Treatment of duodenal ulcer with the histamine H2-receptor antagonist, ranitidine, was assessed in a double-blind, randomized, multicenter trial in which patients were treated for two consecutive 4-week periods with ranitidine 150 mg b.i.d. or a placebo. All patients were allowed to take antacids as necessary for symptoms. Three hundred eighty-two patients were entered and 355 completed the first 4-week trial period. Ranitidine significantly improved healing at 2 weeks (37 versus 19%, p < 0.01) and at 4 weeks (73 versus 45%, p < 0.01), with better relief of pain and lower use of antacids. In the second 4-week trial period, 124 unhealed patients from the first 4 weeks were re-randomized. Ranitidine treatment resulted in a greater healing rate regardless of previous treatment (p < 0.05). In this trial, side effects were uncommon and not different between placebo and the tested drug. One case of hepatitis in the ranitidine treated group was presumed on the evidence to be non-A non-B. Ranitidine is effective and appears to be safe in the treatment of duodenal ulcer and its symptoms.

<p>The G protein-coupled receptors (GPCRs) are important targets in drug discovery. In several cases, the endogenous ligands that activate the GPCRs of pharmaceutical interest are peptides. Unfortunately, peptides are in general not suitable as drugs, since the peptide structure is associated with several disadvantages, such as low oral bioavailability, rapid degradation and low receptor subtype selectivity. Thus, there is a strong need for drug-like nonpeptide ligands to peptide-activated GPCRs. However, to discover nonpeptide ligands that mimic the effect of the endogenous peptide, i.e. peptidomimetics, is a tremendous challenge. In fact, morphine and the related opioids were the only known examples of peptidomimetics before 1995 and these ligands were known long before the native endogenous peptide ligands were discovered. </p><p>The main objective of the work described in this thesis was to design, synthesize and biologically evaluate selective nonpeptide agonists to the peptide-activated GPCR AT₂. The AT₂ receptor belongs to the renin–angiotensin system, where the octapeptide angiotensin II (Ang II) is the major effector peptide. Ang II mediates its effects through the two GPCRs AT₁ and AT₂. The AT₁ receptor is already an established target in the treatment of hypertension. The physiological role of the AT₂ receptor, which is up-regulated in certain pathological conditions, is not fully understood but it seems to include positive effects such as vasodilatation, tissue repair, tissue regeneration and neuronal differentiation. </p><p>In the current investigation we started from the nonpeptide and nonselective (AT₁/ AT₂) compound L-162,313. This ligand is a known AT₁ receptor agonist but its effect on the AT₂ receptor was unknown at the start of this project. We were able to show that it acts as an agonist also at the AT₂ receptor. Furthermore, stepwise synthetic modifications of L-162,313 led to the identification of the first selective nonpeptide AT₂ receptor agonist. Following the discovery of this compound several selective nonpeptide AT₂ receptor agonists were identified. It was also revealed that a minor structural alteration of one of these compounds interconverted the functional activity from agonism to antagonism. The structural requirement for agonism vs antagonism was therefore studied. The functionality switch was suggested, at least partly, to be due to the spatial relationship between the methyleneimidazole group and the isobutyl side chain of the compounds. To further investigate the bioactive conformation(s) of this series of compounds enantiomerically pure analogues with conformationally constrained isobutyl chains were prepared. This study revealed that the direction of the isobutyl side chain determine whether the compounds act as agonists or antagonists at the AT₂ receptor. Further investigations are required to fully elucidate the bioactive conformation(s) of these nonpeptide AT₂ receptor agonists.</p><p>We believe that the selective nonpeptide AT₂ receptor agonists and antagonists identified in this thesis will serve as important research tools in the continuing investigation of the physiological role of the AT₂ receptor. We also believe that these drug-like compounds might provide potential leads in drug discovery processes.</p>

