Failure of Dietary Protein and Phosphate Restriction to Retard the Rate of Progression of Chronic Renal Failure: A Prospective, Randomized, Controlled Trial

SUMMARY Ninety-five patients (63 male, 32 female), age 45±2 years(mean±SEM) with chronic renal failure of varied aetiologywere randomized to receive either a conventional low proteindiet (0.6 g/kg/day protein, 800 mg phosphate; n=33), a low phosphatediet (providing approximately 1000 mg phosphate plus an orallyadministered phosphate binder, minimum protein intake 0.8 g/kg/day;n=30) or to control (minimum protein intake 0.8 g/kg/day, nophosphate restriction; n=32). Patients were reviewed for a minimumof 6 months before randomization and were withdrawn from thestudy if plasma creatinine exceeded 900 µmol/1, plasmaphosphate was > 2.0 mmol/1 or at the onset of uraemic symptoms. Following randomization patients were studied for an averageof 19±3 months. Mean plasma creatinine rose from 398±33to 600±50 µmol/1. Dietary protein intake was estimatedat 0.69±0.02 g/kg/day in the low protein group, 1.02±0.05in the low phosphate and 1.14±0.05 in the controls, phosphateintake was 815±43, 1000± 47, and 1315±57mg/day, respectively. Urinary urea excretion and protein catabolicrates were significantly reduced (p<0.01) only in those onprotein restriction, at 213±9 mmol/24 hours and 0.71g/kg/day, respectively. Phosphate excretion was significantlylower (p<0.05) in both the low protein group (17.9±0.8mmol/24 hours) and the low phosphate group (18.6±1.0mmol/24 hours) compared to controls. Changes in body weight,muscle mass and serum transferrin, albumin and immunoglobulinswere comparable between the groups. Mean blood pressure followingrandomization was 150/89±3/1 (low protein), 148/87±3/1(low phosphate) and 146/87±3/1 (controls). Progression of renal failure was analysed by rate of fall ofcreatinine clearance (ml/min/ 1.73 m²/month), by rate of deteriorationderived from reciprocal plasma creatinine against time plots(1/mmol/year) and to assess individual patient's response totreatment by two phase linear regression (‘breakpoint’)analysis of reciprocal plasma creatinine/time plots. Progressionwas analysed only in patients seen for at least 3 months followingrandomization. The rate of fall of creatinine clearance was not significantlydifferent between the groups (ANOVA): 0.56±0.08 ml/min/1.73m2/month (low protein, n=28), 0.44±0.07 (low phosphate,n=23) and 0.69±0.11 (control, n=27). In 50 patients (18low protein, 16 low phosphate and 16 control) whose rate ofprogression could be calculated before and after randomization,there was a fall in rate of progression averaging 0.18 ml/min/1.73m2/month in those on low protein diet and those on low phosphatediet, but a rise of 0.08 in the controls. These differenceswere, however, not statistically significant. Similar resultswere obtained when the rates of deterioration were calculatedfrom plasma creatinine. Significant individual improvements(p<0.01) in rates of progression by ‘breakpoint’analysis occurred in 17 patients: six on low protein, sevenon low phosphate and in four controls. Sixty-one (72 per cent)of the patients examined by this method showed no significantchange in the rate of progression while seven patients had acceleratedprogression. There was no difference in the requirement formaintenance dialysis facilities between groups. No significant benefit of protein and phosphate restrictionwas therefore demonstrated.     

Clinical trial: maintenance intermittent therapy with rabeprazole 20 mg in patients with symptomatic gastro‐oesophageal reflux disease – a double‐blind,placebo‐controlled,randomized study

