Periodontal tissue response to a new bioresorbable guided tissue regeneration device: a longitudinal study in monkeys.

This study evaluated periodontal tissue response to a new bioresorbable guided tissue regeneration barrier material following guided tissue regeneration treatment of dehiscence-type defects at 45 teeth in 15 monkeys. The results were clinically and histologically evaluated 6 weeks and 3,6, 12, and 24 months posttreatment. Healing was uneventful and without inflammation or other adverse tissue reactions. Following 6 weeks of healing, the matrix barrier was completely integrated with the surrounding tissues, preventing epithelial downgrowth along the device. There were no inflammatory cell infiltrates adjacent to the material. New attachment (ie, new cementum with inserting collagen fibers) and new supporting bone were found after 6 weeks of healing. The matrix barrier maintained its functional stability for a minimum of 6 weeks. The subsequent slow resorption process of the material occurred without detrimental effects on the surrounding tissues, demonstrating the biocompatibility of the material. The material was completely resorbed after 6 to 12 months. At the final stages of the resorption process, macrophages and multinuclear cells were present within the tissue that replaced the material. The design and the resorption pattern of the matrix barrier are discussed in relation to the regenerative wound healing process.

The effect of an opiate receptor antagonist on the ileal brake mechanism in the rat.

Studies investigated the effect of the opiate antagonist naloxone (10 mg/kg) on stomach to caecum transit (SCTT) during ileal infusion of saline or Intralipid. SCTT of the head of the meal was measured by hydrogen analysis and meal distribution by the radiolabelled meal technique. Intralipid delayed SCTT by delaying both gastric emptying (p < 0.01) and small bowel transit. Naloxone did not affect SCTT during ileal saline infusion, but produced a distal shift (p < 0.05) in the geometric centre of the meal and increased radioactivity in the caecum (p < 0.001) 100 min after gavage. Naloxone abolished the delayed SCTT of the meal induced by ileal lipid infusion, with an associated increase in radioactivity in the caecum at 200 min (p < 0.01), although the geometric centre was shifted proximally within the intestine (p < 0.01). The results suggest that the ileal brake is mediated in part by endogenous opiate pathways.

The effect of liquid fibre on gastric emptying in the rat and humans and the distribution of small intestinal contents in the rat.

A combination of the polysaccharide ethyl-hydroxyethyl-cellulose (EHEC) and the surfactant sodium-dodecylsulphate (SDS) has the extraordinary physical property of being liquid at room temperature but gelling firmly at 37 degrees C. It has been named 'liquid fibre' and its effect on gastric emptying has been tested in rats and humans, as well as its effect on intestinal distribution in rats. Rats were gavaged with 5 ml of radiolabelled liquid fibre, SDS in water, or water control. Subgroups were killed after 25, 50, 100, 200, and 300 minutes, the gut removed, and the distribution of radioactivity measured scintigraphically. Liquid fibre gelled in the stomach and spread exponentially down the small intestine before 25 minutes. This distribution was maintained for 200 minutes after which the stomach began to empty again. In the human study, 10 healthy men drank 250 ml liquid fibre and placebo labelled with 1.85 MBq technetium tin colloid on separate occasions. Gastric emptying was measured by gamma-camera. Half emptying time significantly increased from 17.7 to 55.8 minutes (means, p < 0.05). The time for 10% to empty (which includes any lag time) increased from 7.0 to 19.4 minutes (p < 0.05). Average emptying rate decreased from 4.49%/min for placebo to 1.60%/min for liquid fibre (p < 0.01). The dramatic delay in gastric emptying suggests liquid fibre may have clinical applications while its liquid formulation should improve acceptability.

Objective and subjective efficacy evaluation of various polymer-based saliva substitutes.

Various polymer solutions with and without surfactants were evaluated regarding their lubricating properties on the oral mucosa. After rinsing with the solutions, the oral mucosal friction value was registered with a probe (objective effect). After each rinsing occasion at home, the patients answered a questionnaire (subjective effect). None of the tested polymers showed a longer, clinically significant effect than the other ones. Some of them had the same effect as substitutes available on the Swedish market.

The effect of adrenoceptor antagonists on the ileal brake mechanism in the rat.

