A randomized, controlled pilot study of the safety and efficacy of 4% icodextrin solution in the reduction of adhesions following laparoscopic gynaecological surgery.

BACKGROUND: Adhesion-related readmissions are frequent sequelae to gynaecological surgery. Attempts to prevent adhesions by separating healing peritoneal surfaces include site-specific barriers and hydroflotation by instilled solutions. Rapid absorption limits the effectiveness of solutions such as Ringer's lactated saline (RLS). This pilot study assessed the safety, tolerability and preliminary effectiveness of a non-viscous, iso-osmolar solution of 4% icodextrin, an alpha-1,4 glucose polymer with prolonged intraperitoneal residence, in reducing adhesions after laparoscopic gynaecological surgery. METHODS: Women aged > or = 18 years, requiring laparoscopic adnexal surgery (n = 62), were entered into a randomized, open-label, assessor-blinded, multicentre study to compare 4% icodextrin with RLS. Treatments were coded in blocks of four with equal randomization to each group, and pre-allocated to consecutively numbered patients. At least 100 ml per 30 min was used for intra-operative lavage, with 1 l instilled post-operatively. Per protocol analysis included all eligible patients (n = 53); reformation analysis required one or more baseline adhesion (n = 42). Incidence, extent and severity of post-operative adhesions were assessed at second-look laparoscopy after 6-12 weeks. Procedures were video-taped for third party, blinded assessment. RESULTS: Safety and tolerability (laboratory variables, adverse events, clinical follow-up) were good with no difference between treatments. A shift analysis of incidence-ranked adhesions (n = 53) showed apparent improvements in more patients with icodextrin than RLS (37 versus 15%; not significant). Adhesion score reduction (n = 42) was more frequent in icodextrin- than RLS-treated patients: incidence (52 versus 32%), extent (52 versus 47%), and severity (65 versus 37%). Despite greater baseline adhesions, median reformation was less after icodextrin (24%) than RLS (60%). The pilot study group sizes were not powered for statistical significance. CONCLUSIONS: In this preliminary study, 4% icodextrin lavage plus instillation was well tolerated and reduced adhesion formation and reformation following laparoscopic gynaecological surgery. A Phase III pivotal study is currently in progress.

Fluid dynamics in man of an intraperitoneal drug delivery solution: 4% icodextrin.

Interest in targeting drugs into the peritoneal cavity for intra-abdominal cancers or infections is undergoing a revival as recent clinical trials have demonstrated, not only a regional advantage in concentration of the active agent, but also improved long-term outcomes. Solutions currently used for intraperitoneal (IP) drug delivery have short residence times, however, which can limit the exposure of all areas of the peritoneum to the active agent. Icodextrin 4% solution was compared with saline and a glucose-based peritoneal dialysis solution in a clinical study of IP residence time. The study was carried out during the fortnightly rest phase in 9 patients undergoing 5-fluorouracil (5-Fu) IP treatment for colorectal cancer. The volume remaining in the peritoneal cavity was measured at 0, 12, 24, 48, 72, and 96 hr after an instillation of 2 liters of each fluid. Saline (n = 3 dwells) and glucose (n = 3 dwells) peritoneal dialysis solutions were almost fully absorbed by 24 hr, and the patients experienced discomfort when using these solutions. In contrast, icodextrin 4% solution (n = 188 dwells) maintained its instilled volume for up to 48 hr, and half the instilled volume remained after 72 and 96 hr. This result would allow extensive and prolonged coverage of the peritoneal surface. Icodextrin 4% solution may be an effective vehicle to deliver therapeutic agents into the peritoneal cavity.

Development of a novel glucose polymer solution (icodextrin) for adhesion prevention: pre-clinical studies.

