Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group.

BACKGROUND: Insulin lispro is an insulin analog that was recently developed particularly for a mealtime therapy. It has a fast absorption rate and short duration of action. The efficacy of insulin lispro in the clinical therapy of patients with non-insulin-dependent diabetes mellitus (NIDDM) has not been tested. OBJECTIVES: To compare insulin lispro and human regular insulin in the mealtime treatment of patients with NIDDM. METHODS: A 6-month, randomized, multinational (16 countries), multicenter (80 sites) clinical trial with an open-label, crossover design was performed in 722 patients with NIDDM. Insulin lispro was injected immediately before and human regular insulin 30 to 45 minutes before the meal. RESULTS: Throughout the study, the postprandial rise in serum glucose levels was significantly lower during insulin lispro than human regular insulin treatment. At end point the rise (mean +/- SEM) in serum glucose levels was 30% lower at 1 hour (2.6 +/- 0.1 mmol/L [46.8 +/- 1.8 mg/ dL] for lispro vs 3.7 +/- 0.1 mmol/L [66.6 +/- 1.8 mg/dL] for human regular insulin) and 53% lower 2 hours after the test meal (1.4 +/- 0.1 mmol/L [25.2 +/- 1.8 mg/dL] for lispro vs 3.0 +/- 0.1 mmol/L [54.0 +/- 1.8 mg/dL] for human regular insulin) with insulin lispro compared with human regular insulin therapy (P < .001 for both intervals). During insulin lispro therapy the rate of hypoglycemia overall (P = .01) and overnight (P < .001) was lower and the number of asymptomatic hypoglycemic episodes was smaller (P = .03) than during human regular insulin therapy. Associated with a similar 13% increase (P < .001) in the total daily insulin dose, the glycosylated hemoglobin level decreased (P < .001) equally in both treatment groups. Serum lipid and lipoprotein levels remained unchanged. There were no differences in the adverse events between the 2 treatment groups. CONCLUSIONS: Compared with human regular insulin therapy, mealtime therapy with insulin lispro reduced postprandial hyperglycemia and may decrease the rate of mild hypoglycemic episodes in patients with NIDDM.

Validity of a short form of the category test in relation to age, education, and gender.

Data for 289 subjects participating in an ongoing study of neuropsychological test performance were used to evaluate the relationship between age and prediction of performance on the long form of the Halstead-Reitan Category Test (CAT) from a short form developed by Calsyn, O'Leary, and Chaney (1980). The major questions were whether: (a) age, education, or gender would add to prediction of long (Y) from short form scores (X); (b) regression equations would be different for older and younger groups; (c) percent variance accounted for in long form scores by short form scores would be larger for younger as opposed to older subjects. For these relatively healthy subjects, prediction based on the short form was not enhanced in a clinically significantly manner by adding age, education, and gender as predictors. Regression equations for older and younger groups differed in intercept values but not in slopes. Percent variance accounted for in long form scores from short form scores did not differ when separate equations were used for younger and older subjects.

Clinical efficacy and design changes of "fine bore" nasogastric feeding tubes: a seven-year experience involving 809 intubations in 403 patients.

We report here our clinical experiences of "fine bore" nasogastric feeding tubes. Data have been collated over a 7-year period (1978-1985). A total of 403 patients were intubated on 809 occasions. In the first retrospective study, the clinical use of 491 unweighted tubes was compared with that of fifty 3.5-g weighted tubes. No advantage was found in the use of the weighted tubes. In the second prospective controlled clinical trial, these results were confirmed. Forty-six patients were intubated on 76 occasions with an 85-cm open-ended, unweighted nasogastric feeding tube (Prima, Portex UK), and 57 patients were intubated on 79 occasions with a 91-cm 3.0-g weighted tube (Entriflex, Biosearch, Raritan, NJ). Mean duration of placement was similar in each case, and 62% of both types of tubes were inadvertently removed. Without exception, all the tubes remained in the stomach throughout. Disappointed with the similar and overall performance of both types of tubes, we initiated a design program which resulted in the development of two new nasogastric tubes, one weighted and one unweighted. The tubes were manufactured with polyurethane, rather than polyvinylchloride (PVC), which permitted an increase in diameter of the internal lumen which, in turn, was coated with water-activated lubricant to ease removal of the introducer wire. A specially modeled outflow port was incorporated into the tips of both tubes. The performance of the two new polyurethane nasogastric feeding tubes was assessed under controlled trial conditions; as a reference, a widely used PVC unweighted open-ended tube was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Nocturnal doses of ranitidine and nizatidine do not affect the disposition of diazepam.

