Effect of cysteine ethylester hydrochloride (Cystanin) on host defense mechanisms (V): Potentiation of nitroblue tetrazolium reduction and chemiluminescence in macrophages or leukocytes of mice or rats

L-Cysteine ethylester hydrochloride (Cystanin, ethylcysteine) at doses of 3-30 mg/kg, p.o., potentiated the reduction of nitroblue tetrazolium (NBT) by mouse peritoneal macrophages ex vivo. In in vitro experiments, this drug (30 microM) augmented NBT reduction of mouse peritoneal macrophages induced by opsonized zymosan (OZ). At the same concentration, this drug accelerated the enhancement of the OZ-induced NBT reduction by the addition of concanavalin A, N-formyl-L-methionyl-L-leucyl-L-phenylalanine or phorbol myristate acetate. This enhancing effect of ethylcysteine was completely diminished by the addition of SOD, sodium azide and catalase. In ex vivo experiments, the OZ-induced chemiluminescence of rat peritoneal macrophages and white blood cells was enhanced by the administration of ethylcysteine at doses of 3-10 mg/kg (i.p.) and 3-30 mg/kg (p.o.). In addition, this drug significantly enhanced the lumisphere-induced chemiluminescence of rat peritoneal leukocytes at 30 mg/kg (i.p.), but not the OZ-induced chemiluminescence. In in vitro experiments, this drug (30 microM) did not enhance the OZ-induced chemiluminescence response of rat peritoneal macrophages. These results suggest that ethylcysteine may enhance the intracellular generation of antimicrobial oxidants in macrophages and leukocytes.     

Effect of cysteine ethylester hydrochloride (Cystanin) on host defense mechanism (IV): Potentiating effects on the function of peritoneal or spleen macrophages

L-Cysteine ethylester hydrochloride (ethylcysteine; 30 mg/kg, p.o.) increased the number of la-positive cells (antigen presenting cells) in spleen adherent cells (SAC) and that of Lyt 1.2-positive cells (helper T cells), but not that of Lyt 2.2-positive cells (suppressor T cells) of C57BL/6 mice immunized with sheep red blood cells. The production of hemolytic plaque forming cells (HPFC) in spleens of syngeneic recipient mice was enhanced by the transfer of SAC or spleen lymphocytes of the donor mice pretreated with ethylcysteine. This drug augmented phagocytosis of yeast particles by peritoneal macrophages of ICR mice at concentrations of 1-100 microM. In ex vivo experiments, this drug (30 mg/kg, p.o.) augmented the phagocytosis of yeast particles by mouse macrophages and showed a tendency to increase the macrophage number in the peritoneal cavity. Ethylcysteine (30 mg/kg, p.o.) significantly accelerated the decrease of viable E. coli number in the liver of normal mice 2 and 48 hr after challenge. Furthermore, this drug at the same dose restored the suppression of the decrease of E. coli number in the blood and liver of mice treated with cyclophosphamide (200 mg/kg, i.p.). These results suggest that ethylcysteine augments the functions of macrophages in vitro and ex vivo, and these enhancing effects may lead to the enhancement of host resistance to infections in compromised hosts.     

Stimulation of phagocytic activity of leukocytes and macrophages by traxanox sodium in mice and rats

Phagocytosis of yeast particles by mouse peritoneal macrophages or rat peritoneal polymorphonuclear leukocytes was enhanced by traxanox sodium in vitro. Traxanox sodium (30 and 100 mg/kg, p.o.) enhanced phagocytosis of yeast particles by leukocytes and macrophages in vivo or ex vivo. On the other hand, prednisolone, isoproterenol and theophylline inhibited phagocytosis by leukocytes and macrophages under the same conditions. Traxanox sodium (30 mg/kg, p.o.) prevented the suppression of phagocytosis by the above drugs. Combined with theophylline, isoproterenol synergistically inhibited phagocytosis by leukocytes in vivo. Traxanox sodium (100 mg/kg, p.o.) administered alone had no influence on carbon clearance in normal mice. However, traxanox sodium (1-30 mg/kg, p.o.) prevented the suppression of carbon clearance by the treatment with carrageenan, but not by the treatment with ethyl palmitate. These results suggest that traxanox sodium stimulates the phagocytic activity of leukocytes or macrophages and prevents the drug-induced suppression of the phagocytic activity of these cells.     

