Alpha-tocopherol (vitamin E) and beta-carotene supplementation does not affect the risk for large abdominal aortic aneurysm in a controlled trial.

Antioxidants may retard atherogenesis and limit inflammatory processes involved in aneurysm formation. We evaluated effects of alpha-tocopherol and beta-carotene supplementation on incidence of large abdominal aortic aneurysm (AAA) in a randomised, double-blind, placebo-controlled trial. Subjects (n=29133) were 50-69-years-old male smokers, participants in the Finnish alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) Study. They were randomised to receive either 50 mg/day of alpha-tocopherol, or 20 mg/day of beta-carotene, or both, or placebo in a 2x2 design. Incidence of AAA was evaluated from mortality and hospital registers. During 5.8 years of follow-up, 181 men were diagnosed with either ruptured AAA (n=77) or nonruptured large AAA treated with aneurysmectomy (n=104). Relative risk (RR) for AAA was 0.83 (95% confidence interval [CI] 0.62-1.11) among men receiving alpha-tocopherol compared with those who did not, and 0.93 (95% CI 0.69-1.24) among men receiving beta-carotene compared with those who did not. A modest though nonsignificant decrease in risk for nonruptured AAA was observed among alpha-tocopherol supplemented men (RR 0.71, 95% CI 0.48-1.04) compared with men not receiving alpha-tocopherol. For beta-carotene, RR for nonruptured AAA was 0.86 (95% CI 0.59-1.27) compared with men not receiving beta-carotene. Neither antioxidant affected risk for ruptured AAA. In conclusion, long-term supplementation with alpha-tocopherol or beta-carotene had no preventive effect on large AAA among male smokers.

Life-style factors and risk for abdominal aortic aneurysm in a cohort of Finnish male smokers.

Prospective studies evaluating risk factors for abdominal aortic aneurysm are few. We studied the association of life-style factors with risk for abdominal aortic aneurysm among 29,133 male smokers 50-69 years of age, participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. During a mean follow-up of 5.8 years, 181 were diagnosed with ruptured abdominal aortic aneurysm or nonruptured abdominal aortic aneurysm plus aneurysmectomy. Risk for abdominal aortic aneurysm was positively associated with age [relative risk (RR) = 4.56, 95% confidence interval (CI) = 2.42-8.61 for > 65 vs < or = 55 years], smoking years (RR = 2.25, 95% CI = 1.33-3.81 for > 40 vs < or = 32 years), systolic blood pressure (RR = 1.92, 95% CI = 1.13-3.25 for > 160 vs < or = 130 mmHg), diastolic blood pressure (RR = 1.80, 95% CI = 1.05-3.08 for > 100 vs < or = 85 mmHg), and serum total cholesterol (RR = 1.85, 95% CI = 1.09-3.12 for > 6.5 vs < or = 5.0 mmol/liter). High-density lipoprotein cholesterol showed a strong inverse association with risk for aortic aneurysm (RR = 0.16, 95% CI = 0.08-0.32 for > 1.5 vs < or = 0.9 mmol/liter). High energy intake was associated with lower risk for aortic aneurysm (RR = 0.59, 95% CI = 0.38-0.94 for the highest quartile vs the lowest), whereas no associations with nutrients were evident. We conclude that classical risk factors for atherosclerotic diseases seem to be important in pathogenesis of large abdominal aortic aneurysms.

Prospective study of diet, lifestyle, and intermittent claudication in male smokers.