Intra-abdominal adhesion formation causes significant post-operative morbidity. Controlled studies using animal models have been carried out to assess the tolerability and preventive efficacy of icodextrin solution (a biodegradable, biocompatible, glucose polymer). Reduction of adhesion formation was first evaluated in a rabbit double uterine horn model, applying 10-75 ml of 7.5 and 20%, or 50 ml of 2.5-20% icodextrin solution post-operatively. Significant increases in adhesion free sites (P < 0.005) were observed with volumes > or =25 ml, and at concentrations > or =4%. Efficacy of 50 ml 4 and 20% icodextrin was then evaluated both during and after surgery, demonstrating significant reductions in adhesion formation (P < 0. 002). In one study, intra- plus post-operative use of 4% icodextrin produced the greatest reduction of non-surgical site adhesions; in others, the post-operative effect was predominant. Post-surgical administration of 50 ml 4% icodextrin in a rabbit sidewall model also resulted in more adhesion-free animals, and a significant reduction (P < 0.001) in areas of adhesion formation and reformation. In a rat infection potentiation model, 4% icodextrin produced no difference in mortality, abscess formation or overall abscess score. These data suggest that 4% icodextrin offers a well-tolerated and effective means of reducing post-surgical adhesion formation.

Assessment of the effectiveness, safety, and biocompatibility of icodextrin in automated peritoneal dialysis. The Dextrin in APD in Amsterdam (DIANA) Group.

OBJECTIVE: Our study assessed the efficacy, safety, and biocompatibility of icodextrin (I) solution compared to glucose (G) solution as the daytime dwell in continuous cycling peritoneal dialysis (CCPD). DESIGN: In a randomized, open, prospective, parallel group study of two year's duration, either I or G was used for the long daytime dwell in CCPD patients. METHOD: The study was carried out in a university hospital and teaching hospital. Established CCPD patients and patients new to the modality were both included. Clinic visits were made at three-month intervals. In all patients, clinical data were gathered; ultrafiltration (UF) was recorded; and serum, urine, and dialysate samples and effluents were collected. Peritoneal defense characteristics and mesothelial markers were determined. Every six months, peritoneal kinetics studies were performed, and serum samples for icodextrin metabolites were taken. RESULTS: Thirty-eight patients (19 G, 19 I) started the study. The median follow-up was 16 months and 17 months respectively (range: 0.5 - 26 months and 3 - 26 months, respectively). Daytime UF volumes increased significantly (p < 0.001), and 24-hour UF tended to increase from baseline in the I group. Dialysate creatinine clearance increased non significantly in both groups over time. In I patients, serum disaccharides (maltose) concentration increased from 0.05+/-0.01 mg/mL [mean+/- standard error of mean (SEM)] at baseline, to an average concentration in the follow-up visits of 1.15+/- 0.04 mg/mL (p <0.001). At the same time, serum sodium levels decreased from 138.1 +/- 0.7 mmol/L to an average concentration in the follow-up visits of 135.9 +/- 0.8 mmol/L (p < 0.050). At 12 months, the serum sodium concentration increased to a non significant difference from baseline. Serum osmolality increased, but did not differ significantly from G users at any visit. During peritonitis (P), daytime dwell UF decreased significantly compared to non peritonitis (NP) episodes in G patients (p < 0.0 01), but remained stable in I patients. Total 24-hour UF also decreased in G patients (p < 0.001), but not in I patients. In these I patients, serum disaccharides increased from 0.05 +/- 0.01 mg/mL to 1.26 +/- 0.2 mg/mL during follow-up. During peritonitis, serum disaccharides concentration did not increase further (1.47 +/- 0.2 mg/mL, p= 0.56). Thirty P episodes occurred during follow-up: 16 in G patients and 14 in I patients (1 per 17.6 months and 1 per 21.9 months, respectively.) After one year, absolute number and percentage of effluent peritoneal macrophages (PM phi s) were significantly higher in I patients than in G patients. The difference in percentage persisted after two years. The phagocytic capacity of PM phi s decreased over time, resulting in a borderline significant difference for coagulase-negative staphylococci phagocytosis (p=0.005) and a significant difference for E. coli phagocytosis (p <0.05) in favor of I patients. PM phi oxidative metabolism, PM phi cytokine production, and effluent opsonic capacity remained stable over time with no difference between the groups. Mass transfer area coefficients (MTACs) and clearances were stable and appeared unaffected by G or I treatment. Effluent cancer antigen 125 (CA125) was stable in G users and tended to decrease in I users. Effluent interleukin-8 (IL-8), carboxy-terminal propeptide of type I procollagen (PICP ), and amino-terminal propeptide of type III procollagen (PIIINP) did not change over time and did not differ between the groups. CONCLUSION: The use of I for the long daytime dwell in CCPD led to an increase in total UF of at least 261 mL per day, which was maintained over at least 24 months. During I treatment, serum I metabolites increased significantly and serum sodium concentrations decreased initially. As a result, serum osmolality increased slightly. Clinical adverse effects did not accompany these findings. The UF gain in the I patients was even higher during P, without a