Effect of cysteine ethylester hydrochloride (Cystanin) on host defense mechanisms (II): Restorative effects on the suppression of antibody production

The production of hemolytic plaque forming cells (HPFC) in the spleen of BALB/c mice immunized with sheep red blood cells was significantly inhibited by carrageenan treatment (0.3 mg/kg, i.p.; on days -3 and -1). Cysteine ethylester hydrochloride (ethylcysteine) restored the inhibition of the HPFC production by carrageenan treatment in a dose-dependent manner (10-100 mg/kg, p.o.). Ia positive cells (antigen-presenting cells) increased in the spleen adherent cells (SAC) obtained from immunized mice, whereas they decreased in the SAC obtained from carrageenan-treated mice. An increase of Ia positive cells occurred in the SAC of carrageenan-treated mice given ethylcysteine. Ethylcysteine (10-100 mg/kg, p.o.; on days -2 and -1) prevented both the suppression of the HPFC production and the decrease of the number of thymus lymphocytes and peripheral leukocytes induced by cyclophosphamide treatment (30 mg/kg, i.p.; on days -1 and 0). Lyt 1.2 positive cells (helper T cells) decreased in the spleen T cells of cyclophosphamide-treated mice, but increased in the spleen T cells from cyclophosphamide-treated mice give ethylcysteine. On the other hand, Thy 1.2 negative cells (B cells) did not increase in the spleen cells of cyclophosphamide-treated mice with or without ethylcysteine. These results suggest that ethylcysteine restores the immune response in immunosuppressed mice through the functions of macrophages and/or helper T cells.     

Effects of bifemelane hydrochloride (MCI-2016) on experimental amnesia (passive avoidance failure) in rodents

To further predict the possible activity on memory disorders, the effect of MCI-2016 (bifemelane hydrochloride) was examined using the passive avoidance (PAR) failure technique as an experimental model of amnesia. The amnesia was produced either by post training treatments of electroconvulsive shock (ECS), scopolamine (mice) and cycloheximide or by pre-test injection of scopolamine (rats). In ECS-PAR failure model, the retention test was carried out 3 hr (3 hr experiment) or 24 hr (24 hr experiment) after ECS. MCI-2016 showed a significant improvement when administered just after ECS (3 hr experiment, 30 mg/kg, i.p.) or 0.5 hr before the retention test (24 hr experiment, 10-30 mg/kg, i.p.). Cahopantenate was only active in the 3 hr experiment (500 mg/kg, i.p.), and piracetam was rather active in the 24 hr experiment (60 mg/kg, i.p.). MCI-2016 (30 mg/kg, i.p.) prevented the scopolamine-induced PAR-failure. In this model, physostigmine (0.3 mg/kg, i.p.) exhibited a tendency to improve the failure. In another scopolamine-induced PAR failure model in mice, all of the test drugs showed a significant improvement at different dose levels. The effect of MCI-2016 (25-100 mg/kg, p.o.) was superior to those of piracetam, aniracetam and choline chloride. Higher doses of MCI-2016 were required to improve the cycloheximide-induced PAR failure. Considering the experimental conditions and results, it may be suggested that MCI-2016 ameliorates the amnesia possibly through its influence on memory consolidation and retrieval processes.     

