderate Alzheimer's disease (AD), the Alphase study. Disease-modification was assessed using longitudinal volumetric MRI (vMRI) measurements of the hippocampus in a subgroup of patients. The present study describes the vMRI, cognitive and clinical results obtained in this subgroup. DESIGN: Multi-center, double-blind, randomized, placebo-controlled study in a subset of the 1052 patients of the Alphase study. SETTING: 51 vMRI investigative sites in the United States and Canada. PARTICIPANTS: A total of 508 patients underwent vMRI scanning. Of these, 312 provided scan pairs for assessing hippocampus volume changes and were included in the analyses. INTERVENTIONS: Patients were randomized to receive Placebo BID (n = 109), tramiprosate 100 mg BID (n = 103), or tramiprosate 150 mg BID (n = 100) for 78 weeks. MEASUREMENTS: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum-of-boxes CDR-SB assessments were conducted at Baseline and at Weeks 13, 26, 39, 52, 65 and 78. Exploratory analyses were performed using similar First and Final mixed-effects repeated-measures models that were used for the analysis of the entire patient dataset. RESULTS: Psychometric score results showed numerical trends in favour of tramiprosate that did not reach statistical significance. While there were no statistically significant group differences in hippocampus volume using the First modeling approach, a significant dose-response reduction in hippocampus volume change was found in the Final models. Moreover, there was a marginally significant overall treatment main effect and a significant slope difference in favour of tramiprosate according to the Final model analysis of the ADAS-cog scores. ADAS-cog scores analyzed according to this model also revealed differences in favor of the tramiprosate 150 mg group at weeks 26 and 52, with marginally significant differences at Weeks 13 and 39. Slope analyses of ADAS-cog score changes showed significant differences in favor of the 150 mg BID group, and when both active groups were combined, in comparison to the placebo group. No between-group differences with respect to changes to each visit in the CDR-SB were observed with either modeling approach. Although there was a similar dose-response relationship observed in the hippocampus volume and ADAS-cog Final model analyses, the overall changes in psychometric scores and hippocampus volume were not significantly correlated. CONCLUSION: Exploratory analysis of the vMRI subgroup suggests that tramiprosate slows hippocampal atrophy, and reveals some evidence of a beneficial effect on cognition. The clinical validity of the vMRI biomarker is discussed.

A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease.

BACKGROUND: As a potential disease-modifying treatment for Alzheimer disease (AD), 3-amino-1-propanesulfonic acid (3APS) is a compound that binds to amyloid beta (Abeta), a toxic protein known to aggregate, leading to amyloid plaque deposition in the brain. METHODS: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic effect of 3APS in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or 3APS 50, 100, or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered an open-label phase in which they received 3APS 150 mg BID for 17 months. Assessments included plasma and CSF 3APS concentrations, CSF levels of Abeta (Abeta(40) and Abeta(42)), and total tau, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical (Clinical Dementia Rating scale-Sum of Boxes) measures. RESULTS: 3APS had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild to moderate in severity. Seven 3APS-treated subjects discontinued because of side effects (all causalities) over the course of the study, and there were no 3APS-related serious adverse events. 3APS crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. There were no psychometric score differences between groups over the 3-month double-blind period. CONCLUSION: Long-term administration of 3-amino-1-propanesulfonic acid is safe, tolerated and reduces CSF Abeta(42) levels in patients with mild-to-moderate Alzheimer disease.

Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy.

Amyloid deposits characteristic of cerebral amyloid angiopathy lead to vessel rupture and intracerebral hemorrhage. Proteoglycans associate with the amyloid fibril deposits and are thought to play a role in the polymerization of amyloid proteins and the propagation of the deposition process. A series of low molecular weight anionic compounds was developed to mimic the glycosaminoglycan moieties of these proteoglycans. These compounds were tested in different in vitro systems to determine their anti-Abeta amyloid activity. Specific compounds were identified as being anti-fibrillogenic and protective against Abeta-induced cvtotoxicity. Such compounds also did not show intrinsic cellular toxicity could cross the blood-brain barrier (BBB) in vivo, and showed a good safety profile following chronic' exposure. Molecules showing an anti-amyloid profile combined with the ability to cross the BBB represent promising therapeutics for CAA.