The disposition of diazepam (D) after a single oral dose of 10 mg was evaluated in nine healthy male volunteers under the following conditions (randomized, double-blind, crossover design): D + comedication of placebo and D + nocturnal dosing with 300 mg ranitidine or 300 mg nizatidine. Plasma concentrations of D and its major active metabolite, desmethyldiazepam (DD), were monitored by a gas-liquid chromatography-electron-capture detection assay for 84 hours. Neither ranitidine nor nizatidine had any significant effect on the hepatic elimination of D as characterized by its terminal half-life (mean +/- SD) of 35.3 +/- 24.2 hours (+ ranitidine: 30.1 +/- 9.9 hr; + nizatidine: 37.3 +/- 18.3 hr) or total plasma clearance of 28.2 +/- 12.0 mL/min (+ ranitidine: 26.5 +/- 7.9 mL/min; + nizatidine: 26.7 +/- 10.4 mL/min). Likewise, the formation of DD as measured by its AUC was not affected by ranitidine or nizatidine. Thus, it can be concluded that concomitant once-daily dosing (300 mg nocturnally) with ranitidine or nizatidine does not impair hepatic drug metabolism.

The 24-hour acid suppression profile of nizatidine.

To determine the antisecretory potency of bedtime doses of the new thiazole H2-receptor antagonist nizatidine in the suppression of nocturnal acid secretion, this randomized, cross-over, single-blind study was performed in 10 healthy male subjects. The actions of a single bedtime (2100 h) dose of the H2-receptor antagonist nizatidine (150 mg and 300 mg), ranitidine (300 mg), cimetidine (800 mg), and famotidine (40 mg), as well as placebo on nocturnal gastric acid and volume secretion (2400 to 0600 h) and on overall 24 h H+-ion concentration were studied. Compared with placebo, night-time (2300 to 0700 h) H+ ion concentration was reduced by 70, 79, 95, 75, and 89% (p less than 0.05 to p less than 0.01). Nocturnal acid secretion, too, was significantly lower for the H2-blockers than for placebo (p less than 0.01). A significant reduction in total night-time gastric volume secretion was observed (p less than 0.01). Nizatidine 300 mg nocte, ranitidine, cimetidine and famotidine had no significant carry-over effects on daytime acidity (0800 to 1800 h). No significant pharmacodynamic differences between nizatidine 300 mg nocte, ranitidine 300 mg nocte, cimetidine 800 mg nocte and famotidine 40 mg nocte were observed. Thus, it may be concluded that these four H2-blockers will be equally effective in accelerating peptic ulcer healing and pain relief.

300 mg nizatidine at night versus 300 mg ranitidine at night in patients with duodenal ulcer. A multicentre trial in Europe.

Patients (859) from six countries were randomized into an endoscopically controlled double-blind trial. The objective of this study was to compare the efficacy and safety of nizatidine 300 mg nocte with ranitidine 300 mg nocte in the therapy of duodenal ulceration. Patients fulfilling the entry criteria and completing the protocol numbered 777 (388 nizatidine, 389 ranitidine). Endoscopy was performed on entry and at 4-week intervals (up to 8 weeks) until the ulcer healed, except in Germany where endoscopy was also performed after 14 days. Both groups appeared well matched for population demographics, duodenal ulcer history, previous therapy and pre-study symptomatology. Overall healing rates in the nizatidine group compared favourably with the ranitidine group at 4 weeks (nizatidine 81%, ranitidine 80%) and 8 weeks (nizatidine 92%, ranitidine 93%). Data from Germany alone showed similar ulcer healing rates after 2 weeks therapy (nizatidine 60%, ranitidine 64%). Although there were no differences between or within the treatment groups, overall ulcer healing was significantly impaired (p less than 0.05 or less) in patients with a large ulcer (greater than 15 mm), a family history of peptic ulcer disease, verified disease or greater than 5 years duration, or heavy smokers (greater than 20 cigarettes/day). Age did not influence healing. Overall healing rates were significantly influenced by country of patient origin, being higher in Germany, and lower in Belgium (p less than 0.001). After 2 weeks therapy, about 60% of the nizatidine and ranitidine treated patients were pain free, while 4 weeks therapy was associated with relief of all symptoms in 72% of patients and relief of night pain in more than 90%. Antacid consumption reduced at a similar rapid rate during the study. Events were reported equally in both treatment groups, events compatible with peptic ulcer disease predominating. Events associated with study termination appeared related to documented disease or protocol violations. Monitoring of laboratory data suggested no significant haematological or biochemical abnormalities in the nizatidine group. Nizatidine 300 mg nocte appears to be as effective as ranitidine 300 mg nocte in both ulcer healing and symptomatic response.