Effects of misoprostol, (+/-)-methyl (11 alpha, 13E)-11, 16-dihydroxy-16-methyl-9-oxoprost-13-en-l-oate, on various gastric and duodenal lesions in rats

Male Sprague-Dawley rats (230-280 g), either fasted for 15-24 hr or non-fasted prior to experiments, were used. Misoprostol (3-100 micrograms/kg, p.o.) dose-dependently inhibited the development of 150 mM HCl X aspirin (100 mg/kg)-, 150 mM HCl X 60% ethanol-, and aspirin (150 mg/kg)-induced gastric lesions. Misoprostol (30, 100 micrograms/kg, p.o.), given twice daily for 4 days, significantly inhibited prednisolone (50 mg/kg given once daily for 4 days)-induced gastric lesions. Misoprostol (30 or 2 X 300 micrograms/kg, p.o.) also significantly inhibited water-immersion stress (21 degrees C, 10 hr)-induced gastric lesions or mepirizole (200 mg/kg)-induced duodenal lesions, respectively. In contrast, misoprostol (30-300 micrograms/kg, p.o.) had no effects on indomethacin (25 mg/kg)- and mepirizole (200 mg/kg)-induced gastric lesions. Misoprostol (30 micrograms/kg, p.o.) had no effect on gastric secretion in pylorus-ligated preparations (4 hr), but it (100 or 300 micrograms/kg, p.o.) significantly increased the volume and pepsin output. Gastric motility, either normal or enhanced with indomethacin (25 mg/kg), was inhibited by misoprostol (30 or 300 micrograms/kg, p.o.). Misoprostol (30 micrograms/kg, i.d.) significantly stimulated duodenal HCO3- secretion. Mechanisms by which misoprostol inhibits various gastric lesions remain unknown. However, the stimulatory activity on duodenal HCO3- secretion appears to be involved in the preventive effect of misoprostol on the development of duodenal lesions. The effects of cimetidine and 16,16-dimethyl PGE2 were also studied and compared with those of misoprostol.     

Anti-allergic effects of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046), a specific thromboxane (TX) A2 synthetase inhibitor: effect of OKY-046 on II-IV type allergic reactions

We studied the effects of OKY-046 on types II, III and IV allergic reactions, as classified by Coombs and Gell. In Type II, OKY-046 at 30-100 mg/kg intraduodenally (i.d.) and at 1-30 mg/kg intravenously (i.v.) inhibited the bronchoconstriction in a dose-dependent manner after Forssman antigen injection. Aspirin (3 mg/kg, i.v.) also suppressed it. OKY-046 (30-100 mg/kg, i.d.) suppressed the increase of TXB2 level in the plasma in a dose-dependent manner. However, there was no effect of OKY-046 and aspirin on the decrease in complement activity (CH50), platelets and leukocytes. Additionally, OKY-046 (300 mg/kg, p.o.) prolonged the survival time following Forssman antigen injection. However, the immune hemolysis reaction was not prevented by OKY-046 (10(-6)-10(-3) M). FUT-175 protected against the Forssman shock at 1 mg/kg, i.v. and the in vitro immune hemolysis reaction at 10(-5) M. In Type III, OKY-046 (300 mg/kg, p.o.) significantly suppressed the direct passive Arthus reaction and immune complex nephritis in rats. There was no effect of OKY-046 on the delayed-type hypersensitive response to picryl chloride in mice. We think that OKY-046 should be a beneficial drug for the treatment of types II and III allergic reactions.     

Enhancing activity of anthranilic acid on adjuvant arthritis in rats and antibody formation in mice

Anthranilic acid (ANA), a metabolite of tryptophan, was examined for its immunopotentiating properties. Administration of ANA (12 mg/kg/day, p.o.) significantly enhanced the development of adjuvant arthritis in rats, although not in a dose-related manner. ANA tended to enhance adjuvant disease moderately suppressed by pretreatment with cyclophosphamide (CY), an immunosuppressive agent. ANA (3-30 mg/kg/day, p.o.) also caused a dose-related enhancement in the antibody formation to sheep erythrocytes (SRBC) in mice.     

Stimulatory effect of N-[4-[2-(dimethylamino)-ethoxy] benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion

To estimate the effect of a new gastroprokinetic agent, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it significantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also significantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it enhanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10-100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also increased small intestinal transit, but domperidone and cisapride had no effect. In delayed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspepsia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.     