Pharmacodynamics and pharmacokinetics of clentiazem and diltiazem in closed-chest anesthetized dogs.

In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 micrograms/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (-17% for clentiazem vs. -12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33 +/- 16 l vs. 15 +/- 9 l for diltiazem), while the half-life of elimination (t1/2 beta) was similar (55 +/- 21 minutes vs. 59 +/- 23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0-15 minutes), this ratio was similar (26 +/- 2 for clentiazem vs. 18 +/- 5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.

[Diabetic nephropathy]. / La néphropathie diabétique.

Diabetic nephropathy morbidity and mortality rates are high for both Type I and Type II diabetes. The various stages of diabetic nephropathy have been well documented for Type I diabetes, but not for Type II. We examine the natural history of this problem and recommended treatments, with emphasis on the characteristics of each type.

Clentiazem, diltiazem, and cold cardioplegia in isolated ischemic rabbit hearts: relation between additive cardioprotection, physicochemical properties, and preservation of myocardial lipid components.

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunosuppressive properties of the benzothiazepine calcium antagonists diltiazem and clentiazem, with and without cyclosporine, in heterotopic rat heart transplantation.

In vitro studies have shown that calcium channel blockers (CCB) exert inhibitory effects on immunocompetent cells but conflicting results have been reported as to the translation of these effects into significant in vivo immunosuppression. In this study we evaluated the effects of the benzothiazepine-like calcium blockers diltiazem and clentiazem, given alone or associated with cyclosporine on survival improvement of heterotopic rat heart transplants. Inbred male rats of the Lewis strain were used as recipients and Wistar-Furth as donors. Following abdominal implantation of the graft, recipients were randomly divided into 9 groups (n = 5). Group 1 were control isografts (Lew-Lew); group 2 were control allografts (WFu-Lew), and group 3 were allografts treated with low-dose oral cyclosporine 2 mg/kg/day. Groups 4 and 5 were allografts treated with oral diltiazem 0.25 and 2.50 mg/kg/day. Groups 6 and 7 were treated with oral clentiazem, 0.25 and 2.50 mg/kg/day. Groups 8 and 9 consisted of allografts receiving low-dose cyclosporine with either diltiazem or clentiazem 2.50 mg/kg/day, all drugs were administered daily by gavage. Graft function was monitored by transabdominal palpation, and rejection was considered to be complete when no contraction of the graft could be detected. Mean survival time of untreated allografts was 6.4 +/- 0.5 days. Cyclosporine alone increased the mean survival time to 10.6 +/- 2.7 days (P < 0.05 vs. group 2). At all doses studied, diltiazem and clentiazem significantly increased mean survival time of allografts, clentiazem being slightly more potent than diltiazem. In addition, the observed beneficial effects of the benzothiazepine-like calcium channel blockers were dose-dependent. When combined with cyclosporine, diltiazem and clentiazem interacted synergistically (mean survival time increased to 16.8 +/- 3.4 days for diltiazem and 15.8 +/- 1.4 days for clentiazem). These results demonstrate that the benzothiazepine-like calcium channel blockers, as opposed to phenylalkylamines or dihydropyridines, afford significant immunosuppression when used alone. These observations, and the fact that they beneficially interact with cyclosporine, suggest that the benzothiazepine-like calcium antagonists should be considered the drugs of choice when CCBs are to be selected in transplanted patients.

A dose-response study of clentiazem, a chloro-derivative of diltiazem, in patients with stable angina. CAMCAT Study Group.

