Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis

OBJECTIVES: Esomeprazole, the S isomer of omeprazole, has been shown to have higher healing rates of erosive esophagitis than omeprazole. This study compared esomeprazole with lansoprazole for the healing of erosive esophagitis and resolution of heartburn. METHODS: This United States multicenter, randomized, double blind, parallel group trial was performed in 5241 adult patients (intent-to-treat population) with endoscopically documented erosive esophagitis, which was graded by severity at baseline (Los Angeles classification). Patients received 40 mg of esomeprazole (n = 2624) or 30 mg of lansoprazole (n = 2617) once daily before breakfast for up to 8 wk. The primary efficacy endpoint was healing of erosive esophagitis at week 8. Secondary assessments included proportion of patients healed at week 4, resolution of investigator-recorded heartburn, time to first and time to sustained resolution of patient diary-recorded heartburn, and proportion of heartburn-free days and nights. RESULTS: Esomeprazole (40 mg) demonstrated significantly higher healing rates (92.6%, 95% CI = 91.5-93.6%) than lansoprazole (30 mg) (88.8%, 95% CI = 87.5-90.0%) at week 8 (p = 0.0001, life-table estimates, intent-to-treat analysis). A significant difference in healing rates favoring esomeprazole was also observed at week 4. The difference in healing rates between esomeprazole and lansoprazole increased as baseline severity of erosive esophagitis increased. Sustained resolution of heartburn occurred faster and in more patients treated with esomeprazole. Sustained resolution of nocturnal heartburn also occurred faster with esomeprazole. Both treatments were well tolerated. CONCLUSIONS: Esomeprazole (40 mg) is more effective than lansoprazole (30 mg) in healing erosive esophagitis and resolving heartburn. Healing rates are consistently high with esomeprazole, irrespective of baseline disease severity.     

Esomeprazole 40 mg administered intravenously has similar safety and efficacy profiles to the oral formulation in patients with erosive esophagitis

BACKGROUND/AIMS: An intravenous formulation of esomeprazole has been developed for use in patients where oral administration is not appropriate. This study evaluated safety after 1 and 4 weeks, and efficacy after 4 weeks' esomeprazole 40 mg once daily treatment, administered via an intravenous injection, intravenous infusion or orally, in patients with erosive esophagitis. METHODS: In this double-blind, multi-centre study, patients with endoscopically confirmed erosive esophagitis (Los Angeles grade A-D) were randomized to receive 1 week's treatment of esomeprazole 40 mg once daily, via a 3-min injection, a 30-min infusion or orally, followed by 3 weeks of open treatment with oral esomeprazole 40 mg once daily. Safety variables were evaluated following 1 and 4 weeks' esomeprazole treatment. Healing rates at 4 weeks were estimated. RESULTS: Intravenous and oral esomeprazole were equally well tolerated during the first week, and after 4 weeks' treatment. The 3 treatment groups showed similar levels of healing following 4 weeks' treatment with esomeprazole (injection + oral: 79.7%; infusion + oral: 80.2%; oral alone: 82.6%). CONCLUSIONS: Esomeprazole 40 mg administered via an intravenous injection, intravenous infusion or orally administered for 1 week, followed by 3 weeks of oral dosing, is well tolerated and provides effective healing of erosive esophagitis.     

Low-dose intravenous ondansetron (8 mg) plus dexamethasone: an effective regimen for the control of carboplatin-induced emesis

Twenty-nine patients with gynecologic malignancies were treated with a fixed low dose of intravenous ondansetron (8 mg) plus dexamethasone (20 mg) in an effort to develop an effective and less expensive antiemetic regimen for the control of carboplatin-induced emesis. Twenty-six (90%) of the women participating in this trial experienced complete control of both acute nausea and vomiting (developing within the first 24 h after chemotherapy administration), while 27 (93%) patients exhibited either complete or major control (2 episodes of vomiting, 5 episodes of retching, minimal interference with eating) of emesis. On the basis of our experience in this trial, we conclude that the combination of low dose (8 mg) intravenous ondansetron plus dexamethasone is a well-tolerated and highly cost-effective antiemetic strategy for individuals receiving carboplatin-based chemotherapy.     