Administration of thyrotropin releasing hormone (TRH) to rats releases dopamine in n. accumbens but not n. caudatus.

Bilateral injection of thyrotropin releasing hormone (TRH; 10 μg) into the n. accumbens of rats produced a short-lasting increase in co-ordinated locomotor activity and behavioural changes similar to those produced by injection of dopamine at this site. These effects were potentiated and prolonged by pretreatment with tranylcypromine (5 mg/kg i.p.). Injection of haloperidol (2.5 μg bilaterally) into the n. accumbens blocked the behavioural changes produced by intra-accumbens injection of TRH (10 μg bilaterally. 30min after tranylcypromine 5 mg/kg i.p.). Destruction of the presynaptic dopamine terminals with 6-hydroxydopamine (8 μg bilaterally) abolished the effects of intra-accumbens injection of TRH (10 μg bilaterally) in either untreated or tranylcypromine pretreated rats. This inhibition was not due to non-specific damage to post-synaptic dopamine receptors since these rats showed a normal locomotor response to intra-accumbens injection of dopamine (5 μg bilaterally. 30min after tranylcypromine 5 mg/kg). These results suggest that TRH is acting by release of dopamine.Peripheral injection of TRH (20 mg/kg) produced behavioural changes similar to those observed after central administration of this drug. Although these effects were not enhanced by pretreatment with tranylcypromine (5 mg/kg. 30min before TRH), they were blocked by peripheral injection of haloperidol (1 mg/kg). Injection of thyroid stimulating hormone (TSH: 20 mg/kg i.p.) produced no behavioural changes suggesting that peripherally injected TRH is not acting by release of TSH.Injection of TRH (20 mg/kg i.p.) to unilateral nigro-striatal lesioned rats failed to induce circling. Furthermore pretreatment with TRH (2 mg/kg i.p.) did not enhance the turning produced by methamphetamine (0.5 mg/kg) 3 hr later in tranylcypromine-treated animals.This evidence suggests that in contrast to its effects in the n. accumbens TRH is unable to release dopamine in the n. caudatus.     

General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 2nd communication: effect on the peripheral nervous system and peripheral organs

The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the peripheral nervous system and peripheral organs were studied in various laboratory animals in comparison with those of disopyramide and mexiletine, and the following results were obtained. 1. Large doses (50 or 100 mg/kg p.o.) of SUN 1165 as well as mexiletine had little effects on the pilocarpine-induced hypersalivation and the pupil size in mice. At higher concentration (10(-5) g/ml), SUN 1165 had no effects on the various spasmogen acetylcholine (ACh)-, histamine- or BaCl2-induced contractions in the isolated guinea pig ileum, tracheal smooth muscle and urinary bladder. Disopyramide caused mydriasis, inhibited the pilocarpine-induced hypersalivation at antiarrhythmic doses (10-30 mg/kg p.o.), and suppressed ACh-induced contractions in the various organs. 2. SUN 1165, like disopyramide and mexiletine, decreased the contractile amplitude and diastolic tone of the isolated rabbit ileum. SUN 1165 as well as disopyramide had no effect on the intestinal propulsion even at a large dose (100 mg/kg p.o.). Mexiletine inhibited it at antiarrhythmic doses (10-30 mg/kg p.o.). SUN 1165 only at a large dose (100 mg/kg i.d. or p.o.) inhibited volume of pepsin output in the gastric juice in pylorus-ligated rats and caused a damage to the gastric mucosa. 3. SUN 1165, like disopyramide and mexiletine, slightly potentiated the norepinephrine-induced contraction of the rat vas deferens in vitro. Moreover, SUN 1165 as well as disopyramide and mexiletine slightly potentiated the serotonin-induced contraction of the rat isolated fundus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-rheumatic action of cysteine ethylester hydrochloride