The association between dietary and lifestyle factors and intermittent claudication was investigated in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The cohort comprised 26,872 male smokers aged 50-69 years who were free of claudication at study entry. At baseline (1985-1988), subjects completed a diet history questionnaire. During a median follow-up period of 4 years (ending in spring 1993), 2,578 men reported symptoms of claudication on the Rose questionnaire, which was administered annually. Smoking status was assessed every 4 months. Smoking, systolic blood pressure, serum total cholesterol, and diabetes mellitus were positively associated with risk for claudication, whereas serum high density lipoprotein cholesterol, education, and leisure time exercise were inversely associated with risk. Dietary carbohydrates, fiber, and n-6 polyunsaturated fatty acids were inversely associated with risk for claudication, as were some dietary and serum antioxidants: dietary vitamin C (highest quartile vs. lowest: relative risk (RR) = 0.86; 95% confidence interval (CI): 0.77, 0.97), dietary gamma-tocopherol (RR = 0.89; 95% CI: 0.79, 1.00), dietary carotenoids (RR = 0.82; 95% CI: 0.73, 0.92), serum alpha-tocopherol (RR = 0.88; 95% CI: 0.77, 1.00), and serum beta-carotene (RR = 0.77; 95% CI: 0.68, 0.86). Smoking cessation reduced subsequent risk for claudication (RR = 0.86; 95% CI: 0.75, 0.99). The authors conclude that classical risk factors for atherosclerosis are associated with claudication. High intakes of antioxidant vitamins may be protective. Further research is needed before antioxidants can be recommended for the prevention of intermittent claudication.

The effect of alpha-tocopherol and beta-carotene supplementation on symptoms and progression of intermittent claudication in a controlled trial.

We evaluated the effect of long-term supplementation with vitamin E (alpha-tocopherol) and beta-carotene on occurrence of claudication symptoms and risk for peripheral vascular surgery among men with intermittent claudication. Subjects, 50-69-year old male smokers, were participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who reported intermittent claudication through a structured questionnaire (Rose) at study entry (n=1484). They were randomly assigned to receive either 50 mg/day of alpha-tocopherol, or 20 mg/day of beta-carotene, or both, or placebo, in a 2 x 2 design. During follow-up, claudication was evaluated by repeating use of the questionnaire once a year. Information on peripheral vascular surgery came from the National Hospital Discharge Register. We observed no effect of alpha-tocopherol and beta-carotene supplementation on claudication during a mean follow-up of 3.7 years. A slightly increased risk (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.05-2.44) for vascular surgery was observed among beta-carotene supplemented men compared to those who did not receive beta-carotene. Alpha-tocopherol supplementation had no effect. In conclusion, long-term supplementation with alpha-tocopherol and beta-carotene showed no beneficial effect on symptoms and progression of intermittent claudication.

Effect of alpha-tocopherol (vitamin E) and beta-carotene supplementation on the incidence of intermittent claudication in male smokers.

We examined the primary preventive effect of vitamin E (alpha-tocopherol) and beta-carotene supplementation on intermittent claudication. The subjects--participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study--were male smokers aged 50 to 69 years who were randomly assigned to receive 50 mg of alpha-tocopherol daily, 20 mg of beta-carotene daily, both, or placebo. At baseline, there were 26 289 men with no history or symptoms of intermittent claudication. The Rose questionnaire on intermittent claudication was administered annually to discover incident cases. We observed 2704 cases of first occurrence of typical intermittent claudication during a median follow-up time of 4.0 years. Compared with placebo, the adjusted relative risk for typical intermittent claudication among those who received alpha-tocopherol only was 1.11 (95% confidence interval, 1.00-1.24); among those who received alpha-tocopherol and beta-carotene, 1.02 (0.91-1.13); and among those who received beta-carotene only, 1.02 (0.92-1.14). When we compared the alpha-tocopherol-supplemented subjects with those who received no alpha-tocopherol, the adjusted relative risk for typical intermittent claudication was 1.05 (0.98-1.14), and for beta-carotene-supplemented subjects compared with those who did not receive beta-carotene, the relative risk was 0.96 (0.89-1.04). In conclusion, no primary preventive effect on intermittent claudication was observed among middle-aged male smokers who were supplemented with alpha-tocopherol, beta-carotene, or both.