The involvement of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-α) and the sympathetic nervous system in the development of delayed-onset muscle soreness has not been established. I assessed the effect of etanercept, a TNF- α inhibitor, and atenolol, a β1-receptor antagonist, on DOMS induced in the quadriceps muscle. Thirteen male subjects reported to the exercise laboratory on three separate occasions, 6-15 weeks apart. In a randomised, double-blind cross-over format, I administered etanercept (25mg), atenolol (25mg) or placebo, one hour before the exercise. Subjects then completed four sets of 15 repetitions at 80% of their one repetition maximum (1RM) on a 45° inclined leg press machine. Muscle strength changes were detected by remeasuring the subject’s 1RM 24h, 48h and 72h after the exercise. Sensitivity to pressure of the quadriceps muscle was measured using a pressure algometer before and 24h, 48h and 72h after exercise. The subject’s perception of the pain was measured with the visual analogue scale and McGill Pain Questionnaire. Muscle tumour necrosis factor-alpha concentration was measured before exercise and then 2h and 24h after exercise in four subjects. Muscle strength was impaired 24h and 48h after exercise regardless of agent administered (P < 0.001). At 72h after exercise, muscle strength was significantly improved (P < 0.01) in subjects receiving etanercept and atenolol compared to those receiving placebo. The subject’s were significantly more sensitive to pressure applied to the quadriceps 24h, 48h and 72h after exercise compared to before exercise, regardless of agent administered (P < 0.001). The VAS was elevated significantly at all three time intervals, with no difference after etanercept or atenolol administration compared to that of placebo. There was no significant difference in the muscle TNF-α concentration between any of the time intervals or between subjects receiving placebo and etanercept (P=0.065). The administration of atenolol and etanercept, at the regimen used, had no effect on the soreness associated with DOMS.

Atherosclerosis is a slow-developing disease of large and medium sized arteries, and is the premier cardiovascular disease that underlies myocardial and cerebral infarction, aneurysm, stroke and gangrene of the extremities. At least 17 million people die of atherosclerotic complications each year worldwide, with another 15 million surviving unstable events. Despite therapeutic advances such as drug-eluting stents and statins, which reduce cardiovascular events by around 25%, there is an urgent need for additional strategies to complement these treatments and further reduce morbidity and mortality. Inflammation plays a fundamental role in mediating all stages of atherogenesis. The innate immune response has long been implicated in atherogenesis, and activation of the complement system has been associated with all stages of disease. In particular, C5b-9 (membrane attack complex) has been detected in human plaques and may be pathogenic. Since C5b-9 is produced in plaques then the complement activation product 5a (C5a) must also be generated. However, very little is known about the role of C5a in atherogenesis. Indeed, elevated levels of serum C5a have been detected in patients with advanced atherosclerosis and recently the classical C5a receptor, CD88, has been detected on most of the cells found in human atherosclerotic plaques. To date, no studies examining specific C5a receptor antagonism in an animal model of atherosclerosis have been performed. This thesis explored the potential therapeutic benefits of inhibiting C5a, using the C5a receptor antagonist, PMX53, in the ApoE knockout (ApoE-/-) mouse model of atherosclerosis. In Chapter 2, expression of both receptors to C5a, CD88 and C5L2, in aortae of ApoE -/- mice was explored. CD88 and C5L2 mRNA expression was detected in the aorta of ApoE -/- mice at 3, 5, 9,12, 17 and 25 weeks of age. CD88 expression in ApoE -/- mice increased with time, and with macrophage accumulation within the plaque, as indicated by an increase in expression of the macrophage marker, F4/80. Expresssion of CD88 was significantly increased at 17 and 26 weeks of age, compared with age-matched wild-type controls. C5L2 was also expressed albeit at much lower levels compared with wild-type controls. Having established the presence of C5a receptors in ApoE -/- mice, in Chapter 3, the effects PMX53-treatment on ApoE -/- mice on a normal chow diet was examined. PMX53 treatment (3 mg/kg; tri-weekly s.c., plus ~1mg/kg/day p.o. for 20 weeks) resulted in a significant reduction in neointimal area and therefore the intima:media ratio in the brachiocephalic artery compared to untreated controls (P < 0.05; n = 6-8). PMX53 treatment also reduced collagen content and outward remodelling of the brachiocephalic artery. In Chapter 4, studies exploring the effects of PMX53-treatment in the more inflammatory environment created by a high fat (or Western-type diet) were explored. Male ApoE -/- mice were treated with PMX53 from 5 – 25 weeks of age (3 mg/kg; tri-weekly s.c., plus v ~1mg/kg/day p.o.). Mice were placed on a high fat diet from 10 weeks of age. While PMX53- treated did not affect neo-intimal area, it did result in a significant increase in cell density (P<0.01; n=12) and a significant reduction in buried caps (P < 0.05; n = 12) in the brachiocephalic artery compared with untreated animals. Interestingly, PMX53-treated mice also had significantly reduced total cholesterol compared with untreated controls (P < 0.05; n = 12). These results provide the first evidence for a role for C5a in plaque destabilisation and cholesterol metabolism. Finally, Chapter 5 described the expression of CD88 and C5L2 in cultured primary rat vascular SMC was explored. Expression of CD88 and C5L2 was detected by Western blot; immunocytochemical analysis demonstrated intracellular expression of both C5L2 and CD88. Conversely, radioligand binding experiments suggested the presence of ~25000 cell surface receptors with a high affinity to C5a (KD = 0.3 nM). After establishing the presence of receptors to C5a, experiments were conducted to determine whether C5a has any functional effects on these cells. C5a induced a moderate increase in TNF-α release after 4 hours of treatment (P < 0.05, n = 3), but did not affect SMC proliferation (n = 3). In summary, this study is the first to demonstrate the benefits of specifically inhibiting C5a in a mouse model of atherosclerosis. These findings suggest that C5a plays a role in atherogenesis in ApoE -/- mice and that the C5a receptor antagonist PMX53 may have therapeutic potential in human atherosclerotic disease.

