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Laxatives abuse has been associated with an increased risk for colon cancer. However, little is known about laxatives long-term carcinogenic potential in experimental studies. The present study was designed to investigate the effects of bisacodyl (4.3 and 43 mg/kg) and cascara (140 and 420 mg/kg) on azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors. Animals, divided in 10 groups were treated with AOM and laxatives (alone or in combination) for 13 weeks. At the end of treatment animals were killed and the colon removed and analysed for the determination of ACF and tumors. Bisacodyl (4.3 and 43 mg/kg), given alone, did not induce the development of colonic ACF and tumors. Bisacodyl (4.3 mg/kg) coupled with AOM increased the number of crypt per focus, but not the number of tumors. Bisacodyl (43 mg/kg) significantly increased the number of crypt per focus and tumors. Cascara (140 and 420 mg/kg) did not induce the development of colonic ACF and tumors and did not modify the number of AOM-induced ACF and tumors. The results of the present study indicate a possible promoting effect of bisacodyl on rat colon carcinogenesis (especially at higher doses) and absence of any promoting or initiating activity of a laxative and diarrhoeal dose of cascara.

Conventional antidepressants are associated with a range of adverse drug reactions. The herb Hypericum perforatum (St John's wort) might offer another approach to the treatment of depression. Biochemical and animal studies suggest that the phloroglucinol derivative hyperforin is the main active ingredient of St John's wort, and inhibits the synaptosomal uptake of 5-HT, noradrenaline, dopamine, glutamate and GABA. St John's wort has been shown to alleviate symptoms of mild to moderate depression, and seems to offer significant advantages over conventional antidepressants because it is associated with fewer adverse reactions. However, important herb--drug interactions have been described. In view of its efficacy and safety records, St John's wort should be considered for the first-line treatment of mild to moderate depression.

This is the consolidated report of emissions of PCDD/F from facilities in the organic chemical manufacturing chain leading to polyvinyl chloride. Data have been gathered from facilities in the US and Canada from a number of manufacturers and at various steps in the manufacturing process. Estimates of US emissions or transfers of PCDD/F were generated on an "Upper Bound" and "Most Likely" basis. The Most Likely estimate of US emissions of PCDD/F to the open environment, that is, air, water and land surface by facilities in this chain, based on evaluation of non-detects at one-half the detection limit is about 12 g I-TEQ per year. On this same basis, an estimated 19 g is disposed of in secure landfills.

Celastrus paniculatus L. (Celastraceae) (CP), Picrorhiza kurroa L. (Scrophulariaceae) (PK) and Withania somnifera L. (Solanaceae) (WS) are Indian medicinal plants having a remarkable reputation, as a factor of health care, among the indigenous medical practitioners. The plants exhibit varying degrees of therapeutic value some of which useful in the treatment of cognitive dysfunction, epilepsy, insomnia, rheumatism, gout, dyspepsia. In this work, we have investigated the free radical scavenging capacity of methanolic extracts from CP, PK, WS and the effect on DNA cleavage induced by H2O2 UV-photholysis. In addition, we investigated whether these plant extracts are capable of reducing the hydrogen peroxide-induced cytotoxicity and DNA damage in human non-immortalized fibroblasts. These extracts showed a dose-dependent free radical scavenging capacity and a protective effect on DNA cleavage; methanolic extracts from PK was more active than extracts from CP and WS. These results were confirmed by a significant protective effect on H2O2-induced cytoxicity and DNA damage in human non-immortalized fibroblasts. These antioxidant effects of active principle of CP, PK and WS may explain, at least in part, the reported anti-stress, immunomodulatory, cognition-facilitating, anti-inflammatory and antiaging effects produced by them in experimental animal and in clinical situations and may justify the further investigation of their other beneficial biological properties.

