Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole

Aims  Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole.
Methods  Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days.
Results  When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration ( C _max) and the area under the plasma concentration–time curve of voriconazole (AUC_τ) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole C _max or AUC_τ. Time of C _max ( t _max) elimination half-life ( t _1/2) or terminal phase rate constant ( k _el) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events.
Conclusions  Coadministration of the histamine H₂-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.     

Eradication of Helicobacter pylori increases gastric acidity in patients with atrophic gastritis of the corpus-evaluation of 24-h pH monitoring

BACKGROUND: Recent studies have shown that the eradication of Helicobacter pylori results in a gastric acid secretion which decreases to normal levels in patients with duodenal ulcer disease. The aim of this study was to evaluate the effect of eradication of H. pylori in a 24-h study of gastric acidity in patients with atrophic gastritis of the corpus. METHODS: Intragastric acidity was measured by continuous 24-h pH monitoring, and the histology of the gastric antrum and corpus were evaluated in 14 H. pylori-positive patients with histologically proven atrophic gastritis of the corpus (10 men, 4 women; mean age, 57 years) before and 1 year after anti-H. pylori therapy. RESULTS: H. pylori was absent in 13 of 14 patients 1 year after treatment. Both gastritis and atrophy scores were significantly lower after eradication therapy (P < 0.01). The 24-h median pH and the percentage of 24-h pH readings above 4.0 units were significantly decreased after eradication therapy (from 5.12 +/- 0.36 to 2.69 +/- 0.21, and from 65.5 +/- 6.6% to 28.2 +/- 6.1%, P < 0.01, respectively.) CONCLUSION: Eradication of H. pylori increases 24-h gastric acidity in patients with atrophic gastritis of the corpus. Improvement of the histology of the gastric antrum and corpus may lead to the normalization of gastric acidity.     

Mucosal interleukin-1β production and acid secretion in enlarged fold gastritis

Background : We have previously shown that eradication of Helicobacter pylori increases acid secretion in H. pylori -associated enlarged fold gastritis.
Aim : To investigate whether locally produced interleukin-1β is possibly involved in the inhibition of acid secretion in H. pylori gastritis.
Methods : IL-1β release from the gastric body mucosa was determined by short-term culture of biopsy specimens in 13 patients with enlarged fold gastritis (all H. pylori -positive), five H. pylori -positive and 10 H. pylori -negative patients without enlarged folds. The acid-inhibitory effect of locally produced IL-1β was examined by [¹⁴C]-aminopyrine uptake assay using isolated rabbit gastric glands.
Results : IL-1β release was significantly greater in patients with enlarged fold gastritis, significantly correlated with both basal and tetragastrin-stimulated acid outputs in the H. pylori -positive patients ( r  = −0.591 and r  = −0.641, respectively; P  < 0.01), and significantly decreased with concomitant increases in acid secretions after eradication of H. pylori . [¹⁴C]-aminopyrine uptake was inhibited by IL-1β in a dose-dependent manner.
Conclusions : Increased production of IL-1β caused by H. pylori infection is possibly involved in the inhibition of acid secretion in enlarged fold gastritis.     

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N ^G-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics.
Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4  mg  kg⁻¹  h⁻¹ ) with a front loaded bolus (4  mg  kg⁻¹ ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion ( t ₀ ) and after 4, 8, and 12  min ( t ₁, t ₂ and t ₃ ).
Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t ₁ and persisted during the entire infusion period.
Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.     

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V _max /K _m ratio of 0.50–7.26  μl  min⁻¹  mg ⁻¹ protein.
2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K _i of 201±89  μm was obtained for the 3HDZ pathway ( K _m /K _i ratio of 3.0±0.9).
3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K_is of 121±45 and 188±73  μm respectively ( K _m /K _i ratios of 5.2±2.3 and 3.3±1.5 respectively).
4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.     

Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes

Aims Nine antimalarial (plus two metabolites of proguanil) and twelve non-antimalarial drugs were tested for their possible interaction with CYP3A4-catalysed 3-hydroxylation of quinine by human liver microsomes in vitro .
Methods 3-Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective I C ₅₀ values were estimated for the twenty-one drugs and two metabolites of proguanil tested herein.
Results Thirteen drugs exhibited an inhibitory effect on the 3-hydroxylation of quinine. According to the respective mean I C ₅₀ values, the inhibitory rank order of the drugs was: ketoconazole>troleandomycin (TAO, with preincubation)> doxycycline>omeprazole>primaquine>tetracycline=TAO (without preincubation)>nifedipine>erythromycin>verapamil>cimetidine>diltiazem>oleandomycin>hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean I C ₅₀>200 or 500  &mgr;m ). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3-hydroxylation with a mean I C ₅₀ value of 17  &mgr;m, followed by primaquine and tetracycline, with mean I C ₅₀ values of 20 and 29  &mgr;m, respectively.
Conclusions When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co-administrated with quinine.     

[13C]-pantoprazole breath test to predict CYP2C19 phenotype and efficacy of a proton pump inhibitor, lansoprazole

Background  ¹³CO₂ is produced on metabolism of ¹³C-labelled-pantoprazole ([¹³C]-pantoprazole) by CYP2C19.
Aim  To investigate whether the [¹³C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese.
Methods  We classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [¹³C]-pantoprazole. Changes in the carbon isotope ratios (¹³CO₂/¹²CO₂) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (‰). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole.
Results  The DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve ( AUC )_20–60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC _20–60 min of DOB.
Conclusions  [¹³C]-pantoprazole breath test can easily estimate the individual activity of CYP2C19 and predict the efficacy of a PPI (i.e. lansoprazole). This test would be useful for individualized medicine with a PPI.     

Omeprazole versus ranitidine: short-term triple-therapy in patients with Helicobacter pylori-positive duodenal ulcers

Aim : To compare the results of two short triple-therapy regimens, different only in the antisecretory drugs used, in patients with active duodenal ulcer and Helicobacter pylori infection.
Methods : All patients received a combination of clarithromycin 250 mg b.d. and tinidazole 500 mg b.d. for 1 week, in addition to an antisecretory drug: omeprazole 20 mg (50 patients) or ranitidine 300 mg (50 patients) twice daily for 1 week, followed by a single daily dose for a further 3 weeks. Upper gastrointestinal endoscopy, with rapid urease test and histological examination of antral and corpus biopsies, was performed prior to the treatment and at least 2 months after the discontinuation of the antisecretory therapy.
Results : Duodenal ulcer healing was documented in all patients at the endoscopic examination after therapy. H. pylori eradication was achieved in 46 of 50 patients (92%, 95% CI=85–99%) in the omeprazole group and in 43 of 50 patients (86%, 95% CI=76–96%) in the ranitidine group; the difference is not significant.
Conclusion : Omeprazole or ranitidine, in combination with clarithromycin and tinidazole, are equally effective in the eradication of H. pylori infection and healing of duodenal ulcers.     

Treatment with a proton pump inhibitor promotes corpus gastritis in patients with Helicobacter pylori-infected antrum-predominant gastritis

BACKGROUND: Proton pump inhibitors have been reported to modify the level of Helicobacter pylori gastritis. AIM: To quantitatively investigate the effect of a proton pump inhibitor on the mucosal neutrophil reaction. METHODS: Forty-six H. pylori-infected patients (17 duodenal ulcer, 29 gastric ulcer) were enrolled. During endoscopic examination, biopsy samples were obtained from the antrum and the corpus. The tissue content of neutrophil myeloperoxidase was measured by enzyme-linked immunoabsorbent assay, and H. pylori infection was histologically assessed. A proton pump inhibitor was administered orally for 8 weeks. RESULTS: In the patients as a whole, antral myeloperoxidase decreased significantly after proton pump inhibitor treatment, but corpus myeloperoxidase remained largely unchanged. In duodenal ulcer patients, myeloperoxidase significantly decreased in the antrum, but increased in the corpus. In gastric ulcer patients, a significant reduction was observed in antral myeloperoxidase, but corpus myeloperoxidase remained unchanged. In the antral myeloperoxidase > corpus myeloperoxidase subgroup (n=24), antral myeloperoxidase significantly decreased, whereas corpus myeloperoxidase increased. No changes were observed at either site in the corpus myeloperoxidase > antral myeloperoxidase subgroup. Histology showed that the antral bacterial load of H. pylori decreased in all subgroups, but that it was mostly unchanged in the corpus. CONCLUSIONS: Proton pump inhibitor treatment stimulated the neutrophil reaction in the corpus mucosa of duodenal ulcer patients and of patients in whom antral neutrophil accumulation was more predominant than that of the corpus. This phenomenon may not be caused by increased bacterial density.     