Esomeprazole once daily for 6 months is effective therapy for maintaining healed erosive esophagitis and for controlling gastroesophageal reflux disease symptoms: a randomized, double-blind, placebo-controlled study of efficacy and safety

OBJECTIVE: Esomeprazole, the S-isomer of omeprazole, achieves a significantly greater healing rate and symptom resolution of erosive esophagitis than that achieved by omeprazole. The objective of this study is to assess the efficacy of the new proton pump inhibitor esomeprazole in preventing relapse over a prolonged period in patients with healed erosive esophagitis. METHODS: A total of 318 gastroesophageal reflux patients whose erosive esophagitis was healed in a comparative study of esomeprazole 40 mg, 20 mg, or omeprazole 20 mg, were randomized to maintenance therapy with once daily esomeprazole 40 mg, 20 mg, or 10 mg, or placebo in a U.S., double-blind multicenter trial. RESULTS: After 6 months, healing was maintained (cumulative life table rates) in 93.6% (95% CI 87.4-99.7) of patients treated with esomeprazole 40 mg, 93.2% (95% CI 87.4-99.0) treated with esomeprazole 20 mg, and 57.1% (95% CI 45.2-69) treated with esomeprazole 10 mg; p < 0.001 vs placebo (29.1%; 95% CI 17.7-40.3). Of patients relapsing, mean time to first recurrence of esophagitis increased with dose, from 34 days (placebo) to 78 days (10 mg), 115 days (20 mg), and 163 days (40 mg). Patients treated with esomeprazole had less frequent and less severe heartburn than those treated with placebo. At month 6, more than 70% of patients being treated with esomeprazole remained symptom-free. CONCLUSIONS: Esomeprazole is effective and well tolerated in the maintenance of a healing erosive esophagitis. Esomeprazole 40 mg and 20 mg maintain healing in over 90% of patients while providing effective control of heartburn symptoms.     

A Multicenter, Randomized, Double-Blind, 8-Week Comparative Trial of Low-Dose Esomeprazole (20 mg) and Standard-Dose Omeprazole (20 mg) in Patients with Erosive Esophagitis

The objective of this trial was to compare the efficacy of esomeprazole, 20 mg, with that of omeprazole, 20 mg, in patients with erosive esophagitis (EE). In this multicenter, double-blind, parallel-group trial, 1176 patients with EE confirmed by endoscopy (Helicobacter pylori-negative by serology) were randomized to once-daily treatment with 20 mg esomeprazole or 20 mg omeprazole for 8 weeks. The primary outcome was the proportion of patients with healed EE through week 8. Secondary outcomes included diary and investigator assessments of heartburn symptoms. Cumulative life-table healing rates at week 8 were similarly high for 20 mg esomeprazole (90.6%; 95% confidence interval, 88.1%–93%) and 20 mg omeprazole (88.3%; 95% confidence interval, 85.5%–91.0%). The two treatments were comparable for other secondary measures and had similar tolerability profiles.     

Double blind comparison of omeprazole (40 mg od) versus cimetidine (400 mg qd) in the treatment of symptomatic erosive reflux oesophagitis, assessed endoscopically, histologically and by 24 h pH monitoring.

This double blind, double dummy study compares the rate of healing of erosive reflux oesophagitis, assessed endoscopically, with four and eight weeks treatment using omeprazole or cimetidine, and the effect of four and eight weeks treatment of reflux oesophagitis with omeprazole or cimetidine on reflux symptoms, microscopic healing, and in a subgroup of patients, oesophageal pH measurements. Omeprazole 40 mg once daily achieves (i) greater and more rapid symptom relief, (ii) more rapid and sustained endoscopic and histological healing, and (iii) greater reduction of oesophageal acid exposure than cimetidine 400 mg four times daily.     

Activity and tolerance of a new anti-arrhythmia drug, Cibenzoline (Cipralan), administered orally)

The authors studied the effect of a new anti-arrhythmic agent, the Cibenzoline in 9 patients suffering from numerous ventricular extrasystoles (on average 8 extrasystoles/minute). Efficacy was considered to be excellent in 3 cases (complete disappearance of extrasystoles) good in 3 cases (more than 90% decrease in the number of extrasystoles) and poor in 3 cases (these concerned two patients also resistant to all other anti-arrhythmic agents and one patient with an extreme variability of his arrhythmia from one day to another day). Clinical and biological tolerance was excellent. Electrocardiographic parameters in general remained stable, apart from in one case of severe cardiomegaly. The general rules usually accepted for adequate evaluation of the efficacy of an anti-arrhythmic agent are reviewed and discussed.     

Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies

OBJECTIVES: Two studies compared the effects of intravenous (i.v.) and oral esomeprazole (40 mg and 20 mg) on gastric acid suppression and pharmacokinetics after both single (day 1) and repeated (day 5) dosing. METHODS: Two randomized, two-way, cross-over, comparative studies of similar design were performed in healthy male and female volunteers. In both studies, subjects received esomeprazole as a 30-min i.v. infusion or orally once-daily for 5 days, separated by a wash-out period of at least 13 days. In one study, which was double-blind (double dummy), subjects received 40 mg esomeprazole. In the other open study, subjects were given 20 mg esomeprazole. RESULTS: In total, 40 and 24 subjects were randomized for treatment with 40 mg and 20 mg esomeprazole, respectively. No significant differences were found between i.v or oral administration of esomeprazole with respect to the amount of time with mean intragastric pH>4 throughout day 1 or day 5 of treatment in the 40 mg study (day 1, 10.1 h and 8.8 h versus day 5, 15.9 h and 15.3 h, respectively) and the 20 mg study (day 1, 7.3 h and 6.6 h versus day 5, 11.9 h and 12.3 h, respectively). The area under the plasma concentration-time curve values were higher following i.v. relative to oral administration on day 1 of dosing, with less pronounced differences after repeated (day 5) dosing. Both administration routes were similarly well tolerated. CONCLUSIONS: Esomeprazole, 40 mg and 20 mg i.v., provides similar levels of intragastric acid control on both day 1 and day 5 of treatment compared with oral administration.     

Angiotensin II receptor antagonist telmisartan in isolated systolic hypertension (ARAMIS) study: efficacy and safety of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo

OBJECTIVE: To identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide (HCTZ) 12.5 mg, and are well tolerated, in lowering systolic blood pressure (SBP) in patients with isolated systolic hypertension (ISH). PATIENTS AND METHODS: A 2-4-week single-blind placebo run-in was followed by randomization of 1039 patients (age 36-84 years) with ISH [seated SBP 150-179 mmHg and seated diastolic blood pressure (DBP) < 90 mmHg] to once-daily double-blind treatment with telmisartan 20, 40 or 80 mg, HCTZ 12.5 mg, or placebo. The change in seated trough SBP after 6 weeks compared with baseline was the primary end point. Secondary end points were the percentage achieving the target fall in SBP and the change from baseline in seated trough DBP. Incidence and severity of adverse events and physical examination and laboratory parameters were monitored for the safety evaluation. RESULTS: Baseline demographics in telmisartan 20 mg (n = 206), 40 mg (n = 210), 80 mg (n = 207), HCTZ 12.5 mg (n = 205) and placebo (n = 211) treatment groups were comparable: (mean +/- SD) age, 63.0 +/- 10.9 years; SBP, 162.9 +/- 8.1 mmHg; and DBP 83.4 +/- 5.0 mmHg. No previous antihypertensive therapy had been received by 66% of the patients. Mean reductions in seated trough SBP (adjusted for baseline and country) were: telmisartan 20 mg, 15.6 mmHg (n = 204); 40 mg, 17.9 mmHg (n = 209); and 80 mg, 16.9 mmHg (n = 205), compared with placebo, 11.4 mmHg (n = 208), and HCTZ 12.5 mg, 15.7 mmHg (n = 204). The target fall in seated trough SBP (< or =140 mmHg or reduction by > or =20 mmHg) was achieved in 46.6% (telmisartan 20 mg), 51.7% (telmisartan 40 mg), 53.9% (telmisartan 80 mg), 27.4% (placebo) and 42.7% (HCTZ 12.5 mg); the response rate was significantly higher for telmisartan 80 mg than for HCTZ 12.5 mg (P = 0.03). All-causality adverse events occurred in 19.9, 17.6 and 20.3% receiving telmisartan 20, 40 and 80 mg, respectively; 20.9% receiving placebo and 22.0% receiving HCTZ 12.5 mg. No drug-related serious adverse events occurred. CONCLUSIONS: All doses of telmisartan (20-80 mg) were significantly superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ 12.5 mg. Tolerability of telmisartan was similar to that of placebo.     

Effects of an orally administered prostaglandin analogue (16, 16-dimethyl prostaglandin E2) on human gastric secretion.

The secretory response to 16, 16-dimethyl prostaglandin E2 (DMPG) administered orally in 4 different dosages and to placebo was evaluated in healthy volunteers over a 2-hr period. During stimulation of gastric secretion by histamine, DMPG at the highest dosage (1.5 mug per kg) reduced volume by 47% and acid output by 79%. Pepsin concentration was not affected. At the same dose, DMPG inhibited basal secretion by 54% and 99% for volume and acid output, respectively. There were no side effects secondary to DMPG administration, which indicates that this compound may be useful in treating peptic ulcer disease.     