Objective: To study the effect of nimesulide on acid secretion in mouse isolated stomach., Methods: Isolated lumen-perfused mouse stomachs were monitored by pH-electrodes (1). Gastric acid secretion was stimulated with histamine or 5-methylfurmethide (5-MeF, a stable acetylcholine derivative), and the effect of nimesulide and indomethacin were studied alone and in combination with famotidine., Results: The concentration-dependent stimulation of gastric acid output by histamine (Hill equation fitting parameters: log[A]50 5.44 +/- 0.15; p, 1.01 +/- 0.11; alpha, 0.64 +/- 0.05) was inhibited by famotidine, and also by nimesulide (log r = 0.79 +/- 0.10 at 30 microM). However, nimesulide also reduced the maximum acid output. The shift produced by nimesulide and famotidine in combination indicated a greater than additive effect, suggesting that nimesulide was not acting at histamine H2-receptors (Shankley et al., 1988) (2). Indomethacin reduced acid secretion only at the highest concentration (100 microM). Furthermore, the histamine-receptor-independent stimulation of gastric acid output by 5-MeF was greatly inhibited by nimesulide, which also suggests that nimesulide was acting on the parietal cell signaling pathway at a non-histamine-receptor site., Conclusion: The relatively low risk of gastric mucosal damage with nimesulide is thought to involve its weak inhibition of gastric prostaglandin synthesis and its weak acidity, but another factor might be the ability to reduce gastric acid production. However, the effect of nimesulide on human gastric acid secretion remains to be investigated.

The aim of this study was to assess whether r-hTBP-1 (recombinant human tumor necrosis factor binding protein-1), the soluble form of tumor necrosis factor-alpha (TNF) receptor type 1 might be effective in counteracting the proliferation of ectopic endometrium using an in vivo experimental model of endometriosis. The in vivo model involved transplanting a square fragment of autologus uterine tissue onto the inner surface of the abdominal wall in rats. r-hTBP-1 was administered for 1 week at 10 mg/kg, s.c. divided into two daily injections. The gonadotropin-releasing hormone antagonist antide was used for reference and given at the dose of 2 mg/kg, s.c. every 3 days for 1 week. The animals were killed 2 and 9 days after the last treatment and the size of endometriotic implants measured. Blood samples and spleens were also taken for assessment of estradiol-17beta levels and natural killer (NK) activity in vitro against murine YAC cells, respectively. The results of this study indicate that r-hTBP-1 is effective in reducing the size of the endometriotic-like foci mainly at the later sacrifice time-point when they were significantly decreased by 64% as compared to control animals. As expected, antide induces an almost complete and statistically significant remission both at the 2-day (94%) and the 9-day (88%); sacrifice time-point. Histological examination indicates that, compared to controls, r-hTBP-1 induces a slightly increased degeneration of the stromal tissues of the implants at both examination times and, limitedly to the earlier observation time, of the mucosal epithelium. No differences in the spleen cell NK activity were observed at either sacrifice time-points in any treatment group. Estradiol-17beta concentrations are significantly decreased in the antide-treated groups only at 9 days while no statistically significant changes are found in the animals receiving r-hTBP-1. The results of this study carried out in a rat experimental model of endometriosis provide evidence of the potential effectiveness of r-hTBP-1 in this pathological condition and support the role of TNF in its development.

We have evaluated the effect of cannabinoid drugs, administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.) on upper gastrointestinal transit in control and in croton oil-treated mice. The cannabinoid agonists, WIN 55,212-2 (2-239 nmol mouse(-1)) and cannabinol (24-4027 nmol mouse(-1)), decreased while the CB(1) antagonist SR141716A (2-539 nmol mouse(-1)) increased transit in control mice. WIN 55,212-2, cannabinol and SR141716A had lower ED(50) values when administered i.c.v., than when administered i.p. The CB(2) antagonist SR144528 (52 nmol mouse(-1), i.p.) was without effect. During croton oil (0.01 ml mouse(-1), p.o.)-induced diarrhoea, the ED(50) values of i.p. -injected WIN 55,212-2 and cannabinol (but not SR141716A) were significantly decreased (compared to control mice). However, the ED(50) values of WIN 55,212-2 were similar after i.p. or i.c.v. administration. The inhibitory effects of WIN 55,212-2 and cannabinol were counteracted by SR141716A (16 nmol mouse(-1), i.p.) but not by SR144528 (52 nmol mouse(-1), i.p.) both in control and croton-oil treated mice. Ganglionic blockade with hexamethonium (69 nmol mouse(-1), i.p.) did not modify the inhibitory effect of i.p. -injected cannabinoid agonists either in control or in croton-oil treated mice. The lower ED(50) values of cannabinoid drugs after i.c.v. administration suggest a central (CB(1)) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism.