Nizatidine versus ranitidine in gastric ulcer disease. A European multicentre trial.

Two hundred and seventy five patients from six countries were randomized into an endoscopically controlled, eight-week, double-blind, study. The objective of this investigation was to compare the efficacy and safety of nizatidine, administered as either a single (300 mg nocte) or twice daily (150 mg B.D.) dose, with ranitidine 150 mg twice daily, in the therapy of benign gastric ulceration. Two hundred and fifty-two patients fulfilled entry criteria and completed the protocol (80 nizatidine 150 mg B.D.; 89 nizatidine 300 mg nocte; 83 ranitidine 150 mg B.D.). Endoscopy was performed on entry and at four-week intervals until the ulcer healed. The diagnosis of benign ulceration was always supported by endoscopic histology and/or cytology. On entry into the study, both groups appeared well matched (i.e. for population demographics, duodenal ulcer history, previous therapy and pre-study symptomatology), except for epigastric day pain which was significantly less in the ranitidine group (p = 0.020). Overall gastric ulcer healing rates were similar in the three groups at four weeks (nizatidine B.D. 66.2%: nizatidine nocte 65.2%: ranitidine B.D. 63%) and at eight weeks (nizatidine B.D. 90%: nizatidine nocte 86.5%: ranitidine B.D. 86.7%). Healing was not consistently influenced by country of origin or smoking. After four weeks of therapy, 66% (nocte dose) to 68% (B.D. dose) of nizatidine treated patients were symptom free, while 93% (nocte dose) to 95% (B.D. dose) were free of night pain. Events were similar in the three treatment groups, and the majority were gastro-intestinal.(ABSTRACT TRUNCATED AT 250 WORDS)

Nizatidine versus ranitidine in the prevention of duodenal ulcer relapse. Six-month interim results of a European multicentre study.

Nizatidine, a new H2-receptor antagonist, was compared with ranitidine in a double-blind, randomized, multicentre trial for the prevention of duodenal ulcer relapse. This is the interim analysis of 197 patients admitted to the study by 1 September 1985, having finished a 6-month treatment period by 1 March 1986. At night, 96 and 101 patients received 150 mg nizatidine and 150 mg ranitidine, respectively. Both groups were well matched for demographic data, duration and severity of ulcer disease. Calculating cumulative relapse rates by the life-table method of Cutler and Ederer, 18% on nizatidine and 13% on ranitidine had experienced a symptomatic or asymptomatic recurrence. The difference is not statistically significant. The symptomatic response was identical in both groups, 3/4 of the patients in both groups being free of any symptom over all 6 months. During maintenance treatment, 24% of the patients on nizatidine and 32% of those on ranitidine reported new symptoms, listed as 'adverse events'. However, none of these events was likely to be drug related. There was no difference between the two groups concerning the percentage change of laboratory variables from baseline to endpoint.

Effect of peptide chain length on absorption of egg protein hydrolysates in the normal human jejunum.

The influence of the peptide chain length of partial enzymic hydrolysates of protein on nitrogen and amino acid absorption was studied in 12 subjects using a jejunal perfusion technique. Three hydrolysates of egg white and an equivalent amino acid mixture were perfused at 30 mmol/L and 100 mmol/L in two separate experiments. Two hydrolysates (OH1 and OH2) contained mainly dipeptides and tripeptides, whereas the third (OH3) comprised tripeptide to pentapeptides as judged chromatographically. Nitrogen absorption was significantly slower from the higher chain length mixture, OH3, than from the short chain mixtures, OH1 and OH2, at both concentrations. Similarly, several amino acid residues were absorbed less well from OH3 than from OH1 and OH2. These data demonstrate that the chain length of heterogeneous mixtures of peptides affects absorption of nitrogen and individual amino acid residues, and suggest that brush border hydrolysis of tetrapeptides and pentapeptides limits absorption from enzymic hydrolysates of protein which simulate the composition of the postprandial luminal contents.

Nocturnal acid suppression with a new H2 receptor antagonist--nizatidine.