Quality of life and angina pectoris. Comparison of the effects of 2 nitrate derivatives administered discontinuously: transdermal 10 mg nitroglycerine patch (12 hours) and long-acting oral 40 mg isosorbide-5-mononitrate (once a day)

A comparative, randomised, 12-week (two periods of six weeks) cross-over study including 150 patients (mean age: 63.4 years) suffering from stable but symptomatic (a minimum of three attacks per week) angina pectoris was performed in order to compare the effect on quality of life of two discontinuous nitrate treatments: transdermal 10 mg nitroglycerine patch (12 hours) and long-acting oral 40 mg isosorbide-5-mononitrate (once a day). The efficacy and safety were also compared. The two treatments equally and significantly improved patients' quality of life. The number of attacks and sublingual nitrate consumption significantly decreased under treatment. Attack severity was lower under nitroglycerine than isosorbide-5-mononitrate treatment. Finally, even though nitroglycerine more frequently induced headache than did isosorbide-5-mononitrate (13 cases versus 8), patients, and in particular those having received nitroglycerine treatment in the second period of the study, preferred the transdermal nitroglycerine treatment. In conclusion, results did not show any relevant difference in terms of efficacy or tolerability between the two treatments. Nevertheless, the facility of use and the feeling of protection were better under transdermal nitroglycerine patch than oral isosorbide-5-mononitrate treatment.     

Efficacy and Safety of Alirocumab as Add‐on Therapy in High–Cardiovascular‐Risk Patients With Hypercholesterolemia Not Adequately Controlled With Atorvastatin (20 or 40 mg) or Rosuvastatin (10 or 20 mg): Design and Rationale of the ODYSSEY OPTIONS Studies

The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double‐blind, active‐comparator, 24‐week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add‐on therapy in ～ 650 high‐cardiovascular (CV)‐risk patients whose low‐density lipoprotein cholesterol (LDL‐C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV‐risk category, high and very high CV risk, respectively, with atorvastatin (20–40 mg/d) or rosuvastatin (10–20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1‐mL injection by prefilled pen every 2 weeks (Q2W) as add‐on therapy to atorvastatin (20–40 mg) or rosuvastatin (10–20 mg); or to receive ezetimibe 10 mg/d as add‐on therapy to statin; or to receive statin up‐titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL‐C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL‐C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL‐C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision‐making when patients with CV risk require additional lipid‐lowering therapy to further reduce LDL‐C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL‐C reduction required to achieve the desired LDL‐C level.     

Comparison of blood glucose and insulin concentrations in man after intravenous injection of 1.0, 0.1 and 0.01 mg of glucagon (author's transl)]

The effect of various doses of glucagon on hyperglycemic action and insulin secretion was studied in 12 healthy volunteers to determine whether 1.0 mg of glucagon, the usual dose, is indeed necessary to obtain an adequate hyperglycemic response. For this purpose 2.0, 1.0, 0.5, 0.1 and 0.01 mg of glucagon (Novo) were used respectively to confirm the existence of a dose response relationship. Of these doses, three different doses were administered to one subject within a week after overnight fasting. Maximum increment of blood glucose was not statistically significant between 1.0 (32.5+/-4.4mg/dl) and 0.01 mg (29.5+/-2.7 mg/dl), averaging about 30 mg/dl. The peak time of blood glucose concentration was 30 min. with 1.0 mg, and 10 min. with 0.01 mg. On the contrary, insulin secretion after glucagon injection decerased as the dose decreased. Maximum blood insulin (IRI) concentration was 69.7+/-17.2muu/ml with 1.0 mg, and 25.3+/-11.3 muu/ml with 0.0l mg (p less than 0.05). The peak time of insulin concentration was 2 min. with 1.0 mg, and 10 min. with 0.01 mg. From these data it is concluded that the dose response relationship after intravenous glucagon injection of between 1.0 mg and 0.01 mg doses exist concerning insulin sercretion, but not concerning hyperglycemic response.     

High-dose melphalan (200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (>or=65 years) myeloma patients: comparison with younger patients treated on the same protocol

Limited information is available on the feasibility and efficacy of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients >65 years of age. In 1995-2005, 22 myeloma patients >or=65 years (median 68, eight >or=70) and 79 patients <65 years (median 57) were included in an identical treatment protocol. The first progenitor cell mobilization with cyclophosphamide plus granulocyte-colony stimulating factor (G-CSF) was successful in 95 and 96% of the patients, respectively. To date, 92 patients have received MEL (melphalan) 200 mg/m2 supported by ASCT. No early treatment-related deaths were observed among 22 elderly patients, whereas one younger patient died early. Engraftment and the need for supportive care were comparable between groups. The elderly patients tended to have more WHO grade 3-4 oral or gastrointestinal toxicity when compared to the younger patients (45 vs 23%, P=0.06). After ASCT, a complete response was observed in 44% of the elderly patients and 36% of the younger patients, respectively. No difference was observed between these age groups in progression-free survival (23 vs 21 months) or overall survival (57 vs 66 months) after ASCT. We conclude that MEL200 is a safe and efficacious treatment in selected elderly myeloma patients.