Peritoneal kinetics and mesothelial markers in CCPD using icodextrin for daytime dwell for two years.

OBJECTIVE: To evaluate the safety, efficacy, and biocompatibility of icodextrin (Ico), continuous cycling peritoneal dialysis (CCPD) patients were treated for 2 years with either Ico- or glucose (Glu)-containing dialysis fluid for their daytime dwell (14 - 15 hours). Prior to entry into the study, all patients used standard Glu solutions (Dianeal, Baxter BV, Utrecht,The Netherlands). DESIGN: Open, randomized, prospective two-center study. SETTING: University hospital and teaching hospital. PATIENTS: Both established patients and patients new to CCPD were included. A life expectancy of more than 2 years, a stable clinical condition, and written informed consent were necessary before entry. Patients aged under 18 years or with peritonitis in the previous month, and women of childbearing potential unless taking adequate contraceptive precautions, were excluded. Thirty-eight patients entered the study (19 Glu, 19 Ico). MAIN OUTCOME MEASURES: Daytime dwell peritoneal effluents were collected every 3 months in combination with other study variables (clinical data, laboratory measurements, dialysis-related data, and urine collection). Peritoneal transport studies were carried out every 6 months. RESULTS: In Glu- and Ico-treated patients, peritoneal transport of low molecular weight solutes and protein clearances neither changed during follow-up nor differed between the two groups. Peritoneal membrane markers (CA125, interleukin-8, carboxyterminal propeptide of type I procollagen, and aminoterminal propeptide of type III procollagen) measured in effluents did not differ between the groups and did not change over time. All these markers showed a dialysate/plasma ratio of more than 1, suggesting local production. Residual renal function remained stable during follow-up and adverse clinical effects were not observed. CONCLUSIONS: Peritoneal membrane transport kinetics and markers remained stable in both groups over a 2-year follow-up period. Membrane markers were higher in effluents than in serum, suggesting local production. No clinical side effects were demonstrated. Icodextrin was a well-tolerated effective treatment.

Icodextrin use in CCPD patients during peritonitis: ultrafiltration and serum disaccharide concentrations.

BACKGROUND AND METHODS: In a randomized study on the biocompatibility of icodextrin (I) versus glucose (G) in CCPD we used icodextrin or glucose for the long daytime dwell. During the night-time dwells glucose was used in all patients. In case of peritonitis icodextrin was continued. In all patients ultrafiltration (UF) was recorded and serum icodextrin metabolites were determined every 3 months and during peritonitis in I-users when available. RESULTS: Thirty-eight patients ( 19 G, 19 I) entered the study and suffered 30 peritonitis episodes (16 G, 14 I). During peritonitis (P), daytime dwell UF decreased significantly in G (P=0.001), but remained stable in I patients compared to non-peritonitis (NP) episodes. Total 24-h UF decreased in G (P=0.001) and in I patients (P=0.04), as the result of a decreased daytime UF and night-time UF, respectively. There was no difference in the used glucose concentrations during the P versus NP episodes. In five I-patients serum disaccharides increased from 0.05+/-0.01 to 1.26+/-0.23mg/ml during follow up. During peritonitis serum disaccharide concentrations did not increase further (1.47+/-0.24 mg/ml, P= 0.56). In I patients total carbohydrate minus glucose rose to 5.72 +/- 1.2 mg/ml during follow up, and to 6.63 +/- 1.04 mg/ml during peritonitis (P=0.7). These concentrations are comparable to CAPD patients despite the longer dwelltime in CCPD (8-10 versus 14-16 h, respectively). Adverse reactions attributable to icodextrin were not encountered. CONCLUSIONS: In contrast to glucose, icodextrin preserved the daytime dwell ultrafiltration during peritonitis. Serum icodextrin metabolites increased during icodextrin use, but remained stable during peritonitis. Adverse effects were not observed.