Minor effect of tolcapone, a catechol-O-methyltransferase inhibitor, on extracellular dopamine levels modified by amphetamine or pargyline: a microdialysis study in anaesthetized rats.

In vivo microdialysis was used to examine the effects of tolcapone (30 mg/kg) on dopamine metabolism in amphetamine (5 mg/kg) and pargyline (75 mg/kg) treated rats. Amphetamine- or pargyline-induced decreases in the extracellular dihydroxyphenyl acetic acid (DOPAC) levels were counteracted by additional tolcapone. Tolcapone also decreased homovanillic acid effluxes below those caused by amphetamine or pargyline. However, dopamine effluxes were not further enhanced by additional tolcapone. These results show that central metabolism of dopamine can be modulated by catechol-O-methyltransferase (COMT) inhibition also without exogenous L-DOPA. However, extracellular dopamine levels are not easily increased.

Gastric injury and protection against alcohol and acid: influence of perturbations in glutathione metabolism.

This study assessed the role that inhibition of glutathione (GSH) synthesis and decreased GSH peroxidase (GPX) activity in the rat played in modulating gastric injury induced by ethanol and acid and its prevention by 16,16-dimethyl PGE2 (dmPGE2) and the mild irritant, 25% ethanol. Although numerous studies have proposed that GSH may be important in maintaining gastric mucosal defense, the exact role of this antioxidant in protecting the stomach from injury remains undefined. The present study addressed this consideration by blocking the synthesis of GSH and altering the major pathway by which it exhibits its antioxidant activity and determining the effect of these perturbations on gastric injury and protection. Four to six rats were used for each experimental group. GSH synthesis was blocked by the potent and specific inhibitor L-buthionine sulfoximine (BSO), 2 or 6 mmole/kg intraperitoneally. The activity of the major form of GPX, which is selenium dependent and utilizes GSH as a substrate to detoxify hydrogen peroxide and other hydroperoxides, was inhibited by placing animals on a selenium-deficient diet for 6 weeks. Gastric damage was induced by 100% ethanol, 50% ethanol in 150 mM HCl, and 0.75 M HCl. Prevention of such injury was accomplished with oral pretreatment using 25% ethanol or dmPGE2 (5 microgram/kg). The damaging effects of 100% ethanol, 50% ethanol/150 mM HCl, or 0.75% M HCl were not adversely affected by BSO pretreatment even though GSH synthesis was inhibited by as much as 80%. Similarly, inhibition of GPX activity by 58% in adult rats and 98% in weanling rats failed to potentiate the damaging effect of 100% ethanol. Furthermore, with both perturbations in GSH metabolism, the protective action of dmPGE2 and 25% ethanol was maintained. Our results indicate that profound alterations in gastric GSH metabolism by themselves do not aggrevate the injurious effects of ethanol or acid, nor do they prevent the protective action of a prostaglandin or mild irritant.

150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects.

Fluconazole, an azole antifungal agent, moderately inhibits the CYP3A-mediated metabolism of midazolam in vitro. We therefore studied whether such an interaction takes place in vivo following oral administration of these drugs, given as relevant double blinded doses in capsule form. In study I parallel groups of healthy subjects received oral midazolam 10 mg (MID 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier. Objective and subjective performance tests were made before, and 30 and 90 min after the intake of midazolam. MID 10 and MID 15 moderately impaired performance on digit symbol substitution, letter cancellation and flicker fusion tests, and visual analogue scales revealed mild sedation. FLU + MID 10 had similar or slightly stronger effects than MID 10; it differed from MID 10 in that it lowered the flicker fusion threshold and produced subjective slowness and overall impairment. In study II 5 subjects received MID 10 after placebo, after FLU, and after 750 mg erythromycin (ERY) at 1-week intervals, following a crossover and double-blinded study design. Blood was sampled before MID intake and 30, 60 and 90 min after it, and performance was measured. FLU and ERY increased the effect of MID on flicker fusion and letter cancellation performances, and increased the HPLC-assayed plasma midazolam (ERY + 100%, FLU + 50%) in comparison to that measured after MID ingested alone. When the concentrations of midazolam together with its active metabolite alpha-OH-midazolam were assayed by radioreceptor technique the increases caused by ERY and FLU were less and compatible with the pharmacodynamic data.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two new inhibitors of catechol O-methylation on striatal dopamine metabolism: a microdialysis study in rats.