To determine the potential efficacy of bedtime doses of the new furan H2 receptor antagonist nizatidine in the suppression of nocturnal acid secretion, this randomized, crossover, single-blind study was performed in 10 healthy male subjects. The actions of a single bedtime (21:00 hour) dose of the H2 receptor antagonists nizatidine (150 mg and 300 mg), ranitidine (300 mg) and cimetidine (800 mg), as well as placebo on nocturnal gastric acid and volume secretion (01:00 to 07:00 hours, and on overall 24 hour H+ ion concentration were studied. Compared with placebo, night-time (23:00 to 07:00 hours) H+ ion concentration was reduced by 70, 79, 95, and 76% (p less than 0.05-p less than 0.01). Nocturnal acid secretion, too, was significantly lower for the H2 blockers than for placebo (p less than 0.05-p less than 0.01). A significant reduction in night-time gastric volume secretion was observed in the hourly intervals from 04:00 to 07:00 hours and in total volume in the whole 6 hours period (p less than 0.05-p less than 0.01). Nizatidine 300 mg nocte, ranitidine and cimetidine significantly decreased H+ concentration for only 1 hour (08:00 to 09:00 hours, p less than 0.05-p less than 0.01) during the subsequent daytime period (08:00 to 13:00 hours). Since no significant pharmacodynamic differences between nizatidine 300 mg nocte, cimetidine 800 mg nocte and ranitidine 300 mg nocte were observed, it may be concluded that at the doses employed, these three H2-blockers will all be similarly effective in the acute therapy of peptic ulcer disease.

Effect of peptide chain length on amino acid and nitrogen absorption from two lactalbumin hydrolysates in the normal human jejunum.

A double lumen jejunal perfusion technique has been used in man to study the effect of peptide chain length on absorption of amino acid nitrogen from two partial enzymic hydrolysates of lactalbumin. Copper-chelation chromatography showed that one lactalbumin hydrolysate (LH2) contained 98% peptides with a chain length greater than 4, whilst the other (LH1) contained a more even spread of chain lengths with 55% less than 4. Absorption of total nitrogen and of 14 amino acid residues occurred to a significantly greater extent from the low molecular weight LH1 than from the higher molecular weight LH2. The results suggest that the pattern of nitrogen and amino acid absorption from partial enzymic hydrolysates of whole protein is markedly influenced by peptide chain length and that brush border peptide hydrolysis has an important rate limiting effect on absorption rates.

Elemental diet administered nasogastrically without starter regimens to patients with inflammatory bowel disease.

The present study questions the concept of routinely using 'starter regimens' at the outset of enteral feeding with chemically defined elemental diets. A hypertonic elemental diet with an osmolality of 630 mOsm/kg was administered by 24-hr nasogastric infusion to 12 patients with exacerbations of inflammatory bowel disease and to two patients with short bowel syndrome. Starter regimens were not used. Upper gastrointestinal symptoms of nausea, abdominal bloating, and colicky pain occurred transiently in only five of 14 patients. Stool frequency did not increase during full-strength feeding, and daily stool weights decreased significantly (p less than 0.01). These findings show that it is safe to administer undiluted hypertonic elemental diets by constant nasogastric infusion to patients with inflammatory bowel disease. Avoiding starter regimens leads to increased nutrient intake and improved nitrogen balance.

Influence of protein composition and hydrolysis method on intestinal absorption of protein in man.

An intestinal perfusion technique has been used in normal human subjects to investigate the influence that starter protein composition and hydrolysis procedure have on absorption of amino acid residues from partial enzymic hydrolysates of whole protein. Five starter proteins were studied. Three (egg albumin, casein/soy/lactalbumin, and lactalbumin) were hydrolysed by papain, a second lactalbumin starter protein, and a meat/soy/lactalbumin blend were hydrolysed by a porcine pancreatic enzyme system. Irrespective of starter protein composition or hydrolysis method used, four amino acid residues (threonine, glutamic acid, phenylalanine, and histidine) were absorbed significantly faster from all hydrolysates compared with absorption from their equivalent free amino acid mixtures. In contrast, both starter protein composition and hydrolysis method influenced absorption characteristics of up to nine other amino acid residues.

Administration of fat emulsions with nutritional mixtures from the 3-liter delivery system in total parenteral nutrition.

A series of studies was performed to test the efficacy and safety of a parenteral lipid emulsion, Lipofundin S, when given as part of a complete nutritive mixture from the three-liter bag total parenteral nutrition (TPN) delivery system. In vitro stability studies with mixtures corresponding to high and low nutritional intakes showed the fat emulsion to be stable during refrigerated storage for at least 6 days. The clinical use of Lipofundin S in 3-liter TPN bags was studied in 39 consecutive patients requiring TPN, and there were no untoward side-effects. Nitrogen balance was maintained in patients with pancreatitis, those recovering postoperatively, and those with miscellaneous conditions. However, patients with multiple trauma remained in negative balance. The ability of sera, from patients on TPN to agglutinate Lipofundin S was compared to that from healthy controls, and acutely ill patients not on TPN. Patients on TPN showed a higher degree of in vitro creaming than acutely ill controls, and this may have been related to the severity of the underlying illness. These studies suggest that this parenteral lipid emulsion can be safely administered to patients requiring TPN when given from the 3-liter bag delivery system.