The G protein-coupled receptors (GPCRs) are important targets in drug discovery. In several cases, the endogenous ligands that activate the GPCRs of pharmaceutical interest are peptides. Unfortunately, peptides are in general not suitable as drugs, since the peptide structure is associated with several disadvantages, such as low oral bioavailability, rapid degradation and low receptor subtype selectivity. Thus, there is a strong need for drug-like nonpeptide ligands to peptide-activated GPCRs. However, to discover nonpeptide ligands that mimic the effect of the endogenous peptide, i.e. peptidomimetics, is a tremendous challenge. In fact, morphine and the related opioids were the only known examples of peptidomimetics before 1995 and these ligands were known long before the native endogenous peptide ligands were discovered. The main objective of the work described in this thesis was to design, synthesize and biologically evaluate selective nonpeptide agonists to the peptide-activated GPCR AT2. The AT2 receptor belongs to the renin–angiotensin system, where the octapeptide angiotensin II (Ang II) is the major effector peptide. Ang II mediates its effects through the two GPCRs AT1 and AT2. The AT1 receptor is already an established target in the treatment of hypertension. The physiological role of the AT2 receptor, which is up-regulated in certain pathological conditions, is not fully understood but it seems to include positive effects such as vasodilatation, tissue repair, tissue regeneration and neuronal differentiation. In the current investigation we started from the nonpeptide and nonselective (AT1/ AT2) compound L-162,313. This ligand is a known AT1 receptor agonist but its effect on the AT2 receptor was unknown at the start of this project. We were able to show that it acts as an agonist also at the AT2 receptor. Furthermore, stepwise synthetic modifications of L-162,313 led to the identification of the first selective nonpeptide AT2 receptor agonist. Following the discovery of this compound several selective nonpeptide AT2 receptor agonists were identified. It was also revealed that a minor structural alteration of one of these compounds interconverted the functional activity from agonism to antagonism. The structural requirement for agonism vs antagonism was therefore studied. The functionality switch was suggested, at least partly, to be due to the spatial relationship between the methyleneimidazole group and the isobutyl side chain of the compounds. To further investigate the bioactive conformation(s) of this series of compounds enantiomerically pure analogues with conformationally constrained isobutyl chains were prepared. This study revealed that the direction of the isobutyl side chain determine whether the compounds act as agonists or antagonists at the AT2 receptor. Further investigations are required to fully elucidate the bioactive conformation(s) of these nonpeptide AT2 receptor agonists. We believe that the selective nonpeptide AT2 receptor agonists and antagonists identified in this thesis will serve as important research tools in the continuing investigation of the physiological role of the AT2 receptor. We also believe that these drug-like compounds might provide potential leads in drug discovery processes.

