Effect of H2-receptor antagonists, cimetidine and ranitidine on reproductive functions in male mice.

Na+,K(+)-ATPase and Ca(2+)-ATPase in testis were inhibited with an oral administration of cimetidine and ranitidine. Cimetidine at dose level of 100 and 30 mg while ranitidine at 70 and 10 mg per kg body wt inhibited the enzyme activities, 24 hr after single administration or daily administration for 15-days. Mg(2+)-ATPase activity was increased with cimetidine while ranitidine inhibited the enzyme. Michaelis-Menten kinetic characteristics revealed mixed type of inhibition for Na+,K(+)-ATPase with cimetidine, whereas it was noncompetitive for Ca(2+)-ATPase with cimetidine as well as ranitidine administration. Inhibition of Na+,K(+)-ATPase with ranitidine was also of noncompetitive type. Mg(2+)-ATPase behaved differently with administration of ranitidine at both the time points used i.e. noncompetitive type of inhibition after 24 hr and mixed type after 15-days. Histologically, signs of degeneration of testicular elements appeared after administration of cimetidine with a significant decrease in tubular diameter and germinal epithelial cell height. Ranitidine administration did not produce any change in the seminiferous tubules of testis. Scanning electron microscopy of spermatozoa from cimetidine-treated mice exhibited distinct departure from the normal morphology such as, (i) breaks at various places along distal portion of the tail, (ii) roughening, wrinkling and disorganization of plasma membrane of the head region, (iii) decapitation of the head and (iv) changes in shape of cytoplasmic droplet. Ranitidine administration showed normal morphology of the spermatozoa.     

Histamine release and SOD, allopurinol and ranitidine pretreatment in haemorrhagic shock in the rat.

Histamine release have been demonstrated in haemorrhagic shock. There are some observations that oxygen free radicals can cause histamine release. Oxygen free radicals play a role in the pathogenesis of gastric mucosal lesions. The goal of this study was to determine whether ranitidine or SOD and allopurinol pretreatment modify the histamine release during and after the haemorrhagic shock in the rat. In the anaesthetized rat 0.1 N HCl was instilled into the stomach and the rat was bled to reduce the blood pressure to 30 mmHg for 20 min. The shed blood was reinfused. Twenty min later the stomach was removed. The area of gastric mucosal lesions were measured, histological grading was made. Blood samples taken from the carotid artery were examined by radioimmunoassay (IMMUNOTECH) to determine the plasma histamine level. Plasma histamine level did not change significantly during the preparative surgery, but there was a significant increase of histamine level by the end of shock period. After the reinfusion of the blood the plasma histamine remained essentially at the same level for five min. Oxygen free radicals did not cause an important histamine release. By the end of the experiment the histamine level decreased dramatically. Ranitidine, allopurinol and SOD pretreatment provided significant protection against the gastric mucosal lesions. Allopurinol and SOD did not influence significantly the histamine level. Ranitidine caused significant histamine release immediately after the injection and every histamine value was significantly higher in this group except for the final value which was lower than the control one. The oxygen free radicals were not found as endogenous histamine releasers in this study.     

Chronotoxicity of methotrexate in mice after intraperitoneal administration

Methotrexate (MTX), an effective agent in treatment of cancer, is one of the most versatile antineoplastic agents in spite of severe toxicity problems. The purpose of this study was to determine the circadian variation of this toxicity in order to decrease the side effects. The experiments were done in mice given a single i.p. dose. The toxicity of MTX, estimated from the relative weight loss, varied according to the time of administration, with a maximum after administration at 0900 (02 HALO). The dose-effect relationship can be described by a linear function: delta P/P versus log (dose). The slope of this line varies with the time of administration. These variations are correlated with the variations in biochemical [dihydrofolate reductase (DHFR) activity] and pharmacokinetic parameters (AUC) studied in previous works.     

Chronopharmacological study of furosemide in rats

The present experiment was undertaken to determine whether or not the effects of furosemide depend upon the administration time and, if so, to study the mechanism(s) for these variations. After administration of furosemide (5 mg/kg) in Wistar rats at 10:00 or at 22:00, urine volume and urinary excretion of sodium, furosemide, and prostaglandin E2 (PGE2) were measured. Urine volume and urinary excretion of sodium and furosemide, but not PGE2, were significantly greater when furosemide was administered at 10:00 than when it was administered at 22:00. There was a good correlation between the urinary output of furosemide and the urine volume, or the urinary sodium. It is concluded that the effects of furosemide vary with the administration time and these variations depend upon the amount of furosemide secreted in urine.     

