Nutrient intakes during diets including unkilned and large amounts of oats in celiac disease.

BACKGROUND/OBJECTIVES: We have shown earlier that consumption of moderate amount of oats improve intakes of vitamin B(1), fiber, magnesium and iron in celiac patients using gluten-free diet (GFD). The objective of this study was to clarify the effect of high amount of both kilned and unkilned oats on food and nutrient intakes in celiac patients in remission. Kilning as an industrial heating process is performed to preserve the main properties of oats and to lengthen its useableness. Kilning may, however, change the protein structure of oats and therefore influence on the intake of nutrients. SUBJECTS/METHODS: The study group consisted of 13 men and 18 women with celiac disease in remission. The patients who were earlier using moderate amount of oats as part of their GFD were randomized to consume kilned or unkilned oats. After 6 months, the patients changed the treatment groups. The goal of daily intake of oats was 100 g. Food records and frequency questionnaire were used to follow nutrient intakes. RESULTS: Type of oats did not affect the amount of oats used. In the group using kilned oats, the intake of vitamin B1 and magnesium and in the group of unkilned oats that of magnesium and zinc increased significantly during the first 6 months (P

No harm from five year ingestion of oats in coeliac disease.

BACKGROUND: Six to 12 months of ingestion of moderate amounts of oats does not have a harmful effect in adult patients with coeliac disease. As the safety of long term intake of oats in coeliac patients is not known, we continued our previous 6-12 month study for five years. AIM: To assess the safety of long term ingestion of oats in the diet of coeliac patients. PATIENTS: In our previous study, the effects of a gluten free diet and a gluten free diet including oats were compared in a randomised trial involving 92 adult patients with coeliac disease (45 in the oats group, 47 in the control group). After the initial phase of 6-12 months, patients in the oats group were allowed to eat oats freely in conjunction with an otherwise gluten free diet. After five years, 35 patients in the original oats group (23 still on an oats diet) and 28 in the control group on a conventional gluten free diet were examined. METHODS: Clinical and nutritional assessment, duodenal biopsies for conventional histopathology and histomorphometry, and measurement of antiendomysial, antireticulin, and antigliadin antibodies. RESULTS: There were no significant differences between controls and those patients consuming oats with respect to duodenal villous architecture, inflammatory cell infiltration of the duodenal mucosa, or antibody titres after five years of follow up. In both groups histological and histomorphometric indexes improved equally with time. CONCLUSIONS: This study provides the first evidence of the long term safety of oats as part of a coeliac diet in adult patients with coeliac disease. It also appears that the majority of coeliac patients prefer oats in their diet.

Lack of cellular and humoral immunological responses to oats in adults with coeliac disease.

OBJECTIVE: Recent research suggests that oats do not harm intestinal villi in adults with coeliac disease. As the immunological effects of oats have not been examined in detail, it was decided to compare the immunological responses of a gluten free diet including oats with those of a conventional gluten free diet. DESIGN: A randomised controlled intervention study over 6-12 months. SUBJECTS: Forty adults with newly diagnosed coeliac disease and 52 with coeliac disease in remission were examined. INTERVENTION: The effects of a gluten free diet including oats and a conventional gluten free diet were compared. MAIN OUTCOME MEASURES: Serum levels of gliadin and reticulin antibodies as well as numbers of intraepithelial lymphocytes (IELs) in intestinal mucosa were examined before and after the intervention. RESULTS: The rate of disappearance of gliadin and reticulin antibodies did not differ between the diet groups in patients with newly diagnosed coeliac disease. Oats also had no effect on gliadin or reticulin antibody levels in the patients with remission. The number of IELs decreased similarly regardless of the diet of newly diagnosed patients, and no increase in the number of IELs was found in the patients in remission with or without oats. CONCLUSIONS: These results strengthen the view that adult patients with coeliac disease can consume moderate amounts of oats without adverse immunological effects.

Nutritional status of newly diagnosed celiac disease patients before and after the institution of a celiac disease diet--association with the grade of mucosal villous atrophy.

No systematic studies have been carried out on the association of nutritional status with the severity of mucosal villous atrophy in newly diagnosed celiac disease patients. We examined the nutritional status of 40 adult patients with newly diagnosed celiac disease classified according to the grade of villous atrophy: partial, subtotal, and total. Nutritional status was determined by food records as well as by anthropometric and biochemical measurements. Anthropometric results did not differ among the three atrophy groups, but serum ferritin and erythrocyte folate were lower in patients with total villous atrophy than in the other groups. Most of the abnormal biochemical values were normalized during 1 y of a gluten-free diet; villous atrophy healed concomitantly. To conclude, patients with total mucosal villous atrophy at diagnosis had low erythrocyte folate and serum ferritin values, but no other major differences were found in nutritional status among celiac disease patients with different grades of villous atrophy.

Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy.

OBJECTIVES: To examine the diagnostic value of gastroscopy and upper abdominal ultrasound, which are frequently used as primary tests in dyspeptic patients in general practice. To test the influence of age for accuracy of both diagnostic methods. DESIGN: Clinical study. SETTING: Four health centres in Kuopio Province, Finland. SUBJECTS: Four hundred unselected consecutive dyspeptic patients (91 less than 45 years of age) who consulted their general practitioners. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values (PV), efficiency and usefulness index (UI) were calculated for upper abdominal ultrasound and for gastroscopy in detecting the causes of dyspepsia in primary care. Final diagnosis was determined after one year follow-up. RESULTS: The sensitivity of upper abdominal ultrasound in detecting the cause of dyspepsia was 0.07, the specificity 0.91, PV+ 0.36, PV- 0.56, and UI -0.001. Ultrasound was not more efficient in older patients. Gastroscopy was the most efficient method with a sensitivity of 0.75, specificity 1.00, PV+ 0.99, PV- 0.83 and UI 0.56. The usefulness of gastroscopy was even better among patients over 45 years of age. CONCLUSIONS: The usefulness of upper abdominal ultrasound is low regardless of patient's age. Gastroscopy is superior to upper abdominal ultrasound as a first line diagnostic method in diagnosing dyspepsia, especially among patients over 45 years of age.

A comparison of diets with and without oats in adults with celiac disease.

BACKGROUND: Wheat, rye, and barley damage the small-intestinal mucosa of patients with celiac disease; maize and rice are harmless. The effects of a diet containing oats are uncertain. METHODS: In a randomized trial, we compared the effects of gluten-free diets without oats and with oats (with a goal of 50 to 70 g per day from three sources: two types of wheat-starch flour mixed with an equal amount of oats, muesli containing 60 percent oats, and rolled-oat breakfast cereal). Fifty-two adults with celiac disease in remission were followed for 6 months and 40 with newly diagnosed disease for 12 months. Endoscopy with duodenal biopsy was performed at the beginning and end of the study. RESULTS: The mean (+/- SD) oat intake in the oat group was 49.9 +/- 14.7 g per day at 6 months for patients in remission and 46.6 +/- 13.3 g per day at 12 months for patients with newly diagnosed disease. The oat and control groups did not differ significantly in nutritional status, symptoms, or laboratory measures. Patients in remission, regardless of diet, did not have worsening architecture of the duodenal villi or increased mononuclear-cell infiltration. All the patients with new diagnoses were in remission at one year, except for one in the control group. Six patients in the oat groups and five in the control group withdrew from the study. CONCLUSIONS: Moderate amounts of oats can be included in a gluten-free diet for most adult patients with celiac disease without adverse effects.

Effects of fasting and chronic alcohol consumption on the first-pass metabolism of ethanol.

The present investigation was undertaken to evaluate what fraction of alcohol ingested in amounts during usual "social drinking" does not enter the systemic circulation. To that effect, on consecutive days, either peroral or intravenous ethanol was administered in both fed and fasted states to 7 nonalcoholic and 18 alcoholic subjects. In nonalcoholics consuming 0.15 g/kg body wt ethanol, the magnitude of first-pass metabolism of ethanol was 3.94 +/- 0.15 mmol/L X h, calculated as the difference of the areas under the curve obtained after oral and intravenous alcohol administration. The first-pass metabolism accounted for 73% of the latter. When the administered dose was increased to 0.3 g/kg body wt ethanol, the corresponding values were 6.46 +/- 0.50 mmol/L X h and 44%. Fasting decreased this effect. When alcoholics consumed 0.15 g/kg body wt ethanol, the corresponding values were 0.92 +/- 0.65 mmol/L X h and 23%. When these alcoholics were fasted, the first-pass metabolism again decreased and it was significantly lower than in the nonalcoholics tested under the same conditions. We conclude that in humans a significant fraction of ingested alcohol undergoes first-pass metabolism but that this effect is reduced in alcoholics and by fasting. The magnitude of this process determines the bioavailability of alcohol and thus modulates its potential toxicity.