Aliment Pharmacol Ther 31 , 950–960

Summary

Background Optimal long‐term management of symptomatic gastro‐oesophageal reflux disease (sGERD) patients has not been established. Aim To determine the clinical value of maintenance intermittent treatment with rabeprazole 20 mg vs. placebo in patients with sGERD. Methods This multicentre, US study enrolled patients with sGERD (≥3‐month history of GERD symptoms and ≥4 days/week of heartburn during a 2‐week placebo run‐in) without oesophageal erosions. Patients with complete heartburn control after 4 weeks of open‐label rabeprazole 20 mg daily treatment were randomized to 6‐month, double‐blind, maintenance intermittent treatment (7‐ to 14‐day courses when heartburn recurred) with rabeprazole 20 mg or placebo. Results The primary efficacy end point, mean percentage of heartburn‐free days, was significantly greater with rabeprazole vs. placebo: 82.58% and 62.17% (ITT; P < 0.0001) [per protocol 86.74% rabeprazole vs. 74.93% placebo (P < 0.0254)]. Compared with placebo group, the rabeprazole group also experienced a significantly higher percentage of heartburn‐free daytime (84.06% vs. 63.39%; P < 0.0001) and nighttime (95.41% vs. 90.25%; P = 0.0021) periods, had significantly fewer discontinuations because of insufficient heartburn control (6.3% vs. 36.3%; P < 0.0001) and took fewer antacid tablets daily (0.58 vs. 1.16; P = 0.0021). Conclusion Intermittent use of rabeprazole may be an effective maintenance treatment strategy for patients with sGERD and warrants further investigation. This trial was registered with http://clinicaltrials.gov under the number NCT00165841.     

Evaluation of a Direct Blood Pressure Measurement Technique for Canine Toxicity Studies

Evaluation of a Direct Blood Pressure Measurement Techniquefor Canine Toxicity Studies. KUTZ, S. A., DETWEILER, D. K.,CIMPRICH, R. E., SMITH, S. G., AND DEBAECKE, P. J. (1985). Fundam.Appl. Toxicol. 5, 391–398. Repeated direct puncture ofthe central ear (intermediate auricular) artery to obtain meanarterial blood pressure in control and hypertensive dogs wasevaluated. Unilateral nephrectomy and partial constriction ofthe contralateral renal artery were performed on four dogs tocreate hypertension. Ear artery blood pressure measurementsand electrocardiograms were recorded twice pretest and aftersurgery at Weeks 1, 2, 4, 6, 8, 9, 10, and 11 on control (n= 6) and hypertensive (n = 4) dogs. Mean ear arterial bloodpressures from the hypertensive dogs were significantly increasedfrom Weeks 2 to 11. Indwelling omocervical artery catheterswere implanted in both control and hypertensive dogs at Week8. Mean omocervical artery blood pressures from hypertensivedogs were significantly increased at Weeks 8 through 11. Meanomocervical artery pressures were only significantly increasedover mean ear artery pressures at Week 8 for control dogs andat Week 10 for hypertensive dogs. Nonspecific electrocardiographicchanges in the ST–T segment and U waves occurred withgreater frequency in hypertensive dogs than in control dogs.Hypertensive dogs developed subendothelial proliferation inthe renal artery and aorta, and a proliferative vasculopathyin the heart and lungs. This ear artery technique was used successfullyin two canine toxicity studies of different ICI pharmaceuticalcompounds. The ear artery method for measuring mean arterialblood pressure is suitable for canine toxicity studies and isa reasonably accurate measurement of systemic pressure.     

Extraesophageal and atypical manifestations of GERD

Abstract   Extraesophageal manifestations of gastroesophageal reflux disease (GERD) are essentially complications of GERD that primarily involve organs that are in proximity to the esophagus. Non-cardiac chest pain (NCCP) is an atypical manifestation of GERD, because symptoms originate in essence from the esophagus. In both atypical and extraesophageal manifestation of GERD frequent heartburn is uncommon and lack of GERD symptoms is not unusual. Esophageal mucosal injury is rarely present making upper endoscopy a low-yield procedure in both conditions. While association with GERD has been commonly reported, the extent of causality remains unknown. In NCCP, the usefulness of the proton pump inhibitor (PPI) test in diagnosing GERD-related NCCP has been established. Similar value in extraesophageal manifestations of GERD has been proposed, but rarely studied. While treatment of extraesophageal manifestations of GERD remains a challenge, PPIs in at least double the standard dose, should be considered for the initial therapy. Properly designed therapeutic studies are still lacking as well as the exact role of antireflux surgery in this patient population.     

The pathophysiology of non-cardiac chest pain

Abstract:   Various underlying mechanisms have been described in patients with non-cardiac chest pain (NCCP). By far, gastroesophageal reflux disease (GERD) is the most common cause and thus requires initial attention when patients with NCCP are managed. Esophageal dysmotility can be demonstrated in 30% of the NCCP patients, but appears to play a very limited role in symptom generation. A significant number of patients with NCCP lack any evidence of GERD and have been consistently shown to have reduced perception thresholds for pain. Peripheral and/or central sensitization have been suggested to be responsible for visceral hypersensivity in NCCP patients. Further understanding of the underlying mechanisms for pain in patients with NCCP will likely improve our current therapeutic approach.     