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C

Background  The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated.
Aim  To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin.
Patients and methods  Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment.
Results  At week 4, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.376, P  = 0.002) and AUC _0→12h of ribavirin plasma level ( r  = −0.277, P  = 0.018). At week 12, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.384, P  < 0.0001) and AUC _0→12h of ribavirin plasma level ( r  = −0.257, P  = 0.002). In genotype 1 patients, AUC _0→12h ribavirin and C _min were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12.
Conclusion  C_min of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.     

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1   Eight healthy subjects received 50, 100, 300, 600 and 900  mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.
2   The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50  mg 1MX infused intravenously over 20  min, was used to measure the inhibition of xanthine oxidase.
3   The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50  mg to 600  mg day⁻¹, with a weak indication of saturation at the higher 900  mg day⁻¹ dose rate.
4   The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E_max model and the C ₅₀ values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08  μm, respectively.
5   1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C ₅₀ for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.
6   The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C ₅₀, was lower than those often observed in clinical practice.     

Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.
Methods A single 5  mg  kg⁻¹ dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5  mg dl⁻¹ ). CsA whole blood levels were measured for 24  h post-dose by h.p.l.c.
Results Neoral had a higher C _max and AUC( C _max: 943±176  ng  ml⁻¹; AUC: 4612±785  ng  ml⁻¹  h) than those of the CsA capsules ( C _max: 697±187  ng  ml⁻¹; AUC: 3483±873  ng  ml⁻¹  h; P <0.05). There was no difference in t _max and t _1/2,z between the two groups.
Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.     

Attenuation by ACE inhibitor drugs of α-adrenoceptor sensitivity in human vessels: possible differences related to drug lipophilicity

Aims We investigated the effect of angiotensin converting enzyme inhibitors (ACEIs) on postsynaptic adrenoceptor sensitivity and compared the effect of the lipophilic ACEI, quinapril, and that of hydrophilic agent, enalapril in human vessels.
Methods α-adrenoceptor sensitivity was evaluated using the dorsal hand vein compliance technique. The dose–response curves of vasoconstriction to phenylephrine and prostaglandin F_2α were obtained in healthy male volunteers.
Results The ACEIs shifted the dose–response curve of phenylephrine to the right and raised the median effective dose (E D ₅₀; 189.3 (57.6  ng  min⁻¹ ) of phenylephrine. Following quinapril administration, E D ₅₀ increased to 481.1 (101.8  ng  min⁻¹ compared with 266.8 (55.8  ng  min⁻¹ after enalapril (95% CI for differences; 31.1–397.5  ng  min⁻¹ ). Quinapril administration had no effect on the dose–response curve of PGF_2α .
Conclusions ACE inhibition attenuates α-adrenoceptor sensitivity in human vessels. The effect of quinapril, a lipophilic ACEI, was greater than that of enalapril, a hydrophilic ACEI. Lipophilic ACEIs may be more potent in vasodilating effect than hydrophilic ACEIs. Angiotensin II concentration in tissue rather than that in plasma may contribute to the α-adrenoceptor sensitivity of the vessels.     