Do fibre containing enteral diets have advantages over existing low residue diets?

This study investigated the influence of fibre on the pattern of absorption of protein and carbohydrate following administration of polymeric enteral diet and also the effect of added fibre on frequency of bowel action, stool weight and gastrointestinal side effects during enteral nutrition. No difference was seen in frequency of bowel action, stool weight or gastrointestinal side effects in five patients fed with either a fibre free polymeric diet or with the same diet augmented with 24 g fibre/24 h. Addition of fibre did not significantly alter breath hydrogen excretion. In an oral tolerance test on six normal subjects, the post prandial rises in blood glucose and levels of 17 amino acids were similar on ingestion of a fibre containing or fibre free test meal.

Relation between osmolality of diet and gastrointestinal side effects in enteral nutrition.

One hundred and eighteen patients with normal gastrointestinal function were randomly allocated to one of three feeding regimens in a double blind study to determine the relation between the tonicity of the diet and gastrointestinal side effects related to the diet and to evaluate the efficacy of "starter" regimens in reducing gastrointestinal side effects during enteral nutrition. Patients received a hypertonic diet with an osmolality of 430 mmol (mosmol)/kg (group 1), the same diet but with the osmolality increasing from 145 to 430 mmol/kg over the first four days (group 2), or an isotonic diet (300 mmol/kg) (group 3). All diets were prepared aseptically and administered by 24 hour nasogastric infusion. The mean daily nitrogen intake in group 1 was significantly greater (p less than 0.05) than that in both groups 2 and 3, and the mean overall daily nitrogen balance was significantly better (p less than 0.05) in group 1 than groups 2 and 3. The incidence of side effects related to the diet was similar in all three groups, but diarrhoea was significantly (p less than 0.001) associated with concurrent treatment with antibiotics. These findings show that undiluted hypertonic diet results in significantly better nitrogen intake and balance, that starter regimens reduce nutrient intake but not symptoms, and that diarrhoea is significantly related to treatment with antibiotics and not to administration of an undiluted hypertonic polymeric diet.

Effect of catheter tunnelling and a nutrition nurse on catheter sepsis during parenteral nutrition. A controlled trial.

In a three-year controlled trial of subcutaneous catheter tunnelling as a method of reducing total parenteral nutrition (TPN) catheter sepsis 99 silicone catheters (52 tunnelled, 47 untunnelled) were inserted into the subclavian (94%) or jugular (6%) veins under aseptic conditions. The influence of a nutrition nurse, who joined the nutrition team after 18 months, on catheter sepsis rate was also documented. Catheter sepsis was confirmed in 13 of 47 (28%) untunnelled catheters and only 6 of 52 (11.5%) tunnelled catheters (p less than 0.05). A nutrition nurse reduced sepsis rate from 33% (tunnelled 6, untunnelled 11) to 4% (0 tunnelled; 2 untunnelled) (p less than 0.001). There was no significant difference between tunnelled and untunnelled catheters in sepsis rates after the arrival of the nutrition nurse. Although 85% patients had concurrent internal sepsis, the pathogens implicated in catheter sepsis came from superficial sites in 16 of 19 cases (p less than 0.01). Rigorous aseptic nursing care is thus the most significant factor in the reduction of TPN catheter sepsis, but tunnelling can reduce sepsis rate when nursing care is suboptimum.

Enteral nutrition in malnourished patients with hepatic cirrhosis and acute encephalopathy.

Ten patients with histologically proven cirrhosis, admitted in grade I to II acute hepatic coma, received in addition to a standard dietary protein free "anticoma" regime, a continuous nasogastric infusion of a branched-chain amino acid enriched chemically defined enteral diet (Hepaticaid) containing an equivalent of 70 g protein/day for a mean of 7.3 days (range 3-23). No complications of therapy were observed and, specifically, the use of fine bore tubes did not provoke variceal hemorrhage. Overall positive nitrogen balance (4.3 +/- 1.7 g N/day) was observed in patients fed 7 or more days. Improvement to coma grade 0 was seen in all patients save one, who died from hepatorenal failure. While serum ammonia levels remained elevated during the study period, there was a significant increase in the branched-chain/aromatic ratio (p less than 0.01) as plasma branched-chain amino acids rose (p less than 0.05) and tyrosine levels fell (p less than 0.05).