Ethylcysteine showed a prophylactic effect on collagen-induced arthritis in rats at 100 mg/kg, p.o., and the effect continued even after stopping the administration. However, it was not dose-dependent. D-penicillamine showed no effect under the same condition. Ethylcysteine tended to inhibit collagen-induced arthritis when it was administered therapeutically at 300 mg/kg, p.o. Moreover, it had little effect on the acute inflammatory and type I allergy models such as carrageenin induced edema, 48 hr homologous PCA, and 6 hr and 24 hr Evans blue-carrageenin pleurisy in rats. In the in vitro assay, ethylcysteine had the following effects: inactivation of the rheumatoid factor, the acceleration of the denaturation of human gamma-globulin and the inhibition of bone alkaline phosphatase. The effect were as potent as those of D-penicillamine. As to the results, the mode of action of ethylcysteine is the same as that of D-penicillamine in terms of the biochemical properties. However, ethylcysteine showed an inhibitory effect on collagen-induced arthritis which was not demonstrated with D-penicillamine, so this drug may have a clinically anti-rheumatic action.     

The curative effects of cysteamine,cysteine, and dithiocarb in experimental paracetamol poisoning

In a curative test (i.p. injection 1 hr after administration of paracetamol) cysteamine (100 mg/kg), cysteine (200 mg/kg), and dithiocarb (100 mg/kg) reduced the death rate from paracetamol poisoning (1.5g/kg p.o.) in male mice from 67 to 10, 15 or 10%, respectively. A reduction of mortality rate to 30 or 35% was induced by glutathione (100 mg/kg) and thiazolidine carboxylic acid (50 mg per kg), respectively, whereas penicillamine, thioctic acid, silymarin, and dimercaprol were ineffective. When given 2 or 4 hrs after paracetamol, cysteine, unlike cysteamine, had a curative effect on paracetamol toxicity.Hepatotoxic activity of paracetamol (0.5 g/kg p.o.) was evident by high increases in the levels of serum enzymes (GOT, GPT, GLDH, SDH). Paracetamol-induced enzyme elevations were prevented completely by treatment with cysteamine (50 mg/kg) or cysteine (100 mg/kg) and partially by treatment with dithiocarb (100 mg/kg) 1 hr after paracetamol. LD₅₀ values (i.p. injection) were 450 mg per kg for cysteamine, 660 mg/kg for cysteine, and 1800 mg/kg for dithiocarb. With regard to the therapeutic index cysteamine, cysteine, and dithiocarb can be recommended as antidotes for paracetamol poisoning.A nearly total depletion of hepatic glutathione occurred after paracetamol (0.5 g/kg p.o.). Administration of cysteine (100 mg/kg), one hr after paracetamol, induced a complete repletion of liver glutathione whereas cysteamine (100 or 200 mg/kg) and dithiocarb (100 mg/kg) induced a partial repletion. Glutathione repletion probably accounts for the antidote efficiency of cysteine, cysteamine, and dithiocarb. Its mechanism, however, remains obscure.     

The anti-pyretic mechanism of alminoprofen]

The anti-pyretic activity of alminoprofen (AP), a non-steroidal anti-inflammatory agent, and its mode of action were investigated in conscious febrile rabbits. A fever was evoked by i.v. injection of lipopolysaccharide (LPS), intracisternal (i.c.) injection of leukocytic pyrogen (LP) or i.c. injection of arachidonic acid (AA). The amount of PGE2 or AP in the cerebrospinal fluid (CSF) after i.v. LPS was estimated using an RIA or HPLC method. AP (3-30 mg/kg, p.o.) dose-dependently inhibited the LPS (0.5 micrograms/kg, i.v.)-induced fever; AP, ibuprofen, indomethacin and pranoprofen had ED50 values of 9.64, 26.45, 4.41 and 11.91 mg/kg, p.o., respectively. PGE2 in the CSF was markedly increased during the elevation of body temperature after i.v. LPS (0.5 microgram/kg). AP (30 mg/kg, p.o.) markedly inhibited the increase in PGE2 that was observed in the CSF during fever developed in response to i.v. LPS (0.5 micrograms/kg). The AP concentration in the CSF 2 hr after AP (30 mg/kg, p.o.) was 2.86 x 10(-6) (1.15-4.57 x 10(-6) M, a concentration too low to inhibit PG synthesis. A dose-dependent fever was observed after i.c. LP (1-8 unit) or AA (10-100 micrograms). AP (30 mg/kg, p.o.) shifted the dose-response curves for the i.c. LP-induced fever to the right, but did not have any effect on the i.c. AA-induced fever. These results suggest that AP has a relatively potent anti-pyretic activity, and its mechanism of action involves competition with LP at a site in the CNS, but does not involve an inhibition of cyclooxygenase at a central site, which has been considered as an anti-pyretic mechanism of nonsteroidal anti-inflammatory drugs.     