We have studied the effect of SR141716A (0.1-5 mg/kg, i.p.), a cannabinoid CB, receptor antagonist, and WIN (0.1-5 mg/kg, i.p.), a cannabinoid receptor agonist, on acute defaecation and gastrointestinal transit in mice and on intraluminal fluid accumulation in the rat small intestine. SR141716A increased while WIN 55,212-2 decreased defaecation, gastrointestinal transit and fluid accumulation. A per se non-effective dose of SR141716A (0.3 mg/kg) counteracted the inhibitory effect of WIN 55,212-2 (1 mg/kg) on gastrointestinal functions studied. The effect of SR 141716 on both intestinal fluid accumulation in rats and gastrointestinal transit in mice was inhibited by atropine (1 mg/kg, i.p.), but not by hexamethonium (1 mg/kg, s.c.), SR140333 (20 microg/kg, i.p.) or SR48968 (20 microg/kg, i.p.), antagonists of NK1 and NK2 receptors, respectively. These results suggest that intestinal fluid accumulation and motility are inhibited by endogenous cannabinoid(s) acting at the cannabinoid CB1 receptors. This effect may be mediated by mechanisms involving muscarinic cholinoceptors.

Under the auspices of its Dioxin Characterization Program, members of The Vinyl Institute (VI), have analyzed for potential polychlorinated dibenzodioxin/furan (PCDD/F) concentrations in polyvinylchloride (PVC) resins, treated wastewater effluent and ethylene dichloride (EDC) product at EDC, vinyl chloride monomer (VCM) and PVC manufacturing facilities in the U.S. and Canada. No 2,3,7,8-tetrachlorodibenzodioxin (TCDD) was detected in any sample analyzed under the program to date. Trace concentrations (low pg/g) of PCDD/F were detected in only a few samples of PVC resins and EDC product. Treated wastewater contained low ppq concentrations of PCDD/F. All concentrations are expressed as Toxic Equivalents (TEQ). Extrapolation of these data shows that the contribution of EDC/VCM/PVC manufacturing via these media constitutes substantially less than 1 percent of the estimated annual U.S. dioxin releases to the environment.

1. The effect of cannabinoid drugs has been investigated on cholinergic and non-adrenergic non-cholinergic (NANC) contractile responses to the circular smooth muscle of guinea-pig ileum elicited by electrical field stimulation (EFS). 2. The cannabinoid receptor agonist WIN 55,212-2 (1-1000 nM) and the putative endogenous ligand anandamide (0.1-100 microM) both produced a concentration-dependent inhibition of the cholinergic (9-57% and 1-51% inhibition) and NANC (9 55% and 2-57% inhibition) contractile responses. WIN 55,212-2 and anandamide did not modify the contractions produced by exogenous acetylcholine or substance P. 3. Apamin (30 nM), a blocker of Ca2+-activated K+ channels, reduced the inhibitory effect of WIN 55,212-2 on cholinergic, but not NANC, contractile response. NG-nitro-L-arginine methyl ester (100 microM), an inhibitor of nitric oxide synthase, or naloxone (1 microM), an opioid receptors antagonist, did not modify the inhibitory effect of WIN 55,212-2 on both cholinergic and NANC contractions. 4. The inhibitory effects of WIN 55,212-2 and anandamide on both cholinergic and NANC contractile response was competitively antagonized by the cannabinoid CB1 receptor antagonist SR 141716A (10-1000 nM). 5. In absence of other drugs, SR 141716A (1-1000 nM) enhanced cholinergic (1-45% increase) and NANC (2-38% increase) contractile responses elicited by electrical stimulation, but did not modify the contractions produced by acetylcholine or substance P. 6. It is concluded that activation of prejunctional cannabinoid CB1 receptors produces inhibition of cholinergic and NANC excitatory responses in the guinea-pig circular muscle. The inhibition of cholinergic (but not NANC) transmission involves activation of apamin-sensitive K+ channels. In addition, an endogenous cannabinoid ligand could inhibit cholinergic and NANC transmission in the guinea-pig ileal circular muscle.