Cimetidine-resistant Zollinger-Ellison syndrome: successful management with ranitidine.

In a patient with the Zollinger-Ellison syndrome who had undergone vagotomy, pyloroplasty and, later, gastrojejunostomy, epigastric pain and stomal ulceration recurred despite the use of high doses (2700 mg/d) of cimetidine. Ranitidine, a new histamine H2-receptor antagonist, reversed all symptoms and healed the stomal ulcer without side effects, thus obviating the need for further surgery. Ranitidine may prove to be the drug of choice in the medical management of patients with the Zollinger-Ellison syndrome.     

Variations in the serum levels of thyroid hormones and TSH after intake of a dose of L-thyroxine in euthyroid subjects and in adequately-treated hypothyroid patients

The aim of the present study was to determine whether the temporary variations in blood thyroid hormone levels secondary to a therapeutic dose administration of L-thyroxine observed in adequately treated hypothyroid patients also occur in spontaneously euthyroid subjects under analogous conditions. Serum levels of T3, T4, FT3, FT4 and TSH were measured over 6 hours following a single oral administration of L-thyroxine (dosage 85 mcg/mq body surface area) in a group of 18 euthyroid volunteers and 8 hypothyroid patients adequately compensated with replacement therapy. In the euthyroid subjects there was a significant increase in T4 and a significant fall in TSH values at 60', while a significant decrease in FT3 and FT4 as compared to initial values was observed at 120'. In the treated hypothyroid patients serum T3 and T4 increased at 120', while FT4 concentrations, already significantly higher at 120', still remained higher than initial levels at 360'. The different behaviour of the hypothyroid patients, in spite of being compensated with therapeutic doses of L-thyroxine, reflects the persistence of a thyroid-metabolic condition substantially different to the physiological feature, which appears to be realized by means of a reduced iodothyronine clearance and a lower sensitivity in TSH feedback.     

Day and Night Aspirin-Induced Gastric Mucosal Damage and Protection by Ranitidine in Man

The severity of gastric mucosal injury produced by aspirin (ASA) was endoscopically assessed during morning and evening studies in 10 healthy, male volunteers. In a randomized, double-blind design, subjects received either ASA (1300 mg) alone or ASA (1300 nig) plus Ranitidine (150mg) or placebo tablets during morning and evening studies. Each subject had 3 morning and 3 evening studies. The severity of damage produced by ASA was assessed by counting the number of punctate mucosal hemorrhages observed in the gastric antrum and low-body. This study demonstrated (1) wide intersubject variability in the severity of damage produced by ASA (range of 47-1030 lesions/subject in morning studies), (2) significant protection against ASA-indueed damage by Ranitidine and (3) significantly greater damage produced by ASA in the morning compared to the evening studies. Because evening acid secretory rates are higher and because ASA-induced damage is believed to be acid-dependent, this last observation was unexpected. It suggests mucosal resistance is higher in the evening and raises the possibility that there may be circadian variation in gastric mucosal resistance.     

Day and Night Aspirin-Induced Gastric Mucosal Damage and Protection by Ranitidine in Man

The severity of gastric mucosal injury produced by aspirin (ASA) was endoscopically assessed during morning and evening studies in 10 healthy, male volunteers. In a randomized, double-blind design, subjects received either ASA (1300 mg) alone or ASA (1300 nig) plus Ranitidine (150mg) or placebo tablets during morning and evening studies. Each subject had 3 morning and 3 evening studies. The severity of damage produced by ASA was assessed by counting the number of punctate mucosal hemorrhages observed in the gastric antrum and low-body. This study demonstrated (1) wide intersubject variability in the severity of damage produced by ASA (range of 47-1030 lesions/subject in morning studies), (2) significant protection against ASA-indueed damage by Ranitidine and (3) significantly greater damage produced by ASA in the morning compared to the evening studies. Because evening acid secretory rates are higher and because ASA-induced damage is believed to be acid-dependent, this last observation was unexpected. It suggests mucosal resistance is higher in the evening and raises the possibility that there may be circadian variation in gastric mucosal resistance.     