Use of whole-body plethysmography to compare bronchodilator inhaler efficacy.

Whole-body plethysmography is not included in guidelines from regulatory authorities for the development of treatments or delivery devices for lung disease, despite its potential advantages compared to spirometry. Two separate studies were undertaken to assess the use of specific airway conductance (sGaw) as a pharmacodynamic endpoint for the comparison of two bronchodilator delivery systems (a novel dry powder inhaler and a standard metered dose inhaler). The first pilot study involved delivery of a single dose of salbutamol (200 micrograms) to 12 healthy volunteers and determination of sGaw up to 120 min after treatment. The second study involved delivery of cumulative doses of salbutamol (100, 200 and 400 micrograms) to 19 healthy volunteers with demonstrated reversibility of sGaw to the bronchodilator and measurement of sGaw up to 240 min after treatment. In both studies, increases in sGaw after treatment were significant compared to placebo and larger than the recorded increases in FEV1. Increases in sGaw were similar for both delivery devices and support the therapeutic equivalence of the two products. Power calculations indicated that the second study had appropriate statistical power to discriminate between treatments. It is concluded that the assessment of sGaw in healthy volunteers may be a useful and sensitive pharmacodynamic endpoint for use in the development of bronchodilators and their delivery devices.

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler.

AIMS: The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI. METHODS: A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30 min following inhalation of 2 x 100 micrograms salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24 h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body. RESULTS: The mean (s.d.) 30 min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9) micrograms, respectively (P < 0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24 h period after inhalation was 187.9 (77.6) and 137.6 (40.0) micrograms (P < 0.05). CONCLUSIONS: The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.

Serum disaccharides and osmolality in CCPD patients using icodextrin or glucose as daytime dwell.

OBJECTIVE: To evaluate the safety, efficacy, and biocompatibility of icodextrin- and glucose-containing dialysis fluid during continuous cycling peritoneal dialysis (CCPD), patients were treated for 2 years with either icodextrin- or glucose-containing dialysis fluid for their daytime dwell (14-15 hours). Prior to entry into the study, all patients used a standard glucose solution (Dianeal 1.36%, 2.27%, or 3.86%, Baxter, Utrecht, The Netherlands). DESIGN: Open, randomized, prospective, two-center study. SETTING: University hospital and teaching hospital. PATIENTS: Both established and patients new to CCPD were included. A life expectancy of more than 2 years, a stable clinical condition, and written informed consent were necessary before entry. Patients aged under 18, those with peritonitis in the previous month, and women of childbearing potential, unless taking adequate contraceptive precautions, were excluded. Thirty-eight patients entered the study, and 25 (13 glucose, 12 icodextrin) had a follow-up period of 12 months or longer in December 1996. MAIN OUTCOME MEASURES: Serum icodextrin metabolites: one to five glucose units (G1-G5), a high molecular weight fraction (G > 10), and total carbohydrate level, as well as a biochemical profile were determined every 3 months in combination with all other study variables. RESULTS: In icodextrin-treated patients, serum disaccharide (maltose) concentrations increased from 0.05 +/- 0.01 (mean +/- SEM) at baseline, to an average concentration in the follow-up visits of 1.14 +/- 0.13 mg/mL (p < 0.001). All icodextrin metabolites increased significantly from baseline, as illustrated by the serum total carbohydrate minus glucose levels: from 0.42 +/- 0.05 mg/mL to an average concentration in the follow-up visits of 5.04 +/- 0.49 mg/mL (p < 0.001). At the same time, serum sodium levels decreased from 138.1 +/- 0.7 mmol/L to an average concentration in the follow-up visits of 135.4 +/- 0.8 mmol/L (p < 0.05). However, after 12 months the serum sodium concentration increased nonsignificantly (NS) from baseline to 136.6 +/- 0.9 mmol/L, after an initial decrease. Serum osmolality increased significantly from baseline in icodextrin users at 9 and 12 months, but did not differ significantly from glucose users in any visit. In icodextrin-treated patients, the calculated serum osmolal gap increased significantly from 4.1 +/- 1.4 mOsm/kg to an average of 11.8 +/- 1.7 mOsm/kg (p < 0.01). The sum of the serum icodextrin metabolites in millimoles/liter equaled the increase in osmolal gap. Body weight increased in icodextrin users (71.9 +/- 2.8 kg to 77.8 +/- 3.0 kg; NS). Clinical adverse effects did not accompany these findings. Residual renal function remained stable during follow-up. CONCLUSIONS: The serum icodextrin metabolite levels in the present study increased markedly and were the same as those found previously in continuous ambulatory peritoneal dialysis patients treated with icodextrin, despite the longer dwell time for CCPD patients (14-16 hr versus 8-12 hr). The initial decrease in serum sodium concentration was followed by an increase to a concentration not different from baseline at 12 months. The pathophysiology of this finding is speculated. Calculated osmolal gap in icodextrin patients increased significantly (p < 0.01) at every follow-up visit, and could be explained by the serum icodextrin metabolite increase. We encountered no clinical side effects of the observed levels of icodextrin metabolites.