1. Effects of two new inhibitors of catechol O-methylation (CGP 28014 and entacapone; 30 mg kg-1, i.p.) were compared by means of brain microdialysis in rats treated with L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa (50/50 mg kg-1, i.p., respectively) or saline. 2. In saline-treated rats, CGP 28014 maximally (max) increased striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) effluxes by 41% and 49%, respectively, whereas homovanillic acid (HVA) levels were decreased by 71%. 3. In the presence of L-dopa/carbidopa, a peripherally active inhibitor of catechol O-methyltransferase (COMT) entacapone had a short-lasting increasing effect on L-dopa efflux. Compared to the effects of L-dopa/carbidopa alone 3-O-methyldopa (3-OMD) levels were effectively reduced (max 79%) by entacapone, but not by CGP 28014. 4. Entacapone, in contrast to CGP 28014, increased striatal dopamine efflux (max 492% of that after L-dopa/carbidopa alone). Also DOPAC levels were increased by entacapone (255% at 180 min), but not significantly by CGP 28014 (159% at 180 min). 5. Both compounds initially decreased HVA efflux. The effect of CGP 18014 was longer-lasting. By the end of the measurement, entacapone even increased HVA levels (max 259%). 6. Our results demonstrate that entacapone is a peripheral COMT inhibitor and support the view that CGP 18014 is mainly a centrally acting inhibitor of O-methylation.

Adverse effects of vagotomy on ethanol-induced gastric injury in the rat. Absence of a role for glutathione redox cycle.

Truncal vagotomy is known to aggravate the damaging effects of alcohol-induced gastric injury and prevent the occurrence of adaptive cytoprotection against such injury by a mild irritant. This study was undertaken to determine whether aberrations in glutathione (GSH) metabolism were responsible for these vagotomy-induced effects. Fasted rats (6-8/group) were subjected to truncal vagotomy and pyloroplasty or sham vagotomy and pyloroplasty. One week later they were given 2 ml of oral saline or the mild irritant, 25% ethanol (EtOH). Thirty minutes following such treatment, animals were either sacrificed or orally received 2 ml of 100% EtOH and then were sacrificed 5 min later. At sacrifice, in each experimental group, stomachs were removed and either evaluated macroscopically for the degree of injury involving the glandular gastric epithelium or samples of the mucosa were prepared for measurement of total GSH levels or GSH peroxidase (GPX) and GSH reductase (GRT) activity. In nonvagotomized animals, saline treatment prior to 100% EtOH exposure resulted in injury to the glandular epithelium involving approximately 18%. Treatment with 25% EtOH prior to 100% EtOH exposure virtually abolished this injury. In vagotomized animals, 100% EtOH elicited almost three times the amount of injury observed in the nonvagotomized state and the protective effect of 25% EtOH pretreatment was prevented. Effects of the various treatment modalities on GPX and GRT activity were not significantly different from control values. When mucosal GSH results were plotted against the presence or absence of gastric injury among the various groups studied, no significant correlation was apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of three types of catechol O-methylation inhibitors on L-3,4-dihydroxyphenylalanine-induced circling behaviour in rats.