OBJECTIVES: The efficacy and safety of clentiazem were assessed in 199 patients with stable angina in a dose-ranging, placebo-controlled, double-blind, parallel design study. BACKGROUND: To date, this is the first large efficacy and safety study of clentiazem in patients with stable angina. METHODS: After washout and a 1-week placebo run-in period, patients received 20, 40, 80 or 120 mg/day of clentiazem tablets or placebo as a twice-daily dosage for 1 week of treatment after 1 week of dose titration. A symptom-limited exercise tolerance test was performed 4 and 12 h after dosing at the end of treatment and results were compared with baseline measurements. RESULTS: At 4 h after dosing, improvement of exercise duration from baseline value was significantly greater with clentiazem at doses of 40 mg/day (63 +/- 11 s), 80 mg/day (99 +/- 10 s) and 120 mg/day (70 +/- 11 s) than with placebo (34 +/- 10 s). Moreover, clentiazem (80 and 120 mg/day) increased the time to onset of angina and to > or = 1 mm of ST segment depression significantly more than did placebo. At submaximal exercise, clentiazem (40, 80 and 120 mg/day) decreased rate-pressure product, mainly as a result of a decrease in heart rate. At 12 h after dosing, improvement of exercise duration from baseline was significantly greater with clentiazem in doses of 80 mg/day (77 +/- 9 s) and 120 mg/day (70 +/- 10 s) than with placebo (42 +/- 9 s). The incidence of treatment-related adverse events with placebo (27%) and clentiazem (29%) was similar. The most frequently reported treatment-related adverse events with clentiazem were asthenia, headache (both 7.9%), first-degree atrioventricular block and dizziness (both 4.4%). CONCLUSIONS: The results of this short-term study suggest that clentiazem given twice daily in doses of 80 or 120 mg/day is safe and effective monotherapy in the treatment of stable angina.

Effects of clentiazem (TA-3090) and nifedipine on basal circulating catecholamine levels and on stimulation-evoked adrenal catecholamine secretion in anesthetized dogs.

The effects of TA-3090 (clentiazem) and nifedipine on basal sympathoadrenal activity and on the adrenal medullary response during splanchnic nerve stimulation were studied in dogs anesthetized with sodium pentobarbital. Plasma concentrations of epinephrine and norepinephrine were measured in aortic and adrenal venous blood before and after acute administration of the drugs, as well as during left splanchnic nerve stimulation before and after administration of drugs. Following intravenous injections, TA-3090 (30, 100, and 300 micrograms/kg) did not affect basal circulating catecholamine levels, whereas nifedipine (10, 30, and 100 micrograms/kg) markedly increased aortic epinephrine and norepinephrine concentrations in a dose-dependent manner in correlation with progressive decreases in mean arterial pressure. The changes in aortic epinephrine and norepinephrine concentrations were inversely related to those in mean arterial pressure (r = 0.603, p < 0.01; r = 0.536, p < 0.01; respectively). In response to direct splanchnic nerve stimulation (2 Hz, 2 ms, 1 min, 12 V), adrenal venous epinephrine and norepinephrine concentrations significantly increased, with a high degree of reproducibility. The catecholamine responses to splanchnic nerve stimulation were not affected by either TA-3090 or nifedipine at any dose tested. The present results suggest that the increases in circulating catecholamine levels following nifedipine administration are due to baroreflex activation secondary to the drug-induced hypotension. The study indicates that both TA-3090 and nifedipine did not significantly affect L-type Ca2+ channels related to catecholamine release in the adrenal medulla under the present experimental conditions.

The effect of a new calcium channel blocker (TA-3090) on lipoprotein profile and intestinal lipid handling in rodents.