First pass metabolism of ethanol--a gastrointestinal barrier against the systemic toxicity of ethanol.

Both in men and rats, most of the ethanol ingested at a low dose is metabolized before it reaches the systemic circulation. Oxidation of ethanol (mainly in the stomach) accounts for the bulk of this effect. This "first pass" metabolism (FPM) may be viewed as a barrier which protects against the systemic toxicity of ethanol. This barrier can be overcome by large doses of ethanol. Its efficiency is also reduced by a decrease in gastric alcohol dehydrogenase (ADH) activity secondary to chronic alcohol consumption.

First pass metabolism of ethanol: an important determinant of blood levels after alcohol consumption.

Alcohol consumption by rats fed ethanol-containing liquid diets is considerably greater than the measured rate of ethanol elimination from the blood, suggesting that a significant fraction of the alcohol ingested does not enter the systemic circulation. To assess the possibility of a first pass metabolism of ethanol, we compared the areas under the blood ethanol concentration curves after administration of various doses through various routes in alcohol-fed and control rats. In both groups, blood ethanol concentrations were significantly lower after intragastric than after intraportal or intravenous (femoral) administrations and, to a lesser extent, than after an intraduodenal dose. By contrast, the rise in blood acetate, a product of ethanol oxidation, was faster after intragastric administration. Moreover, absorption of the ethanol dose was virtually complete at the time of ethanol disappearance from the blood. The fraction of the dose that did not enter the systemic circulation was proportionally greater with the smaller doses. These results indicate that there is a significant first pass metabolism of ethanol which takes place in the gastrointestinal tract and particularly in the stomach, where alcohol dehydrogenase (ADH) activity is the highest. Chronic alcohol administration decreased ADH activity (probably secondary to gastric mucosal injury) and also decreased the magnitude of the first pass metabolism. The amount of ethanol ingested which does not enter the systemic circulation accounts for the apparent dissociation between alcohol consumption, blood ethanol levels and rate of blood ethanol elimination in alcohol-fed animals.

Pharmacokinetics of sulfaethidole in the rat: nonlinear multicompartment solution.

Sulfaethidole distribution and elimination in the rat was studied over a 90-fold dose range. This experimental design produced marked nonlinearity in the binding of sulfaethidole to proteins in both interstitial fluid an plasma. Using a multicompartmental model consisting of binding of sulfaethidole to plasma and interstitial fluid proteins, sulfaethidole distribution in the body could be simulated. Urinary and biliary elimination of sulfaethidole depended on the unbound drug mass in the plasma and urine flow. The results confirm the central role of the unbound species in the distribution and elimination of drugs with marked binding to plasma proteins.

A model solution for intestinal absorption of warfarin. A drug with non-linear distribution pharmacokinetics in the rat.

A non-linear multicompartment model with saturation kinetics of binding to plasma and interstitial fluid proteins and with non-saturable binding to tissues has been applied to the absorption of warfarin (8 mg/kg of warfarin sodium) from the rat small intestine in situ. The absorption was best described with two pathways, one into plasma and the other instantaneously into the interstitial fluid. According to the results from the best computerized curve fitting, absorption is rapid, the apparent absorption rate constant being 0.258 min -1. At hypothetical zero time 0.253 of the dose (1.0) would be located in plasma, 0.597 in interstitial fluid 0.150 in tissues.

Distribution pharmacokinetics of warfarin in the rat, a non-linear multicompartment model.

Preliminary analysis and linear two-compartment solutions of warfarin plasma concentrations recorded in the rat after intravenous bolus injections of 1, 2, 8 and 40 mg/kg of sodium warfarin revealed marked non-linearities. The half-life of total warfarin concentration in the plasma from 1-12h remained unchanged with all the doses used, but that of free warfarin was shorter with 40 mg/kg, possibly as the result of an increase in the binding of the drug to plasma proteins as the high total warfarin concentration decreased. The apparent volume of distribution generally increased with increasing dose, and differed according to the method used for its calculation. Liver warfarin data could be solved with Langmuir type saturation kinetics, but the saturation phenomena were slight in the concentration range studied. A non-linear multicompartment model was constructed, the physiological spaces of which were plasma, interstitial fluid and tissue. The binding of free warfarin to plasma proteins, interstitial fluid proteins and tissue structures was assumed to occur instantaneously, with saturable binding to plasma and interstitial fluid proteins, and a constant binding to tissues. The fluxes between the free warfarin pools of plasma and interstitial fluid as well as elimination were assumed to be linear. Following parameters were simulated simultaneously, using an analog hybrid computer: two for the above-mentioned fluxes, four for zero time drug mass distribution between plasma and interstitial fluid, and one for tissue binding. According to the best fits, warfarin is preferentially distributed into plasma, interstitial fluid and highly perfused tissues. The solution suggests that non-linearities in the pharmacokinetics of warfarin, a highly plasma protein-bound drug, first occur in plasma and interstitial fluid. Therefore, it is believed that the quantitative non-linear multicompartment approach presented in this paper might be useful in studying the kinetic behaviour of other highly plasma protein-bound drugs, too.