Review article: gastro-oesophageal reflux disease and psychological comorbidity

Background  A growing number of studies have shown the impact of psychological comorbidities on gastro-oesophageal reflux disease (GERD) patients' symptom reports and healthcare-seeking behaviour.
Aim  To review the reported relationship between GERD and psychological comorbidity.
Methods  Review of the literature on GERD and psychological comorbidity.
Results  Psychological comorbidity is common among GERD patients and appears to afflict all GERD phenotypes. Sexual and physical abuse is also common in GERD patients. Stress enhances perception of oesophageal acid exposure. Treatment for GERD, especially in those who are not responsive to antireflux treatment, may require further evaluation for psychological comorbidity.
Conclusions  Psychological comorbidity is very common in GERD patients and is likely to play an important role in response, or failure of response, to proton pump inhibitor treatment.     

Pharmacokinetic comparison of orally-disintegrating metoclopramide with conventional metoclopramide tablet formulation in healthy volunteers

Background  Oral tablet formulations of metoclopramide are effective therapies for gastroparesis and gastro-oesophageal reflux disease; however, difficulty swallowing tablets or nausea/vomiting may reduce patient adherence to therapy. Because of this, a metoclopramide orally-disintegrating tablet (ODT) has been developed.
Aim  To evaluate the bioequivalence of a single administration of a 10-mg metoclopramide ODT and a conventional 10-mg oral metoclopramide tablet in healthy volunteers.
Methods  In a randomized, single-dose, crossover study, healthy volunteers received single administration of 10-mg metoclopramide ODT and 10-mg conventional metoclopramide tablet, with a 7-day interval between treatments. Serial blood samples were collected before dosing and during 24 h post-treatment.
Results  Forty-one volunteers completed both treatment arms. Metoclopramide ODT was bioequivalent to conventional tablets; 90% CIs for geometric mean treatment ratios of C _max [91.6% (90% CI, 87.7–95.8%)], AUC _last [97.3% (90% CI, 94.5–100.2%)] and AUC _inf [97.6% (90% CI, 94.5–100.8%)] were within the predefined range. Of the 44 volunteers included in the safety analysis, 9 (20%) reported AEs after ODT, compared with 13 (30%) after conventional tablets.
Conclusion  In healthy volunteers, single administration of 10-mg metoclopramide ODT was well tolerated and bioequivalent to single administration of a conventional 10-mg metoclopramide tablet.     

Clinical trial: the effects of the proton pump inhibitor dexlansoprazole MR on daytime and nighttime heartburn in patients with non-erosive reflux disease

Background  The proportion of patients who respond to proton pump inhibitor (PPI) therapy is about 20% lower in those with non-erosive reflux disease (NERD) than in those with erosive oesophagitis.
Aim  To assess efficacy and safety of dexlansoprazole MR, a PPI using Dual Delayed Release technology, in NERD patients.
Methods  In this 4-week, double-blind, placebo-controlled study, 947 NERD patients randomly received dexlansoprazole MR 30 mg, 60 mg or placebo once daily (QD). The percentages of 24-h heartburn-free days (primary) and nights without heartburn (secondary) were assessed from patients' daily diaries. Investigators also assessed symptoms. Patients completed validated quality of life and symptom severity questionnaires.
Results  Dexlansoprazole MR provided significantly greater median percentages of 24-h heartburn-free days (54.9% and 50.0% for the 30- and 60-mg doses vs. 17.5% for placebo, P  <   0.00001) and nights without heartburn (80.8% and 76.9% vs. 51.7%, P  <   0.00001 vs. placebo). Dexlansoprazole MR also reduced symptom severity. Quality of life improvements in patients receiving dexlansoprazole MR were consistent with clinical efficacy endpoints. Percentages of patients experiencing treatment-emergent adverse events were similar among groups.
Conclusions  Dexlansoprazole MR 30 and 60 mg were superior to placebo in providing 24-h heartburn-free days and nights in NERD patients. Treatment was well tolerated.