The effects of three new, selective inhibitors of catechol O-methylation were compared regarding their potentiation of L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa-induced contralateral circling behaviour in male rats. Some studies were also done with amphetamine, which causes ipsilateral turning. A peripherally acting compound, entacapone, a peripherally and centrally acting compound, tolcapone, and an atypical compound, CGP 28014 (3, 10 or 30 mg/kg) increased the effect of L-dopa/carbidopa (2/30 or 5/30 mg/kg) on contralateral circling by 2.0-6.1-fold. Addition of clorgyline (3 mg/kg) did not increase, but rather decreased, the entacapone (3 mg/kg) and L-dopa/carbidopa (2/30 or 5/30 mg/kg)-induced peak circling. Amphetamine (2.5 mg/kg)-induced ipsilateral circling behaviour was not affected by tolcapone (30 mg/kg). We conclude that L-dopa-induced circling behaviour is enhanced and prolonged by all types of catechol O-methyltransferase inhibitors regardless of their brain penetration. The results suggest that catechol O-methylation inhibitors may be beneficial as L-dopa adjuncts in the treatment of patients with Parkinson's disease.

Oral single doses of erythromycin and roxithromycin may increase the effects of midazolam on human performance.

Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule from were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam+erythromycin impaired digit symbol substitution and letter cancellation, and triazolam+roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg+erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg+erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg+roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of rat brain endogenous dopamine metabolism by new inhibitors of catechol O-methyltransferase.

The extraneuronal and intraneuronal metabolism of rat brain endogenous dopamine was stimulated by amphetamine (5 mg/kg) and pimozide (2 mg/kg), respectively. Additional metabolic effects of two inhibitors of catechol O-methyltransferase (entacapone and tolcapone (both 30 mg/kg)) and a putative central uptake2 inhibitor (CGP 28014 (30 mg/kg)) were assessed. Amphetamine increased striatal dopamine and 3-methoxytyramine and decreased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The latter two effects were reversed by tolcapone and CGP 28014, but not by entacapone. Tolcapone, CGP 28014 and even entacapone decreased striatal homovanillic acid (HVA) levels. Pimozide-induced striatal DOPAC levels were further increased by tolcapone and CGP 28014. Both substances also decreased striatal HVA levels. Striatal 3-methoxytyramine levels were significantly lowered only by tolcapone. Our results show that enhanced central dopamine metabolism is modified by the inhibition of catechol O-methyltransferase even in the absence of L-3,4-dihydroxyphenylalanine (L-DOPA). The results also suggest that the mechanism of action of CGP 28014 may be other than true inhibition of catechol O-methyltransferase.

Protective action of oral N-acetylcysteine against gastric injury: role of hypertonic sodium.

N-acetylcysteine (NAC), when administered orally as a 20% solution, is a potent protective agent against gastric injury in the rat stomach induced by absolute ethanol. The present study was undertaken to define the means by which this protection is mediated. The notion that NAC acts as a glutathione precursor was excluded when N-acetylserine (NAS) was noted to be equally protective against alcohol injury. The NAS molecule contains a hydroxyl moiety at the site where NAC contains a sulfhydryl. To orally administer 20% NAC at a neutral pH, NaOH is added to the free acid form to keep NAC in solution. We determined by titration that a sodium concentration of 1.2 M results. Thus it became apparent that the protective effect of NAC might be mediated through the sodium employed to titrate NAC. Accordingly, we examined various sodium salts and assessed their relative protective effects against alcohol injury. Both sodium acetate and sodium chloride in 1 M solutions were found to be equally effective in preventing alcohol injury with the same efficiency as 1 M sodium solutions of NAC and NAS, excluding the acetate portion of NAC and NAS as being of primary importance for protection to occur. Further study, using different concentrations of sodium chloride (i.e., 150-1,000 mM) revealed that the 1 M solution was most optimal in preventing alcohol injury. One molar sodium by itself and when administered as part of the NAC solution also prevented gastric injury by concentrated acid and base.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical and psychomotor interactions of new selective COMT inhibitors with clorgyline and nomifensine in levodopa-treated rats and mice.