1. Studies were carried out in the rat to investigate the effect of adrenoceptor antagonists on stomach to caecum transit time under control conditions and during ileal infusion of Intralipid. Stomach to caecum transit time (SCTT) of the head of the meal was measured by use of environmental hydrogen analysis and the distribution of the meal was assessed by a scintigraphic technique. 2. Four adrenoceptor antagonists were used in these studies, the alpha 1 antagonist prazosin, the alpha 2 antagonist, idazoxan, the beta 1 antagonist atenolol and the beta 2 antagonist ICI 118551. 3. None of the antagonists affected SCTT of the head of the meal during ileal infusion of saline. However, the alpha 1 and beta 1 antagonists significantly reversed (P less than 0.05) the delay in SCTT induced by ileal infusion of Intralipid whereas the alpha 2 antagonist, idazoxan, potentiated this delay (P less than 0.05). 4. Study of the distribution of the radiolabelled meal showed that the Intralipid delayed SCTT by slowing both gastric emptying (P less than 0.05) and small bowel transit (P less than 0.05). 5. Prazosin delayed gastric emptying under control conditions (P less than 0.001) but did not alter significantly the effect of ileal lipid on the distribution of the meal, 100 min or 200 min after gavage.6. The meal distribution was more compatible with the hydrogen analysis after administration of the ,beta-adrenoceptor antagonists. The reversal of the lipid-induced delay in SCTT caused by atenolol was associated with more radioactivity in the large intestine 200min after the gavage. ICI 118551 had no significant effects on either the distribution of the meal or the SCTT of the head of the meal.7. In conclusion, the data confirm that the sympathetic nervous system normally modulates or mediates the mechanisms that influence gastrointestinal transit in the rat and suggest that these mechanisms may be involved in the ileal brake effect. Nevertheless the data also suggest that simple measurement of the transit of the head of the meal by use of environmental hydrogen analysis may sometimes give a misleading impression of the action of drugs on gastrointestinal transit of the bulk of a test meal.

Characteristics of lipid substances activating the ileal brake in the rat.

Studies were carried out in 36 adult male rats to determine the characteristics of lipid substances which, after infusion into the ileum, slow the stomach to caecum transit time of the head of a bean meal in the rat. Stomach to caecum transit time was measured by environmental hydrogen analysis. Ileal infusion of a range of free fatty acids including petroselinic, oleic, myristoleic, erucic, linoleic, and linolenic all significantly slowed stomach to caecum transit time, as did the detergents (sodium bis (2-ethyl hexyl) sulphosuccinate and sodium linoleyl sulphate), the triglyceride corn oil, and the phospholipid lecithin. Although the lipid soluble deconjugated bile acid deoxycholic acid slowed stomach to caecum transit time, the water soluble conjugated bile acid taurocholic acid accelerated it. Infusion of the lipid alcohol oleyl alcohol and the calcium chelating agent disodium edetate (EDTA) into the ileum did not delay the passage of the meal through the stomach and small intestine. The diversity of lipid substances activating the ileal brake suggest a nonspecific effect by lipid soluble substances that can penetrate cell membranes. The lack of effect of EDTA suggested that calcium binding was not important.

Retention of selenium (75Se), Zinc (65Zn) and manganese (54Mn) in humans after intake of a labelled vitamin and mineral supplement.

The whole body retention of 75Se, 65Zn, and 54Mn after intake of a labelled vitamin and mineral supplement was followed in 12 healthy volunteers. The supplement had a vitamin and mineral content according to recommended dietary allowances or the so-called "safe and adequate levels" for trace elements, including 15 mg of zinc as zinc citrate, 50 micrograms of selenium as sodium selenite and 2.5 mg of manganese as manganese sulphate. The supplement was taken either in the fasting state or together with a light meal. Retention day 14 was 48 +/- 6%, 33 +/- 6% and 5 +/- 2% (mean +/- SD) for selenium, zinc and manganese, respectively, when the supplement was taken fasting and 45 +/- 3%, 8 +/- 1% and 1.0 +/- 0.2% when it was taken with food. During day 1-14, 27%, 1% and less than 0.01% of the administered selenium, zinc and manganese radionuclides, respectively, were excreted in the urine. Based on the rate of turnover of the radionuclides and the urinary losses of 75Se, the absorption of selenium, zinc and manganese from the supplement was estimated to be 89 +/- 5%, 38 +/- 7%, 9 +/- 3% (mean +/- SD) in the fasting state and 87 +/- 4%, 10 +/- 2% and 2 +/- 1% with food. These results indicate that when a supplement is taken with food the minerals are absorbed and metabolized in the same way as are native minerals in food. When the supplement is taken in the fasting state, the absorption of zinc and manganese can be substantially higher.

Comparison of two enteric-coated acetylsalicylic acid preparations by monitoring steady-state levels of salicylic acid and its metabolites in plasma and urine.