Neurochemical investigation on the effects of a new diphenylpiperazine calcium antagonist, KB-2796, on the central dopaminergic system of rats.

The effects of KB-2796, a new diphenylpiperazine calcium antagonist, on the striatal dopaminergic system of rats were investigated in comparison with various calcium antagonists and the dopamine antagonist chlorpromazine. The inhibiting effect of KB-2796 on [3H]spiperone binding to striatal membranes in vitro was weaker than those of chlorpromazine and the other diphenylpiperazine analogues, flunarizine and cinnarizine, and more potent than those of verapamil and nicardipine. Diltiazem and nifedipine were inactive. KB-2796 (30, 100 mg/kg, p.o.) had no effect on Kd and Bmax values of in vitro [3H]spiperone specific binding to striatal membranes obtained from the rat at 36 hr and 7 days after repeated administration for 18 days, whereas flunarizine (30 mg/kg, p.o.) and chlorpromazine (3 mg/kg, p.o.) increased Bmax values by 47% and 31%, respectively, at 36 hr, but not at 7 days after the final administration. At 1 hr after the single administration, KB-2796 (30, 100 mg/kg, p.o.) had no effect on the content of dopamine and its metabolites in the striatum, whereas flunarizine (30 mg/kg, p.o.) and chlorpromazine (3 mg/kg, p.o.) increased the level of homovanillic acid. These results indicate that flunarizine may affect dopaminergic neurotransmission by partially blocking dopamine D2 receptors, while KB-2796 has negligible in vivo effect on the dopaminergic system.     

Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat

The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.     

Acute and subacute (30-day) toxicological investigations of 4-(p-chlorophenylthio) butanol (W-2719) in mice, rats and dogs

The acute and subacute toxicity of 4-(p-chlorophenylthio) butanol (W-2719), on anti-allergy agent, was investigated in mice, rats and dogs. Acute LD50 values in the mouse (1145.0 mg/kg p.o.) and rat (greater than 1400.0 mg/kg p.o.) and maximum tolerated dose in the dog (420.0 mg/kg p.o.) were very high, indicative of a high degree of safety following a single oral dose. The subacute toxicity studies were conducted by repeated daily oral administration of the compound for 30 days. In the rat, W-2719 did not produce any significant toxicity up to a dose level of 100.0 mg/kg/day, when administered as a drug-diet admixture. A higher dose, i.e., 200.0 mg/kg/day, produced marked reductions in body weight gain, food consumption, RBC and WBC (females especially), and other hematological parameters. In the purebred beagle dog, W-2719 did not produce any significant toxicity up to a dose level of 100.0 mg/kg/day, the highest dose level tested in this species.     