The effects of three new catechol O-methyltransferase (COMT) inhibitors (nitecapone, entacapone and Ro 41-0960) were assessed on brain neurochemistry and psychomotor tests in levodopa/carbidopa-treated rats and mice. In neurochemical studies in rats, neither nitecapone (3 mg/kg) nor Ro 41-0960 (3 mg/kg) enhanced the levodopa/carbidopa (15/30 mg/kg)-induced dopamine levels in the hypothalamus and striatum, whereas 3-O-methyldopa (3-OMD) levels were suppressed. Adding clorgyline (8 mg/kg) elevated dopamine in the hypothalamus and striatum. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were suppressed in the striatum and, to a lesser extent, also in the hypothalamus. Adding nomifensine (10 mg/kg) reversed the action of Ro 41-0960 on the 3-OMD levels and raised the homovanillic acid levels in the striatum. All COMT inhibitors (30 mg/kg) slightly enhanced levodopa/carbidopa (15/30 mg/kg)-induced hypoactivity in rats. Ro 41-0960 also augmented the effects of clorgyline and nomifensine on the locomotor activity. Levodopa/carbidopa (10/10, 25/25, 50/50, 100/100 mg/kg) dose-dependently decreased rectal temperature, rotarod time and spontaneous motility in mice. Additional COMT inhibition (30 mg/kg) had only minor effects on behavior. Ro 41-0960 (30 mg/kg) potentiated several behavioral effects of clorgyline (4 mg/kg) in the levodopa/carbidopa (10/10 mg/kg)-treated mice.

Gender differences in ethanol oxidation and injury in the rat stomach.

A significant fraction of orally consumed ethanol is metabolized by the alcohol dehydrogenase (ADH) enzyme present in the gastric mucosa. Human studies have shown that this "first pass metabolism" of ethanol correlates quite closely with gastric ADH activity which has been demonstrated to be greater in men than women. The present study was undertaken to determine if gender influences the magnitude of ethanol-induced injury in rat gastric mucosa and whether any differences can be linked to altered levels of ADH activity. Since prostaglandins (PGs) have been shown to markedly attenuate the severity of gastric injury induced by ethanol in the rat stomach, a further goal of this study was to determine whether the efficiency of PG's protective action was in any way influenced by gender. Accordingly, both male and female rats were pretreated subcutaneously with 16,16-dimethyl PGE2 (10 micrograms/kg) or saline 30 minutes prior to administering an oral dose of 50% ethanol in saline or saline alone. They were then sacrificed 5 minutes later. In a portion of animals (n = 6 per group), samples of mucosa from the glandular stomach were obtained and kinetic activity of ADH determined. In another portion of animals (n = 6 per group), gastric tissue samples from the glandular mucosa were examined by light microscopy and the magnitude of mucosal injury quantified. Alcohol-treated females showed significantly (p less than 0.05) less superficial and more deep mucosal injury than male counterparts. Further, ADH kinetic activity in female rats was significantly less than that observed in male counterparts of similar weight (83% of males; p less than 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of dimethylthiourea against mucosal injury in rat stomach. Implications for hydroxyl radical mechanism.

The present study was undertaken to determine whether dimethylthiourea (DMTU), a hydroxyl radical scavenger, could prevent gastric injury in the rat stomach induced by various noxious agents. Fasted rats (N = 6-8/group) were given a 1-ml oral bolus of saline or DMTU over the dose range 10-500 mg/kg. After 30 min, animals received 1 ml of 100% ethanol orally and were sacrificed 5 min later. At sacrifice, stomachs were harvested and the degree of macroscopic damage was assessed by planimetry. In selected animals, specimens of gastric mucosa were also processed for histology. Saline pretreatment prior to ethanol exposure resulted in 22.5% injury to the glandular epithelium when assessed macroscopically. DMTU pretreatment prevented such injury in a dose-related fashion with only 2% of the mucosa showing injury with a 500 mg/kg dose (P less than 0.01 vs control). Although the superficial injury involving surface mucous cells induced by ethanol was not altered by DMTU, the deep damage to gastric glands was almost completely prevented. Other experiments in which DMTU was given intraperitoneally demonstrated similar protective effects against ethanol injury. Additional studies showed that indomethacin did not prevent the protective effects of oral or intraperitoneal DMTU, excluding a role for endogenous prostaglandins, and that DMTU was equally protective when administered within minutes or as long as 2 hr prior to ethanol exposure. Furthermore, DMTU was also shown to be protective against gastric injury induced by concentrated acid or base. In in vitro studies in which hydroxyl radicals were actually generated, DMTU was noted to scavenge the hydroxyl radical in a dose-related fashion. The ability of DMTU to prevent gastric injury by three different damaging agents suggests that the hydroxyl radical may play a major role in the pathogenesis of such injury and that DMTU mediated its protective action by scavenging this radical species.