In a randomized three-way crossover study, 12 healthy male volunteers were given multiple oral doses, i.e. 1.5 g b.i.d. for 7 days, of two different types of enteric-coated acetylsalicylic acid (ASA) preparations, one being a conventional enteric-coated tablet (ET) and the other enteric-coated granules (EG) in a capsule; conventional ASA tablets were used as a reference. Plasma levels and excretion of salicylic acid and some of its metabolites were investigated under steady-state conditions. Plasma salicylic acid (SA) and salicyluric acid (SUA) levels were determined using a liquid chromatographic method. Two separate analyses were done to quantitate the metabolites in urine. SA, SUA, and gentisic acid were each assayed by the method used for plasma. Total salicylate was also determined. There was no significant difference in urinary excretion of total salicylate between the three formulations. A diurnal variation in the excretion of SUA and SA in urine was found. The two enteric-coated formulations provided significantly higher morning plasma concentrations than the conventional aspirin. The AUC was found to be significantly higher for ET than for the other two formulations. EG gave more uniform plasma levels during the studied 12-h intervals and also less inter- and intra-individual variations than ET, indicating that a b.i.d. regimen may be suitable for EG.

Absorption of acetylsalicylic acid from enteric-coated tablets in relation to gastric emptying and in-vivo disintegration.

The absorption of acetylsalicylic (ASA) acid from enteric coated tablets was studied in relation to gastric emptying and in-vivo disintegration. ASA tablets labelled with 51Cr were given to six healthy subjects under fasting and non-fasting conditions. The position and disintegration of the 51Cr-labelled tablets was followed by external radiation measurement and the amount of salicylic acid in blood and urine was analysed. The absorption of ASA from the studied enteric coated tablets was usually correlated with gastric emptying and in-vivo disintegration. However in some cases the absorption can be delayed between 10-20 h even if gastric emptying and disintegration of the tablet have occurred.

Increased metabolism to dihydrodigoxin after intake of a microencapsulated formulation of digoxin.

A capsule preparation containing small, enteric-coated granules of digoxin was developed to prevent acid hydrolysis of the drug in the stomach and to diminish the variation in plasma glycoside concentration during the intervals between doses. The absorption and metabolism of tritiated digoxin after a single oral loading dose of this formulation (Formulation C) were compared to those after ingestion of a digoxin solution (Formulation S) by 8 healthy men. Drug concentrations were measured by radioimmunoassay (RIA) and liquid chromatography (LC). The percentage of the digoxin dose excreted in the urine during 72 h, as measured by RIA, was significantly lower after the capsule (20.5 +/- 2.0% vs 36.2 +/- 3.0% after S, mean +/- SEM) but total urinary radioactivity after the two treatments was similar (C 35.3 +/- 5.2 and S 41.2 +/- 2.6%; p greater than 0.05). The discrepancy was mainly due to significantly greater excretion of dihydrodigoxin after the capsule (m 12.8%, range 0-28.6% of the dose) than after the digoxin solution (m 5.4%, range 0-14.5%). Dihydrodigoxin was not measured by the RIA. The recovery of hydrolysis metabolites (LC) was greater during the first 24 h after S (2.3 +/- 0.6% vs 0.9 +/- 0.3% after C; p less than 0.05). The peak plasma concentration of digoxin (RIA) was significantly reduced and delayed after intake of C (2.5 +/- 0.4 nmol/l at 3.8 +/- 0.3 h vs. 8.3 +/- 0.8 nmol/l at 0.9 +/- 0.1 h after S), and so was the shortening of electromechanical systole at 1.5 h, 2.5 h, and 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary pH and plasma levels of salicylate after administration of different buffered acetylsalicylic acid formulations.

In a controlled cross-over study comprising eight healthy subjects of effervescent acetylsalicylic acid (ASA) and an experimental ASA formulation were compared with unbuffered ASA and placebo concerning effects on the urinary pH within a dosage interval after 2 days' medication with 3 g ASA daily. The effects on the urinary pH were related to the morning plasma salicylate concentrations observed. Both the buffered formulations significantly increased the median pH of the period studied compared to unbuffered ASA, the effervescent by 1.5 units and the experimental by 0.6 units. Unbuffered ASA significantly decreased the median pH compared to placebo. Those subjects with the most acidic urine during placebo treatment showed the most pronounced pH elevations due to effervescent ASA. The plasma salicylate concentration was significantly lower with the effervescent formulation compared with unbuffered ASA, but there was no statistical difference between the experimental tablet and unbuffered ASA. The variable effects on the urinary pH and the plasma salicylate concentrations induced by the two buffered preparations are explained by the different absorbabilities of the buffering agents included. The results presented are consistent with recommendations not to use bicarbonate-containing ASA formulations continuously when high plasma levels are desirable.