Background: Clonidine, an alpha 2 agonist, is known to prolong the action of local anesthetics, and to provide a satisfactory analgesia; hypotension and bradycardia have been observed after its intrathecal administration. The aim of our study was to determine whether intrathecal administration of clonidine can reduce the dose of local anesthetic, and the effects of clonidine on the cardiovascular system, and on arousal level., Methods: In a prospective, randomized study we evaluated 56 patients scheduled for minor surgical procedure (spermatic vein ligature) under unilateral spinal anesthesia with hyperbaric bupivacaine 1%. One half of patients received clonidine (105 micrograms) in addition to bupivacaine. Mean arterial pressure, heart rate were recorded baseline until 1 hour after surgery. Cardiac output, stroke volume, ejection fraction, systemic vascular resistance and left cardiac work were measured, by thoracic electric bioimpedance method, baseline until 1 hour after surgery. Sensory block, motor block and sedation level were measured at the beginning of anesthesia and for 6 hours after the end of surgery., Results: In the clonidine treated group we did not observe variations of cardiovascular parameters; in the same group we did observe sensory block and motor block significantly prolonged, a higher sedation level and a significant postoperative analgesia., Conclusions: In summary, the addition of clonidine to hyperbaric bupivacaine seems to be particularly useful in unilateral spinal anesthesia, exerting minimal influence on haemodynamic parameters, and guaranting a satisfactory postoperative analgesia.

Objective: To study the antiinflammatory effect of different doses of intraarticular somatostatin in experimental arthritis in rabbits., Methods: Chronic arthritis was induced by a single injection of fibrin into the knee joint of rabbits previously sensitized to this antigen. The effects of sequential intraarticular injections of somatostatin into the rabbit knee, at doses of 500, 750, and 1,000 micrograms, were monitored by measuring knee joint circumferences and hematologic parameters. The measurements were compared with those obtained following use of triamcinolone acetonide and placebo. At the end of the experiments, the knee joints were examined histologically., Results: Somatostatin treatment induced a statistically significant and dose-related reduction of knee joint swelling. This effect was shorter than that produced by triamcinolone acetonide; however, the antiinflammatory activity elicited by successive doses of triamcinolone acetonide declined both in extent and duration, while the effects of somatostatin remained unchanged at each successive treatment. Histopathologic observations showed that both somatostatin and triamcinolone acetonide reduced the inflammatory signs in the joint structures, although triamcinolone acetonide appeared to be more effective., Conclusion: These findings suggest that somatostatin exerts an antiinflammatory effect in this model of experimental arthritis and may represent a valid and safer alternative to corticosteroids for intraarticular therapy of arthritis.

Follicle stimulating hormone (FSH) is a heterodimeric glycoprotein secreted by anterior pituitary cells. Its main actions are to lead ovarian follicles to maturation and to maintain spermatogenesis. Up to now the FSH preparations used in clinical practice (CAS 9002-68-0 and CAS 97048-13-0) have been purified from human postmenopausal urine. Only recently, a product was successfully obtained by recombinant-DNA technology, r-hFSH (Gonal-FTM). This recombinant protein is highly pure and has a very high specific activity. In view of its clinical use, this hormone has been submitted to an extensive panel of general pharmacology studies with the aim of defining its pharmacological profile and determine possible side effects not related to the main therapeutic action. Subcutaneous or intravenous doses of 5 to 500 IU/kg were assayed in several tests for their effects in vivo on various systems in different animal species. The substance under study was also tested in vitro on isolated guinea-pig ileum preparations at final concentrations of 0.05 to 2 IU/ml of bath. The results of this study showed that r-hFSH does not influence the general activity and behaviour of mice, as measured by the multidimensional Irwin's test. Similarly, the drug was not found to affect the normal body temperature in rats nor the locomotor activity in mice for as long as 7 h post-injection; in addition, it was not found to induce pharmacologically significant alterations of the cardiovascular and respiratory parameters in rats and dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Orgotein is a copper- and zinc-containing protein with superoxide-dismutase activity which can be isolated from bovine liver and erythrocytes. The effects of this drug on adjuvant -induced arthritis in rats, and particularly on the changes in erythrocytes sedimentation rates and plasma fibrinogen levels induced by this experimental infection, were studied. Orgotein was also assayed on nystatin-induced paw edema, passive cutaneous anaphylaxis and Arthus reaction, in rats. Finally, studies on platelet aggregation and the prostaglandin system were conducted. Given at doses of 2.5 and 5 mg/kg i.p. for 14 days to arthritic rats, orgotein normalized the serum changes, inhibited the foot swelling and improved the performance time on the rotating bar. The drug reduced, after a single dose, the nystatin-induced edema, whilst it showed no effects on the immunological inflammations, platelet aggregation and prostaglandin system. The probable mechanism of action is discussed.