Seven-day treatment for Helicobacter pylori infection: ranitidine bismuth citrate plus clarithromycin and tetracycline hydrochloride

Background: Dual therapy with ranitidine bismuth citrate plus clarithromycin twice daily for 14 days is an effective regimen for eradicating Helicobacter pylori infection.
Aim: To determine whether this regimen can be improved by the addition of a second antibiotic, tetracycline hydrochloride, whilst reducing the duration of treatment to 7 days.
Methods: Sixty-one out-patients were enrolled to this open treatment study. All had H. pylori infection, as determined by ¹³C-urea breath test and, for those undergoing endoscopy, by rapid urease test. Patients were treated with ranitidine bismuth citrate 400 mg, clarithromycin 500 mg and tetracycline hydrochloride 500 mg all twice daily for 7 days. Eradication of H.␣pylori was assessed by two separate ¹³C-urea breath tests, the first 28–68 days after the completion of treatment, the second 28–162 days later. H. pylori infection was considered cured if both tests were negative.
Results: All 61 patients were included in the intention-to-treat efficacy analysis. Successful eradication of H.␣pylori was achieved in 55/61 patients (90 %; 95% CI: 82–98%). Fifty-nine out of sixty-one patients reported 100% compliance; one patient missed a single dose of medication and the other withdrew at 48 h due to nausea and vomiting. Minor adverse events were reported by 30/61 patients.
Conclusion: One-week triple therapy with ranitidine bismuth citrate, clarithromycin and tetracycline, all twice daily, is a safe and well-tolerated regimen which eradicates H. pylori in 90% of infected patients.     

Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during and after 12 months of treatment with ranitidine and lansoprazole in patients with duodenal ulcer disease

Background:

Several studies have shown that acid-suppressing treatment leads to aggravation of Helicobacter pylori gastritis in the corpus. It remains unclear whether this augmentation of the inflammation reverts to baseline after termination of treatment.

Methods:

In 114 H. pylori-infected duodenal ulcer patients we investigated the gastritis parameters in antral and corpus mucosa before treatment, after 6 and 12 months of therapy, and 6 months after termination of treatment with 15 mg lansoprazole or 150 mg ranitidine/day.

Results:

Lansoprazole and ranitidine led to a significant aggravation of gastritis in the corpus after 6 and 12 months of treatment. However, while there was no change in gastritis in the antrum with ranitidine, treatment with lansoprazole led to partial elimination of H. pylori with improvement of the inflammation in this part of the stomach. Following termination of therapy, the observed changes reverted to baseline. No increase in intestinal metaplasia and/or atrophy in the antrum or corpus was observed.

Conclusion:

Both substances are associated with an aggravation of H. pylori gastritis in the corpus. However, only lansoprazole leads to a partial elimination of H. pylori with improvement of the inflammation in the antrum. The changes provoked by acid-suppressing treatment revert to baseline after termination of therapy.

     

In vitro comparative study of three pancreatic enzyme preparations: dissolution profiles, active enzyme release and acid stability

Background  Various pancreatic enzyme preparations are used for the treatment of pancreatic insufficiency but their bioequivalence is often unknown.
Aim  To determine in vitro the pH-dependent release and acid resistance of enzymes from three commercially available pancreatin capsules, two containing enteric-coated (Creon 25000; Eurobiol 25000) and one uncoated (Eurobiol 12500) microspheres.
Methods  Dissolution experiments were performed at pH values ranging from 4.0 to 5.8. Lipase, chymotrypsin and amylase activities were measured in the solution as a function of time.
Results  Eurobiol 25000 started to release its enzymes significantly at pH 5.0 ( t _1/2 = 71 min), whereas the enzymes from Creon 25000 were only released at higher pH value (5.4; t _1/2 = 49.2 min). Unlike chymotrypsin, lipase and amylase were highly sensitive to acidic conditions at the lowest pH values tested. Both enzymes were also found to be sensitive to proteolytic inactivation at the highest pH values tested. Overall, Eurobiol 25000 released higher amounts of active amylase and lipase than Creon 25000 at the pH values usually found in duodenal contents. The uncoated Eurobiol 12500 preparation was, however, the only one that could immediately release rather high levels of active chymotrypsin and lipase at low pH (4.5).
Conclusion  These findings suggest that pH-sensitive enteric-coated pancreatin products containing similar amounts of enzymes might not be bioequivalent depending on the pH of duodenal contents.     