Cytoprotective activity of tiquizium bromide (HSR-902) and its mechanism

The effects of HSR-902, an antimuscarinic agent, on acute gastric mucosal lesions induced by various necrotizing agents, gastric mucus secretion and gastric HCO3- secretion in rats were compared with those of pirenzepine.2HCl (pirenzepine), an antiulcer agent. 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently prevented the gastric mucosal lesions induced by ethanol-HCl (60% ethanol in 150 mM HCl), aspirin-HCl (150 mg/kg of aspirin in 150 mM HCl), 0.6 N HCl and 0.2 N NaOH; and the cytoprotective effects of HSR-902 were almost equal or somewhat more potent than those of pirenzepine. 2) HSR-902 (30 mg/kg, p.o.), like pirenzepine, increased the alcian blue binding to gastric mucosa and both hexosamine and N-acetylneuramic acid in gastric juice and reversed the decrease of alcian blue binding to gastric mucosa in water-immersion stress. 3) HSR-902 (30 mg/kg, p.o.), unlike pirenzepine and atropine sulfate, increased the gastric HCO3- secretion in the pylorus-ligated preparations. 4) The cytoprotective effect of HSR-902 (30 mg/kg, p.o.), when examined using gastric mucosal lesion induced by aspirin-HCl, was not abolished by the pretreatment with indomethacin (10 mg/kg, s.c.) or N-ethylmaleimide (10 mg/kg, s.c.). 5) HSR-902 (30 mg/kg, p.o.) did not influence the gastric mucosal potential difference. These results suggest that HSR-902 is a promising drug for the treatment of gastritis and peptic ulcers.     

Pharmacological evidence for a role of lipoxygenase products in platelet-activating factor (PAF)-induced hyperalgesia

Platelet-activating factor (PAF), a potent inflammatory mediator, decreases the nociceptive threshold in the rat hindpaw. Pain sensitivity, measured by the applied pressure necessary to induce vocalization, was increased maximally at 3 and 4 hr after injection of synthetic PAF. The hyperalgesic response to PAF was specifically inhibited by agents that interfere with the lipoxygenase pathway of arachidonic acid metabolism and was not affected by cyclooxygenase inhibitors. BW-755C (3-30 mg/kg, p.o.) and L-615,919 (0.01-0.3 mg/kg, p.o.) significantly reduced PAF-induced hyperalgesia, whereas indomethacin had no effect. The finding that L-615,919, a specific 5-lipoxygenase inhibitor, was a potent inhibitor of this model of hyperalgesia leads to speculation that leukotrienes are important mediators of inflammatory pain.     

Effects of methyl o-(4-hydroxy-3-methoxycinnamoyl) reserpate (CD-3400) on erection and ejaculation in dogs

Effects of methyl o-(4-hydroxy-3-methoxycinnamoyl)reserpate (CD-3400), a new antihypertensive agent belonging to the class of rauwolfia alkaloids, on erection and ejaculation in dogs were investigated and compared with such effects of reserpine and rescinnamine in dogs. A single dose of CD-3400 (0.125 mg/kg) administered orally to normal dogs produced no effects on erection and ejaculation, although the same dose of reserpine and rescinnamine resulted in a marked suppression of only ejaculation at 24 and 48 hr after administration. CD-3400 (0.5 mg/kg) administered orally, as well as reserpine (0.125 mg/kg) and rescinnamine (0.125 mg/kg) suppressed ejaculation at 24 hr after administration; however, the suppressive effect of CD-3400 on ejaculation was weaker and shorter than that of reserpine or rescinnamine and recovered 96 hr after administration. The order of the suppressive effect of the agents was as follows: reserpine greater than rescinnamine greater than CD-3400. Repeated administration of reserpine (0.01 mg/kg/day p.o.) for 20 days, produced a marked suppressive effect on ejaculation, whereas the effect of CD-3400 (0.06 mg/kg/day p.o.) was also weaker than that of reserpine. 24 hr after oral administration in a single dose of CD-3400 (0.5 mg/kg), reserpine (0.125 mg/kg) or rescinnamine (0.125 mg/kg), the ratios of dopamine (DA) to serotonin (5-HT) in the anterior hypothalamus and hippocampus were decreased significantly as compared with the control. These results indicate that CD-3400 results in a weaker suppressive effect on ejaculation as compared to reserpine and rescinnamine, and CD-3400-induced suppression may be due to a decrease in the ratio of DA to 5-HT in the anterior hypothalamus and hippocampus.