Healing of gastric ulcers after one,two, and three months of ranitidine.

Ranitidine (150 mg twice daily) was compared with placebo in 42 patients with gastric ulcer. The study was conducted as a double-blind trial for one month, followed by an open assessment of one, two, and three months of ranitidine in the patients with persistent ulceration. Thirty-eight patients completed the double-blind trial. Repeat endoscopy confirmed complete healing in 16 of the 21 who had received ranitidine and five of the 17 who had received placebo (p less than 0.01). The remaining 17 patients with persistent ulceration participated in the open assessment. The combined cumulative healing rates of ranitidine at four, eight, and 12 weeks were 73%, 88%, and 97%. There were no adverse effects or unusual reasons for withdrawal from the study (four patients). Ranitidine appears to be a safe and highly effective treatment of gastric ulceration, with about 90% of ulcers healed after eight weeks.     

Circadian Phase-Dependent Protein and Tissular Binding of Three Local Anesthetics (Bupivacaine, Etidocaine, and Mepivacaine) in Mice: A Possible Mechanismof Their Chronotoxicokinetics?

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperito-neally at 10:00,16:00,22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.     

Circadian Phase-Dependent Protein and Tissular Binding of Three Local Anesthetics (Bupivacaine,Etidocaine, and Mepivacaine) in Mice: A Possible Mechanismof Their Chronotoxicokinetics?

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperito-neally at 10:00,16:00,22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.     

Effects of thyroxine on the synthesis of folate coenzymes in rat liver

1. The effects of thyroidectomy and of ;acute' and ;chronic' administration of thyroxine on the synthesis of folate coenzymes were studied by determining the liver contents of folate active derivatives and the enzymic activities involved in their biosynthesis. The effect of thyroxine on the same enzymes in vitro was also studied. 2. In thyroidectomized rats the liver contents of folate coenzymes did not change except for a slight decrease in the contents of 5-formyltetrahydrofolate and tetrahydrofolate compared with those in control rats. 3. In the same animals serine hydroxymethyltransferase and formyltetrahydrofolate synthetase activities decreased markedly. 4. The ;chronic' administration of thyroxine to thyroidectomized rats caused more evident variations in the liver contents of folate coenzymes and in particular a decrease in the contents of 5-formyltetrahydrofolate, tetrahydrofolate, 5(or 10)-formyl derivatives of tetrahydropteroylpolyglutamate and of 5(or 10)-formyl derivatives of pteroylpolyglutamate. 5. The enzymic activities did not show significant variations. 6. The ;acute' administration of thyroxine caused changes in the liver contents of some folate derivatives such as 10-formyldihydrofolate, 10-formylfolate, tetrahydrofolate and the 10-formyl derivative of dihydropteroylpolyglutamate. In these animals also the enzymic activities were unchanged. 7. No effect of thyroxine on enzymic activities in vitro was observed.     

Enhancement of the 5-HT neurotransmission by antidepressant treatments

The hypothesis of an etiopathogenic role of 5-HT and that of a mediation by the 5-HT system in the effect of antidepressant treatments have often been confused. Little unequivocal evidence exists for a 5-HT deficit in depression. However, several recent animal and clinical data suggest that the 5-HT system might contribute to the therapeutic effect of various antidepressant treatments. Long-term administration of tricyclic antidepressant (TCA) drugs induces a sensitization of rat forebrain neurons to iontophoretically-applied 5-HT. Repeated electroconvulsive shocks result also in an increased sensitivity of forebrain 5-HT receptors. However, chronic administration of a new antidepressant drug, zimelidine, a potent and long-lasting 5-HT uptake blocker, fails to modify 5-HT receptor sensitivity. These results suggest that enhancement of 5-HT neurotransmission obtained via either pre- or postsynaptic mechanisms might determine the antidepressant effect of these treatments. In a recent clinical study, we observed that lithium administration to TCA-resistant depressive patients induced a rapid relief of depression. It is possible that the presynaptic enhancing effect of lithium on the 5-HT system might unveil the TCA-induced sensitization of the postsynaptic 5-HT receptors. Most depressed patients exhibit marked diurnal variations of mood. Preliminary experiments in rats revealed that the responsiveness of hippocampal neurons to iontophoretically-applied 5-HT is enhanced in the evening. Similar diurnal variations of 5-HT receptor sensitivity might occur in human brain and be related to diurnal variation of mood in depression. Since normal individuals do not show these fluctuations of mood, it is proposed that the "mood regulating system" might become 5-HT dependent in depressed patients.     