Recent interest has focused on findings that drugs used to lower blood pressure may adversely modify plasma lipids and lipoprotein metabolism. This observation may explain why pharmacologic control of hypertension has failed to reduce the incidence of morbidity and mortality from coronary artery disease. The present study aims to evaluate the effect of TA-3090, a new calcium channel blocker, on fasting plasma lipids and lipoproteins, as well as on processes of intestinal fat absorption. Rats were treated by gavage with TA-3090 (10 mg/kg twice daily) for 4 days and compared with controls (n = 6 per group). Plasma cholesterol was increased in the treated group to (mean +/- SE) 74 +/- 2 vs 60 +/- 4 mg/dl (P less than 0.01), due mainly to an increased high density lipoprotein-cholesterol level (50 +/- 2 vs 37 +/- 3 mg/dl, P less than 0.005). Notably plasma triglycerides (TG) and low density lipoprotein-cholesterol were not significantly affected. Another group of TA-3090-treated animals was given an intraduodenal fat meal, and the rise in plasma TG and chylomicrons followed over 4 hr. Postprandial hypertriglyceridemia and chylomicronemia were significantly lower at 2 hr (P less than 0.05) and 3 hr (P less than 0.01) compared with controls. In a separate group of animals, the addition of TA-3090 to a 2% intralipid infusion intraduodenally was associated with significantly reduced TG and chylomicron-TG transport into lymph (P less than 0.05). Furthermore, experiments in rats pretreated with TA-3090 intraperitoneally and then given 2% intralipid intraduodenally were shown to have a significant decrease in mean flow rate (27%), TG transport (31%) and chylomicron-TG output (37%), when compared with controls. In vitro studies using jejunal organ culture to examine the effect of TA-3090 on intracellular lipid synthesis and secretion revealed that the addition of the drug to the medium resulted in significantly decreased TG synthesis and secretion. These data suggest that TA-3090 could be effective in increasing HDL-cholesterol and reducing postprandial chylomicronemia. Our findings support a role for TA-3090 directly on enterocyte absorption and/or intracellular lipid transport, and thus indicate the importance of intracellular calcium on these processes.

Effect of clentiazem on lipid profile, lipoprotein composition and aortic fatty streaks in cholesterol-fed rabbits.

Numerous experimental studies have reported that common antihypertensive drugs such as diuretics, beta-blockers, and methyldopa have adverse effects on plasma lipids and lipoproteins. The present study was designed to define the effect of clentiazem (10 mg/kg/day) an antihypertensive drug, on hyperlipidemia in rabbits on a cholesterol-rich diet (1%) for 12 weeks. Compared with controls, clentiazem treated rabbits had lower plasma concentrations of triglycerides (55%), total cholesterol (24%), free cholesterol (27%), esterified cholesterol (23%) and phospholipids (24%). The decrease in cholesterol was accounted for by a reduction of VLDL-cholesterol (13%), IDL-cholesterol (24%) and primarily LDL-cholesterol (45%). Neither HDL-cholesterol nor chemical composition of VLDL, IDL, LDL and HDL was altered. When the aortic atherosclerotic involvement was evaluated by computerized planimetry, a 24% reduction of lesions was noted in clentiazem treated animals (P less than 0.05). Similarly, cholesterol content extracted from aortic wall was decreased. Our data therefore demonstrated that clentiazem is a potential antiatherosclerotic agent capable of decreasing plasma lipids and atherogenic lipoproteins as well as aortic fatty streaks.

Peripheral vasodilator and cardiac properties of the 1,5-benzothiazepine calcium antagonist analog, TA-3090, in dogs.

Diltiazem, a 1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous cardiovascular diseases. TA-3090, a newly synthetized 1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of TA-3090 (n = 16) or diltiazem (n = 15) (15, 50, 200, and 400 micrograms/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both TA-3090 and diltiazem elicit slight peripheral and coronary vasodilator properties at low doses (15 and 50 micrograms/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between TA-3090 and diltiazem indicates that both drugs elicit coronary vasodilator selectivity and TA-3090 has a prolonged duration of action compared with that of diltiazem. A straightforward relationship is demonstrated between vasodilator properties and plasma levels of either TA-3090 or diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with TA-3090. Changes of heart rate were not correlated with plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Lipoxygenase inhibitors and allergic conjunctivitis reactions in the guinea-pig.

The role of leukotrienes as mediators of microvascular permeability changes (assessed through the accumulation of [99mTc]albumin) associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva was investigated by means of two novel, structurally dissimilar 5-lipoxygenase inhibitors, L-651,392 and L-651,896. Both compounds, when applied topically in vivo to the eyes of sensitized guinea-pigs as a 0.1% suspension significantly inhibited 5-lipoxygenase in the conjunctiva as assessed by ex vivo challenge with either antigen or ionophore A23187 and measurement of the release of leukotriene B4-immunoreactive material. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs produced changes in conjunctival permeability which were blocked in part by either mepyramine (H1-receptor antagonist) or the 5-lipoxygenase inhibitors. Combinations of mepyramine and L-651,896 resulted in near complete suppression of the permeability response, suggesting that the reaction is mediated only by histamine and leukotrienes.