Fasting and postprandial absorption of digoxin from a microencapsulated formulation.

The absorption of digoxin from a capsule preparation containing a large number of small, enteric-coated granules of the glycoside (Preparation CR) was compared in 10 volunteers with that from a rapidly dissolving tablet (Preparation L). Plasma and urine digoxin concentrations were measured by radioimmunoassay. In the fasting state, after a loading dose of digoxin (0.76 mg), peak plasma concentrations were significantly (p less than 0.001) lower after CR (2.0 +/- 0.5 nmol/l, mean +/- SD) than L (4.7 +/- 1.1 nmol/l). Peak concentrations after CR were significantly (p less than 0.001) delayed compared to L (3.3 +/- 0.6 h vs 1.1 +/- 0.4 h). Also, postprandial peak plasma concentrations at steady state, were significantly (p less than 0.01) lower after CR (1.0 +/- 0.3 nmol/l) than L (2.7 +/- 0.5 nmol/l), and the peak concentrations occurred later (3.9 +/- 1.7 h vs 1.4 +/- 0.9 h). The area under the plasma concentration-time curves was smaller (p less than 0.01) for CR (17.7 +/- 5.9 nmol X 1(-1) X h) than for L (22.4 +/- 4.1 nmol X 1(-1) X h), and so was the amount of drug excreted in urine (174 +/- 25 micrograms vs 190 +/- 31 micrograms; p less than 0.005). Thus, the absorption rate of digoxin from the enteric-coated formulation was markedly reduced but at the cost of a variable reduction in the amount absorbed.

Metabolism of digoxin and absorption site.

After oral intake of enteric-coated granules containing [3H]-digoxin extensive metabolism was observed. Maximum 66% of the 24 h urinary excretion was identified as [3H]-dihydrodigoxin, using high performance liquid chromatography for the analysis. It is suggested that metabolism of digoxin may depend on the absorption site.

Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects.

The 3-day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4 +/- 2.0 per cent (mean +/- S.E.M.) of the dose. By HPLC 42.4 +/- 2.7 per cent was recovered before and 44.0 +/- 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 +/- 2.9 per cent; of this 0.7 +/- 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 +/- 0.3 per cent before and 3.4 +/- 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4-8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.

Gastric emptying and absorption of acetylsalicylic acid administered as enteric-coated micro-granules.

Enteric-coated and uncoated microgranules of acetylsalicylic acid (ASA), labelled with 51Cr, were administered orally to six healthy male volunteers in a cross-over study. Gastric emptying was studied using a profile scanning radiation technique. Absorption of ASA was followed by measuring the plasma concentration of salicylate. Gastric emptying both of uncoated and enteric-coated granules varied considerably between individuals, but in most cases was gradual and extended over a period of several hours. The median time until 50% and 90% were emptied from the stomach was 1 and 3-3.5 h, respectively, for both the uncoated and enteric-coated granules. The absorption of ASA from the uncoated granules occurred in parallel with the gastric emptying. However, with the enteric-coated granules, absorption was delayed for about 3 h after gastric emptying. It was concluded that the slow absorption of ASA from enteric-coated granules could be explained partly by gradual gastric emptying and partly by slow dissolution of the ASA granules in the intestine.

Absorption of digoxin from a new microencapsulated formulation.

The absorption of digoxin from two capsule preparations containing a large number of small, enteric-coated granules of the glycoside (0.38 mg) was compared with that of the same amount from ultrarapidly dissolving commercial tablets. Eight volunteers were studied during steady state conditions. Digoxin concentrations in plasma and urine were measured by radioimmunoassay. Peak plasma concentrations of digoxin were significantly (p < 0.01) delayed after taking the capsules (2.6 +/- 1 h and 2.6 +/- 0.9 h, mean +/- SD) as compared to the tablets (1.3 +/- 0.7 h). The peak concentrations produced by the capsules were 3.1 +/- 1.0 and 2.6 +/- 1.1 nmol/l; only the latter was significantly (p less than 0.05) lower than after the tablets (3.4 +/- 1.0 nmol/l). Areas under the plasma concentration-time curves during a 24 h dosage interval were similar for the three preparations, and so was the 24 h urinary excretion of digoxin, which averaged 60-63% of the daily dose. Thus, this particular enteric coating of digoxin delayed absorption without reducing the amount absorbed.