Lansoprazole, clarithromycin and metronidazole for seven days in Helicobacter pylori infection

Background : This study determines the efficacy and safety of a 1-week triple therapy regimen of lansoprazole, clarithromycin and metronidazole in an area with a high prevalence of pre-treatment metronidazole-resistant strains of Helicobacter pylori .
Methods : Seventy-five H. pylori positive patients with gastritis or duodenal ulcer were entered into an open study of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. H. pylori status was determined by CLOtest, histology, culture and by ¹³C-urea breath test (repeated 28 days after treatment).
Results : Seventy-one patients completed the treatment and returned for follow-up. H. pylori was eradicated in 61 of 71 (86%) patients by per-protocol analysis, and in 61 of 75 (81%) patients by intention-to-treat analysis. H. pylori was eradicated in 12 of 16 (75%) patients with metronidazole-resistant strains compared with 22 of 24 (92%) in patients with metronidazole-sensitive strains of H. pylori ( P = 0.14). Forty-five patients reported at least one adverse event, and three patients stopped treatment due to them (two with headaches and one with diarrhoea).
Conclusions : A 1-week course of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. eradicates H. pylori in up to 86% of patients. It is of proven benefit in patients with pre-treatment metronidazole-resistant strains of H. pylori .     

幽门螺旋菌在慢性胃炎和消化性溃疡中的分布

本文对幽门螺旋菌(Hp)在慢性胃炎和消化性溃疡中的分布进行了观察。发现胃窦部Hp感染率慢性胃炎组为61.13％,Hp感染率随患者年龄的增加而增高,消化性溃疡组为96.88％,较慢性胃炎组明显为高;十二指肠球部Hp感染率,十二指肠溃疡大于非溃疡病例。Hp寄生密度,在胃窦部球溃疡组大于慢性胃炎组,在十二指肠球部二者无显著差别,二组又全显示胃窦部Hp数量比球部高。提示Hp感染与慢性胃炎和消化性溃疡的发病相关,但单独Hp感染产生的损伤尚不足以造成溃疡的发生,还应有其它因素存在。     

1-Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect

Aims In the present study we have investigated the use of caffeine, administered in the form of instant coffee, as a prodrug for 1MX to validate the use of the 1MU:1MX ratio following caffeine administration as a pharmacodynamic measure of oxypurinol effect on xanthine oxidase.
Methods Five healthy volunteers took caffeine 75  mg 8 hourly administered as instant coffee over a 7 day period. They were given allopurinol 600  mg on day 4. Urine was collected in 8  h aliquots from day 1–day 7. The ratio of 1-methyluric acid (1MU) to 1-methylxanthuric (1MX) was determined.
Results The relationship between the plasma oxypurinol (the active metabolite of allopurinol) concentration at the midpoint of each caffeine dosage interval and the decrement in the urinary 1MX to 1MU ratio fitted well by a sigmoid E_max model. Mean (±s.d.) values of the oxypurinol E C ₅₀(3.9±1.4  mg  l^{− 1} ), E C ₉₀(8.7±1.8  mg  l^{− 1} ) and the exponent, n (3.0±1.2) were similar to those obtained previously following either the direct administration of 1MX or the use of theophylline as a prodrug for 1MX.
Conclusions These data indicate that the use of caffeine as a source of 1MX could provide a simple and ethically acceptable method for monitoring oxypurinol effect in patients taking allopurinol for the treatment of gout.     

(−)-Timolol is a more potent antagonist of the positive inotropic effects of (−)-adrenaline than of those of (−)-noradrenaline in human atrium

1 The affinity of (−)-timolol for β₁- and β₂-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol were measured.
2 The antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93±0.09 for (−)-adrenaline, 0.97±0.09 for (−)-noradrenaline].
3 The inotropic effects of (−)-adrenaline were antagonized significantly more by each concentration of (−)-timolol than those of (−)-noradrenaline. K _B-values (-log m) were 10.10±0.09 against (−)-adrenaline and 9.43±0.07 against (−)-noradrenaline ( P <0.001).
4 Blocking kinetics of (−)-timolol for the β-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times K _B of (−)-timolol were approximately 30  min for both (−)-adrenaline and (−)-noradrenaline; offset times were similar.
5 It is concluded that (−)-timolol has a higher affinity for the β₂-adrenoceptor than for the β₁-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β₂-adrenoceptor hypersensitivity induced by cardiac β₁-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.