Background: Intracellular glucocorticoid receptors (GRs) mediate the regulation of lung development, including alveolarization, by glucocorticoids (GCs). One potential approach to determining the role of GC-GR signalling in alveolar formation would be by pharmacologic blockade. Hypothesis: CP472555, a novel GR antagonist with negligible anti-PR activity, is a suitable tool for the study of GC-GR regulation of rat alveolarization. Design/Methods: CP472555 doses needed to block GR were estimated in vitro in fetal rat lung primary cultures. Postnatally, a variety of doses were administered intraperitoneally over a range of days. Results: During postnatal days (PN)0-PN10, when GC levels are low, CP472555 induced changes consistent with GR agonist activity. While GC levels increase after PN11, animals exposed to CP472555 from PN11-PN21 exhibit changes consistent with anti-GR antagonist activity. Conclusion: CP472555 causes a degree of GR blockade sufficient to permit further pharmacological investigation of the role of endogenous GC-GR signalling at the end of alveolarization.

Background: Intracellular glucocorticoid receptors (GRs) mediate the regulation of lung development, including alveolarization, by glucocorticoids (GCs). One potential approach to determining the role of GC-GR signalling in alveolar formation would be by pharmacologic blockade. Hypothesis: CP472555, a novel GR antagonist with negligible anti-PR activity, is a suitable tool for the study of GC-GR regulation of rat alveolarization. Design/Methods: CP472555 doses needed to block GR were estimated in vitro in fetal rat lung primary cultures. Postnatally, a variety of doses were administered intraperitoneally over a range of days. Results: During postnatal days (PN)0-PN10, when GC levels are low, CP472555 induced changes consistent with GR agonist activity. While GC levels increase after PN11, animals exposed to CP472555 from PN11-PN21 exhibit changes consistent with anti-GR antagonist activity. Conclusion: CP472555 causes a degree of GR blockade sufficient to permit further pharmacological investigation of the role of endogenous GC-GR signalling at the end of alveolarization.

Previous studies show that coronary artery disease (CAD) is a multi-factors and chronic inflammatory disease, and is associated with lipid metabolism. IL-1ra is a naturally occurring anti-inflammatory molecules that block the action of IL-1. However, little is known about the imbalance between IL-1ra and inflammatory mediators in CAD. We attempted to investigate the relationships between inflammatory mediators and serum IL-1ra levels in patients with CAD. In 95 patients with angiographically defined CAD, and 70 healthy controls were studied in a case-control manner. Serum levels of cytokines and the risk factor of CAD were examined. Polymorphisms for IL-1ra gene were detected by PCR, and genotypes and allelic frequencies in both groups were compared. Our major finding include: (1) The risk factors such as elevated BMI, systolic BP, smoking, hypertension, blood glucose, and TG was more frequently found in the CAD group than the control group ( p < 0.001). However, the HDL-C and bilirubin were significantly higher in control group than the CAD group. (2) The relative risk of those in the highest quartile of ratio of LDL-C to HDL-C, TC to HDL-C, and TG to HDL-C were significantly elevated. ( OR = 2.98, p < 0.01; OR = 5.31, p <0.001; OR = 8.43, p < 0.001 respectively) (3) Five different inflammatory markers were significantly elevated including IL-1ra, hs-CRP, IL-6, leukocyte count, and neutrophil percentage between healthy controls and CAD patients. ( p < 0.01) (4) Levels of IL-1ra and other variables such as blood glucose, BMI, TG, IL-6, hs-CRP, and leukocyte count has significantly correlated, and were inversed correlation in bilirubin, and HDL-C in all study subjects. ( p < 0.01) (5) In the multiple logistic regression analysis, adjustment was made for variables. The relative risk of CAD for the highest quartile of IL-1ra, as compared with the lowest quartile, had an Odds ratio 2.57 ( 95% confidence intervals, 1.12 - 5.91, p = 0.026 ) increase in risk for CAD. (6) Similar results were obtained hs-CRP, IL-6 in the highest quartile were increase risk for future CAD. ( OR = 5.86 and 5.79 respectively; p < 0.001) (7) The join effect cytokines of hs-CRP, IL-6, IL-1ra concentrations may play important role in CAD risk. ( OR = 10.19, p < 0.001 ) (8) In addition, IL-1ra allele 2 genotype and allelic frequencies were no significant association with increase in IL-1ra with CAD. In conclusion, we find a significant association of elevated IL-1ra levels in the patients with CAD. Thus, these results support the hypothesis that inflammation, anti-inflammation cytokines and lipoprotein metabolism provide a useful marker for predicting the development of CAD events.

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