Effect of nitecapone and clorgyline, given intracerebro-ventricularly on L-dopa metabolism in the rat brain.

A new COMT inhibitor, nitecapone (OR-462) or clorgyline, a MAO-A inhibitor, was infused into the 3rd brain ventricle (i.c.v.) of conscious male rats. None of the enzyme inhibitors given alone alter hypothalamic or striatal levels of L-dopa, dopamine or their metabolites. Most of the rats were pretreated with levodopa/carbidopa (LD/CD, 15/30 mg kg-1 intraperitoneally). Now, the action of nitecapone is localized in the hypothalamus since homovanillic acid (HVA) is decreased there, not in the striatum. The levels of 3-O-methyldopa (3-OMD) are not changed in either brain region, suggesting a lack of the peripheral leakage of nitecapone. Clorgyline (3 and 10 micrograms rat-1) elevates hypothalamic and dopamine levels. Nitecapone and clorgyline decrease prolactin (PRL) levels below those reduced by LD/CD treatment.

N-acetyl-cysteine: protective agent or promoter of gastric damage?

N-acetyl-cysteine (NAC), when given orally, has been shown to prevent gastric damage induced by ethanol, but when administered intraperitoneally, it appears to potentiate such damage. In an effort to resolve these seemingly discordant findings, fasted rats (six per group) received 1 ml of saline or 20% NAC orally or intraperitoneally (ip). Two hours or 15 min later, they received 1 ml of 100% ethanol orally. At sacrifice 5 min later, rats receiving oral pretreatment with 20% NAC at both 15 and 120 min prior to ethanol exposure demonstrated a significant reduction in the magnitude of gastric injury when compared with saline controls. In contrast, actual promotion of ethanol damage was noted when NAC was given intraperitoneally, but was more pronounced when NAC was administered 15 min prior to exposing the mucosa to 100% ethanol. In all animals receiving intraperitoneal NAC, large amounts of peritoneal fluid (4-6 ml/rat) were recovered at the time of sacrifice, most of which occurred within 15 min of NAC administration; these more pronounced peritoneal effects at 15 min after NAC correlated with the more severe injury from ethanol at this time period compared to 120 min after intraperitoneal NAC. Saline controls had no peritoneal fluid. Mucosal glutathione (GSH) levels generally paralleled these results in that a significant decrease in tissue GSH occurred at 15 min following intraperitoneal NAC when compared with controls; at 120 min after intraperitoneal NAC, GSH levels were similar to control values. Additional experiments demonstrated that within 15 min following NAC administration, systemic blood pressure dropped by approximately 20% and basically remained unchanged over the next 2 hr; intraperitoneal saline had no sustained adverse effects on blood pressure. It was concluded that the inability of NAC to prevent ethanol injury when given intraperitoneally in contrast to orally is related to the drop in blood pressure secondary to NAC's peritoneal irritant effects, which presumably altered gastric mucosal blood flow, thus obivating its ability to prevent ethanol damage under these conditions. Furthermore, the decreased levels in mucosal GSH following the hypotension induced by intraperitoneal NAC suggest that perturbations in GSH metabolism may also have contributed to the decreased resistance to ethanol injury.