The role of leukotriene D4 as a mediator of allergic conjunctivitis in the guinea-pig.

The role of leukotriene D4 (LTD4) as a mediator of conjunctival microvascular permeability changes associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva has been investigated using two novel, selective LTD4 receptor antagonists, L-648,051 and L-649,923. Changes in microvascular permeability were measured through the accumulation of [99mTc]albumin. LTD4 administered intravenously produced dose-related increases in conjunctival microvascular permeability through a mechanism which does not involve the generation of prostaglandins as indicated by the failure of indomethacin to attenuate the response. The response to LTD4 was significantly blocked by the receptor antagonists, L-648,051 and L-649,923. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs caused significant increases in conjunctival microvascular permeability. Following a single challenge, the antigen response was largely blocked by mepyramine (H1 receptor antagonist), but was unaffected by L-648,051 and L-649,923. Following a second challenge (24 h later) a substantial portion of the response was inhibited by L-648,051 and L-649,923. Indomethacin failed to inhibit either challenge. These results suggest that LTD4 may have a role in chronic allergic conjunctivitis.

Hepatic adrenoceptors involved in the glycogenolytic response to exogenous (-)-norepinephrine in the dog liver in vivo.

Effects of various sympathomimetic amines on the hepatic glucose mobilization were studied in anesthetized dogs. Phenylephrine (30, 100, 300 micrograms), isoproterenol (0.1, 1, 10 micrograms) and (-)-norepinephrine (0.5, 5, 50 micrograms) were injected into the common hepatic artery in three separate groups of dogs. Dose-dependent increases in hepatic venous glucose concentration were observed following the injections of these drugs. Aortic glucose concentration also increased significantly, but to a lesser extent as compared with that in hepatic venous blood. Peak responses were obtained 3 to 5 min after the drug administrations. The increases in hepatic venous glucose concentration induced by the injections of (-)-norepinephrine were significantly diminished to a similar extent in dogs treated with either phentolamine (2 mg/kg, i.v.) or (-)-propranolol (0.2 mg/kg, i.v.). The results indicate that in the dog liver in vivo, both hepatic alpha- and beta-adrenoceptors can be involved in the hepatic glycogenolysis. The glycogenolytic response to exogenously administered (-)-norepinephrine is mediated via alpha- as well as beta-adrenoceptors in the liver of anesthetized dogs.

Correlation between endogenous noradrenaline and glucose released from the liver upon hepatic sympathetic nerve stimulation in anesthetized dogs.

The metabolic role of neurally released noradrenaline (NA) was studied in the liver of anesthetized dogs. Sustained stimulation with various frequencies was directly applied on the anterior plexus of hepatic nerves. Stimulation-induced changes in plasma concentrations of endogenous catecholamines in hepatic venous blood were determined in correlation with concomitant changes in those of glucose (GL). Mean basal values for hepatic venous NA, adrenaline, dopamine, and GL were 0.062, 0.022, 0.032 ng/mL, and 97.9 mg%, respectively. Among these catecholamines, NA was the only one being released significantly during stimulation. While hepatic venous NA increased rapidly during stimulation, being maximum within 3 min, hepatic venous GL increased gradually, reaching a maximum value 5 min after the onset of stimulation. A highly significant correlation (r = 0.90, P less than 0.001) was found between changes in hepatic venous NA and GL concentrations observed during stimulation at various frequencies (2-16 Hz). However, hepatic vasoconstricting responses to stimulation were not correlated with increased hepatic venous GL. An alpha-blockade with phentolamine (2 mg/kg, iv) resulted in diminished release of GL by approximately 50% (P less than 0.05) and reduced hepatic arterial vasoconstriction by approximately 47% (P less than 0.01) upon stimulation (8 Hz, 5 min), even though NA release was markedly enhanced. We conclude that in the dog, NA is the sole catecholamine released within the liver in response to direct hepatic nerve stimulation, and NA thus released mediates the hepatic glycogenolysis via alpha-adrenoceptors.