pH-dependency in diffusion of some weakly acidic drugs, warfarin, sulfaethidole, and barbital, into organic phases.

The diffusion of three weakly acidic drugs (warfarin, sulfaethidole, and barbital) in cyclohexane-buffer and n-octanol-buffer systems was studied by two different methods; shaking and model cell type of experimentation. At low pH values the drugs moved generally more readily into the organic phases than at higher pH. Moreover, when the shaking method was used the drugs moved readily to the n-octanol phase even at higher pH levels. Lecithin improved the diffusion at low more than at high pH levels. Thus, the results varied according to the organic phase selected and the method used. Poor correlation was found between some results of this study and previously reported results of in situ absorption from the rat gastrointestinal tract of the same drugs. The results do not support the assumption that phospholipids may have a role in the absorption of ionized moieties.

The absorption of warfarin from the rat stomach in situ.

The absorption of warfarin from rat stomach was studied in situ by measuring the warfarin concentration in the gastric fluid, plasma, and the gastric wall concurrently. The warfarin concentrations in gastric fluid with initially acidic pH (pH 3 and pH 5) declined more rapidly than in initially neutral (pH 7) or basic (pH 8) fluid. However, the concurrent measurement of warfarin concentrations in plasma revealed that the absorption from initially neutral or basic fluids was faster in comparison with that measured from initially acidic milieu. This discrepancy resulted from a substantial accumulation of warfarin in the gastric wall mainly on mucosa due to the precipitation of the drug in acidic environment.

The absorption of warfarin from the rat small intestine in situ.

The in situ absorption from the rat small intestine of the weakly acidic drug, warfarin (pKa 5-05), at 200 mug ml-1 in the instilled fluid with initial pH levels of 3, 5, 7 or 8 has been examined. These initial pH's in the buffer changed rapidly towards neutrality. The buffers at pH's 3 and 5 probably caused different amounts of warfarin precipitation, which resulted in different rates of warfarin disappearance from the instilled fluid which paralleled the initial rates of accumulation of warfarin in (or on) the intestinal wall. Where greater drug precipitation had probably occurred the initial rates of absorption into the plasma were slower. At the initial pH of 3 and by solubilization of warfarin with propylene glycol, the rate of absorption was similar to that from a fluid of pH 7. Propylene glycol in 15% solution did not affect the system significantly. The relatively high transfer of warfarin into octanol from buffer solution at pH 7 might indicate that the small fraction of unionized drug (1 : 100) at pH 7 is enough for remarkable transfer of this highly lipid-soluble drug.

Dry polyacrylamide batch method for studying drug protein binding.

The validity of a new technique for studying drug protein binding is tested. By this gel diffusion or batch method using dry polyacrylamide, sulfadiazine and sulfafurazole are bound by human plasma proteins to the same extent as reported by other authors with different techniques. The binding of warfarin to fresh human plasma was quantitatively less than expected. This might be due to the possibility that other plasma constituents of non-fasted test persons displace warfarin from protein binding sites, since it is bound more in buffer solutions containing physiological concentrations of human albumin. Phenylbutazone displaced warfarin from its binding sites in diluted human serum albumin concentrations. Quinidine was found to be adsorbed by the otherwise inert polyacrylamide gel and the method is therefore not applicable to quinidine binding studies.

Dry polyacrylamide batch method for determining the binding of various compounds by plasma proteins.

A new modification of the gel diffusion method has been developed using dry polyacrylamide gel. The theoretical background is explained and the mathematical formulas are presented. The properties of the gel are studied, concerning the absorbing capacities and changes in ion equilibria. As a model compound the freely diffusible calcium is assayed and the result obtained (52.4 +/- 2.9%) agrees well with the results from previous methods by other authors. The accuracy of the method is discussed and the theoretical explanation to the sensitivity in determinations is calculated.