Peritonitis occurrence in a multicenter study of icodextrin and glucose in CAPD. MIDAS Study Group. Multicenter Investigation of Icodextrin in Ambulatory Dialysis.

OBJECTIVE: To compare peritonitis occurrence and outcome in a large U.K. study Multicentre Investigation of Icodextrin in Ambulatory Dialysis (MIDAS). DESIGN: Prospective, randomized, controlled 6-month comparison of icodextrin with glucose for the long dwell in continuous ambulatory peritoneal dialysis (CAPD) patients. SETTING: Eleven CAPD units in U.K. teaching hospital. PATIENTS: A total of 209 patients established on CAPD for at least 3 months (103 control, 106 icodextrin). Twenty-three control (C) and 22 icodextrin (I) patients experienced peritonitis during the study. INTERVENTION: Patients who had peritonitis remained on treatment (unless CAPD was withdrawn, temporarily or permanently). MAIN OUTCOME MEASURES: The main outcome measures were the rate of peritonitis and duration of CAPD treatment prestudy; the rate of peritonitis episodes and their outcome during study; the effect of peritonitis on laboratory variables, serum icodextrin metabolites, and ultrafiltration efficacy. RESULTS: Prestudy: Nine (39%) of C but 14 (64%) of I patients had suffered previous peritonitis episode(s), with overall rates of 0.58 and 0.78 episodes per patient-year, respectively. DURING STUDY: There were 31 C episodes and 35 I episodes, with overall rates of 0.76 and 0.93 per patient-year, respectively. The increase in the C and I groups was 31% and 19%, respectively. Serum osmolality and sodium levels were unaffected by peritonitis, and there was no increase in serum icodextrin metabolites during peritonitis. Overnight ultrafiltration volume during peritonitis (mean +/- SD) declined slightly from 218 +/- 354 mL to 185 +/- 299 mL (NS) in the control group, but increased in the icodextrin group from 570 +/- 146 mL to 723 +/- 218 mL (p < 0.01). CONCLUSIONS: Using icodextrin for the long dwell in CAPD does not increase the rate of peritonitis, nor does it alter the outcome of peritonitis. Peritonitis does not affect uptake of icodextrin from the peritoneum.

Intranasal budesonide once daily in seasonal allergic rhinitis.