Effect of ethanol and ethylene glycol on the circadian rhythm of adenylic nucleotide levels in muscles]

The 24-hour's changes in ATP content in the gastrocnemiuses of intact rast are not significant. Both the ADP and AMP content is subjected to 24-hour's variations. It reaches its maximum within the time period from 12 to 15 o'clock p.m. for ADP and at 18 o'clock p.m. for AMP. Intragastric administration of ethanol and ethylene glycol to rats in a dose of 1/3 LD50 once per 24-hour period at 9 a. m. during a 7-days-long period dramatically changes the 24-hour's rhythm of adenylic nucleotide content in the rat gastrocnemius. It has been found that ethanol increases the average 24-hour's content of ATP, but decreases that of ADP. It increases the range of their 24-hour period variations and changes the acrophase. Ethylene glycol decreases the average 24-hour content of the both ATP and ADP, but it increases that of AMP. It changes their acrophases and increases the ranges of 24-hour-period variations of ATP.     

Immuno-corticotropin interactions in a nociceptive environment in the Wistar rat

In pregnant rats, oral administration of ammonium nitrate, stress with ether and antigenic stimulation were found to induce immune variations, hormonal changes and evince the organism's capacities of detoxification. An activation of the immune system and immunosuppression have been recorded respectively during xenobiotics administration and antigenic stimulation, and during stress. Corticotrophe response occurred on the 6th day of gestation and was more pronounced from the 12th day onwards in animals receiving ammonium nitrate. At the end of the gestation period, however, the corticotrophe response became stable in treated animals. Ammonium nitrate administration seemed to drive a major toxicity effect, clearly observed through increased levels of methemoglobine and coincided with a significant decrease in the level of glutathione, confirming a mechanism of detoxification.     

枸橼酸铋雷尼替丁+克拉霉素7天根除幽门螺旋杆菌疗效观察

目的观察枸橼酸铋雷尼替丁(RBC) 克拉霉素根除幽门螺旋杆菌疗效。方法RBC 350Mg 克拉霉素500mg口服,每天2次,共7d。结果治疗后Hp的根除率为86．5％。结论RBC 克拉霉素7d根除Hp效果满意。     

Demonstration of histamine H2 receptors on human melanoma cells

Histamine induced a concentration-dependent increase in intracellular cyclic-AMP of the two human melanoma cell lines SK23 and DX3.LT5.1; maximal stimulation was obtained with 17.8 microM histamine which consistently produced greater than 50-fold increases in the cyclic AMP content of both cell lines. The dose-response curve for histamine in each culture was progressively displaced to the right with increasing concentrations of the histamine H2 receptor antagonist cimetidine. Ranitidine, another H2 receptor antagonist also prevented the histamine-induced cyclic AMP elevation, but the H1 receptor antagonists mepyramine and tripelennamine had no significant effect. These findings indicate that human melanoma cells express histamine H2 receptors, stimulation of which activates adenylate cyclase with a subsequent rise in intracellular cyclic AMP. Mast cell:melanoma interactions mediated by histamine in vivo might therefore be expected to modify some aspects of melanoma cell behaviour.     

The effect of alcohols on daily variations in aspartate amino- transferase activity in rat organs

The 7 day-long intragastric administration of ethanol and ethyleneglycol in a dose of 1/3 DL50 was studied for its effect on the circadian variations of the aspartate aminotransferase activity (AST, EC 2.6, 1.1) in the liver, brain, myocardium and kidney of male rats. The ethanol and ethylene glycol administration reduced the mean circadian enzymic activity in the above organs. Moreover, ethanol significantly reduced the amplitude of circadian variations of the AST activity in the liver, brain and kidney, while ethylene glycol--in the liver, myocardium and kidney.