4,5-Diphenyl-2-bis(2-hydroxyethyl)aminoxazole (ditazole) 200 mg/kg administered orally for 3 days significantly reduced the one-stage prothrombin time in rats treated concomitantly with bishydroxycoumarin (BHC) or warfarin, orally or i.p., as compared with rats given only BHC or warfarin. No significant change occurred in heparin anticoagulant activity when it was administered to rats pretreated with ditazole for 3 days. Warfarin and BHC, in vitro or in vivo, did not influence platelet aggregation or the antiaggregating activity of ditazole. The co-administration of heparin and ditazole enhanced the antiaggregating activity of the two drugs in both in vivo and in vitro tests.

The effects of acetylsalicylic acid (ASA) indometacin and ditazole on prostacyclin production from rabbit aortic rings were studied in comparison to their inhibiting activity on platelet aggregation. The result were expressed as the ratio between the drug dose inhibiting by 50% prostacycline production and the minimum oral antiaggregating dose. The following ratios were found: 2.4 for ASA, 7.3 for indometacin and 20.4 for ditazole.

The effects of the intravenous administration of hyaluronidase (HY; 2,500 IU/kg) and urokinase (UK; 20,000 and 40,000 IU/kg), alone or in combination, on the isoproterenol (ISP) induced myocardial infarction (MI) in rats, were studied. The severity of infarction was determined by measuring the levels of serum enzymes (CPK, GOT, LDH) and by evaluating the extent of the injured areas and the incidence of mortality. Plasma thromboxane B2 (TXB2) levels were also determined. All the treatments reduced the infarction area and the enzyme levels (increased by ISP) to a varying degree. However, a definite potentiating activity was obtained when HY was combined with the highest dose of UK. This combination was also capable of reducing the mortality rate. Finally, both HY and UK or the combined preparation brought the plasma TXB2 levels back to normal. These findings suggest the possibility of complementary activities of HY and UK in the treatment of experimental MI.

The intravenous LD50 of the hypothalamic tetradecapeptide somatostatin was determined in mice and rats of both sexes. It was found that somatostatin has a sex-related toxicity both in mice and rats. The interaction of low and high doses of peptide with the LD50s of two central nervous system (CNS) drugs, namely pentobarbital and strychnine, was also studied in male and female mice. Differential effects were observed as follows: a very low dose (0.1 mg/kg) of somatostatin does not affect the toxicity of these compounds, whereas the injection of 1 mg/kg of peptide increased pentobarbital toxicity and decreased the toxicity of strychnine. However, an increase in the toxicity of both substances was obtained with very high non-lethal doses of peptide (20 and 30 mg/kg, in female and male mice, respectively).

The effects of urokinase on ADP breakdown by vessel-wall, platelet aggregation and the related prostaglandin system "in vitro" were investigated. It is confirmed that urokinase does not induce platelet aggregation both in humans and rabbits "in vitro". Conversely, in high concentrations, urokinase inhibits ADP-induced platelet aggregation in human and rabbit platelet-rich plasma. No effects were observed on rabbit platelet thromboxane A2 release and on rat vascular prostacyclin production, both measured by radioimmunoassay of thromboxane B2 and 6-keto-F1 alpha prostaglandin, respectively. Moreover, the incubation of urokinase with vascular endothelium resulted in an increased disappearance rate.

To explore the therapeutic potential of the thymic hormone preparation thymostimulin (TS) in animal models of cell-mediated and humoral autoimmunity, its effects were investigated on experimental allergic encephalomyelitis in guinea pigs and on anti-erythrocytic autoantibody production in C57B1/6 mice. In both autoimmunity models, TS produced significant therapeutic effects in terms of proportion of diseased animals, disease severity and/or disease duration; however, both the TS dose and the time of treatment start relative to the disease-inducing stimulus critically influenced results. TS effects on the generation and expression of suppressive activity induced in C57B1/6 mice by a supraoptimal immunization with 10(10) SRBC were also examined. TS given after 10(10) SRBC did not influence the level of suppression, and the activity of effectors of suppression was not modified by this agent. Conversely, using a treatment protocol analogous to that effective in reducing murine autoantibody production, TS administration prior to 10(10) SRBC was associated with a significant increase in the subsequent generation of T-dependent, antigen-specific suppressive activity. These findings suggest that effects of TS on the development of suppressor cells may be involved in the activity of this agent in animal models of autoaggression.