A double-blind, parallel-group, multi-centre study was carried out in 248 patients with symptomatic seasonal allergic rhinitis to assess the effectiveness and tolerability of intranasal aqueous budesonide given as a single daily dose each morning of 400 micrograms compared with the conventional dosage regimen of 200 micrograms twice daily. After a 1-week run-in period during which only oral terfenadine was allowed for intolerable symptom relief, symptomatic patients were allocated at random to receive budesonide in one or other dosage regimen for 3 weeks. The results of assessments made by the physician at clinic visits and by patients recording daily data on diary record cards showed that specific nasal symptom incidence and severity were significantly (p less than 0.001) reduced in both treatment groups. The proportions of patients symptom-free at 3 weeks were 40% in the 400 micrograms once daily and 45% in the 200 micrograms twice daily group; in addition, mean nasal symptom scores from the daily diary cards were significantly (p less than 0.001) reduced in both groups, with a reduction in total symptom scores of 53% and 60%, respectively. The differences between the groups were not statistically significant. Total symptom scores were significantly (p less than 0.01) reduced in both dosage groups at all levels of pollen exposure. Patients rated treatment overall as being highly effective, mean scores being very similar in both groups, and tolerability was similar and good whether budesonide was given as a 400 micrograms once daily dose or as 200 micrograms twice daily. Assuming equal symptom control, 74% of patients stated they would prefer once daily to twice daily treatment.

Omeprazole provides quicker symptom relief and duodenal ulcer healing than ranitidine.

In a double-blind, parallel-group clinical trial in 248 patients with symptomatic duodenal ulcers [97% greater than 5 mm diameter], 126 were randomized to receive omeprazole 20 mg once daily in the morning and 122 were randomized to receive ranitidine 300 mg once daily at night for 2 wk and if the ulcers were unhealed for a total of 4 wk. When ulcer healing was assessed on an intention-to-treat basis, 79% of those receiving omeprazole had healed ulcers after 2 wk compared with 62% of those receiving ranitidine (p less than 0.005; therapeutic gain for omeprazole, 18%; 95% confidence intervals, +6% to +29%). At 4 wk the figures were 91% (omeprazole) and 80% (ranitidine) (p less than 0.05). After 2 wk, 77% of omeprazole-treated and 59% of ranitidine-treated patients were free of ulcer pain (p = 0.005). Assessed by diary cards (successfully completed by 92% of patients), daytime pain resolved more quickly in omeprazole-treated patients than in those receiving ranitidine (p less than 0.01). Omeprazole-treated patients took fewer antacids (p less than 0.05) over the first 2 wk. Omeprazole, 20 mg each morning, provides more rapid relief of the symptoms of duodenal ulcer and heals a greater proportion of duodenal ulcers within 2 and 4 wk than ranitidine, 300 mg each night.

Treatment of peptic ulcer in general practice and in hospital: a comparison of omeprazole and cimetidine.

The aim of this study was to compare duodenal ulcer healing and symptom relief after two and four weeks treatment with omeprazole or cimetidine in groups of patients treated in general practice and as hospital out-patients. It was a randomised, double-blind, parallel group study with stratification for trial centre (hospital or GP). Endoscopy was performed at entry, after two weeks and, if unhealed at two weeks, after four weeks. All endoscopies were carried out in hospitals. In all, 189 patients were randomised (98 omeprazole, 91 cimetidine), 79 (42 per cent) of which by GPs, to either omeprazole 20 mg om (n = 41) or cimetidine 800 mg nocte (n = 38) for two to four weeks. After two weeks, ulcer healing occurred in 56 per cent (omeprazole) and 29 per cent (cimetidine) (p less than 0.05) of patients treated by GPs, and 67 per cent (omeprazole) and 36 per cent (cimetidine) (p less than 0.005) of those treated as hospital out-patients. Similar differences in healing rates were seen after four weeks. Omeprazole produces faster duodenal ulcer healing than cimetidine whether patients are treated as hospital out-patients or by GPs.

Randomised, double blind comparison of omeprazole and cimetidine in the treatment of symptomatic gastric ulcer.

In a randomised, double blind, parallel group study in patients with symptomatic gastric ulcer (94% greater than or equal to 5 mm diameter), 102 received omeprazole 20 mg om and 87 cimetidine 400 mg bd. After four weeks 73% and 58% (p less than 0.05) respectively had healed (eight weeks: 84% and 75%, ns). After four weeks, a greater proportion (81%) of omeprazole treated patients was symptom free than of those receiving cimetidine (60%; p less than 0.01). Over the first two weeks, patients receiving omeprazole had less day pain, less night pain and took fewer antacids than those receiving cimetidine (all p less than 0.05). The difference between omeprazole and cimetidine was not appreciably affected by age, smoking, size of the ulcer and trial centre. Tolerability was similar in the two treatment groups. In the treatment of symptomatic gastric ulcer, omeprazole relieves the symptoms more quickly than cimetidine and heals a greater proportion of ulcers within four weeks.

Symptom relief and duodenal ulcer healing with omeprazole or cimetidine. Opus (Omeprazole Peptic Ulcer Study) Research Group.

In a double-blind parallel-group study, 98 patients with symptomatic duodenal ulcer received omeprazole 20 mg o.m. and 91 cimetidine 800 mg nocte for 2 or, if then not healed, 4 weeks. After 2 weeks the healing rates on an intention-to-treat basis were: for omeprazole 62% and for cimetidine 33% (P less than 0.001), and at 4 weeks 85% and 61%, respectively (P less than 0.001). The proportions symptom-free at 2 weeks were 83% of the omeprazole and 63% of the cimetidine-group (P less than 0.01) and at 4 weeks 84% and 72% (P = 0.01). Patients receiving omeprazole took fewer antacid tablets than those receiving cimetidine. Patient tolerance of both drugs was similar and good. In the treatment of duodenal ulcer, omeprazole 20 mg o.m. gives faster symptom relief than cimetidine 800 mg nocte, as well as healing a greater proportion of ulcers within 2 and 4 weeks.

A comparison of felodipine and propranolol as additions to hydrochlorothiazide in the treatment of hypertension.

Eighty one patients with uncomplicated hypertension who required additional antihypertensive medication (diastolic Phase V [dBP] greater than or equal to 95 mm Hg) after 4 weeks treatment with hydrochlorothiazide (HCTZ) 25 mg o.m. were randomized to receive felodipine 5 mg b.i.d. (n = 40) or propranolol (n = 41) 80 mg b.i.d. in addition to HCTZ 25 mg o.m. If the dBP measured about 12 h post-dose was not less than or equal to 90 mm Hg after 4 weeks, the dose of felodipine or propranolol was doubled. The double blind trial period was 8 weeks for all patients. Over the 8 week period, felodipine reduced the seated dBP from 100 to 83 mm Hg and propranolol from 101 to 86 mm Hg. The attained seated dBPs were significantly different in the two groups. About one third of patients in each group received the high dose of second-line therapy. After 8 weeks 91% of patients receiving HCTZ+felodipine and 84% receiving HCTZ+propranolol had a dBP less than or equal to 90 mm Hg. Both regimens were well-tolerated with an equal incidence but different pattern of adverse events (felodipine: flushing, headache and peripheral oedema; propranolol: dyspepsia, fatigue and vasospasm). In this 8-week study, felodipine and propranolol were safe and effective second-line antihypertensive drugs when added to hydrochlorothiazide. At the doses selected, felodipine was at least as effective as propranolol.

Photoaffinity probes for opiate receptors: synthesis and properties of a nitro-azido-derivative of 14-beta-aminomorphinone.

The potential photoaffinity ligand 14-beta-(o-nitro, p-azido)-cinnamoyl-amino-N-cyclopropylmethylnormorphinone (NAM) and its derivative NOM, lacking the p-azido function, were synthesised and their opiate receptor activity determined in isolated tissue preparations. The ligands showed slow receptor kinetics. NAM was a pure competitive antagonist of met5-enkephalin responses in MVD while its antagonism of normorphine responses in GPI appeared non-competitive and non-reversible. In radioligand binding assays NOM completely and irreversibly blocked specific binding of 3H-DHM. Partial blockade of 3H-DADL specific binding was reversible by washing. No binding of NOM to kappa sites was observed. The slow receptor kinetics of NAM preclude its use as a photoaffinity ligand but suggest that a chemically more stable derivative may have a role as a pseudocovalent blocker of mu-receptors.