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Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update.

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Adult↗

A randomized trial of Lactobacillus acidophilus BG2FO4 to treat lactose intolerance.

BACKGROUND: Lactose intolerance is the most common disorder of intestinal carbohydrate digestion. Lactobacillus acidophilus BG2FO4 is a strain of lactobacilli with properties of marked intestinal adherence and high beta-galactosidase activity. OBJECTIVE: This study was designed to determine whether oral feeding of Lactobacillus acidophilus BG2FO4 leads to a lactose-tolerant state. DESIGN: We studied 42 subjects with self-reported lactose intolerance and performed breath-hydrogen tests to determine whether they were lactose maldigesters. Subjects with established lactose maldigestion (n = 24) were invited to be randomly assigned to an omeprazole-treated (hypochlorhydric) group or a non-omeprazole-treated group, but 6 subjects chose not to participate. All randomly assigned subjects (n = 18) ingested Lactobacillus acidophilus BG2FO4 twice per day for 7 d and stool samples were collected. Breath-hydrogen tests were performed and symptom scores were recorded at baseline and after lactobacilli ingestion. RESULTS: Lactose maldigestion was established in 24 of 42 subjects (57%) with self-reported lactose intolerance. In 18 lactose-maldigesting subjects, overall hydrogen production and symptom scores after ingestion of Lactobacillus acidophilus BG2FO4 were not significantly different from baseline values. Live Lactobacillus acidophilus BG2FO4 was recovered in stool samples from 7 subjects. CONCLUSIONS: Lactose intolerance is overreported in subjects with gastrointestinal symptoms after lactose ingestion. Treatment of lactose-maldigesting subjects with and without hypochlorhydria with Lactobacillus acidophilus BG2FO4 for 7 d failed to change breath-hydrogen excretion significantly after lactose ingestion.

Adult↗

Digestion and tolerance of lactose from yoghurt and different semi-solid fermented dairy products containing Lactobacillus acidophilus and bifidobacteria in lactose maldigesters--is bacterial lactase important?

OBJECTIVE: To compare the digestibility and tolerance of lactose from three semi-solid fermented dairy products with the same amount of lactose but different lactase contents and bacterial cultures in lactase deficient adults. DESIGN: Measurement of breath hydrogen (H2) concentration and of clinical symptoms after consumption of the test meals. SETTING: Metabolic ward for healthy volunteers, INSERM U290, Hôpital St. Lazare, Paris. SUBJECTS: Fifteen lactase-deficient healthy adult volunteers (20-45 y) started the study. One subject became a non-H2-producer during the study; therefore the results of 14 subjects are presented. INTERVENTION: Each subject consumed, on four different days and in random order, after a 12 h fast, three semisolid test meals containing 18 g of lactose, and a 10 g dose of lactulose which allowed calculation of lactose malabsorption. The three meals were: traditional yoghurt, fermented milk (Ofilus) that contained Lactobacillus acidophilus and Bifidobacterium sp., and a similar product 'Bulgofilus' enriched with Lactobacillus bulgaricus to increase the lactase content. RESULTS: Compared with lactulose, the sum of symptoms was significantly lower for Bulgofilus (P = 0.05), and bloating was less severe for Ofilus (P = 0.06). Between the fermented milks, there were no differences. The area under the breath H2 curve was significantly lower for each fermented milk when compared to lactulose (P < 0.0001). The degree of maldigestion of lactose did not differ significantly between the products; it was 21 +/- 3% (range 6-52) for Ofilus, 21 +/- 3% (range 6-44) for Bulgofilus, and 18 +/- 3% (range 3-43) for yoghurt. CONCLUSION: Despite the differences in the lactase and bacterial content, lactose was as well digested and tolerated from the three different semi-sold fermented dairy products. This could be due to a slow gastric emptying of the semi-solid milk.

Adult↗

Kefir improves lactose digestion and tolerance in adults with lactose maldigestion.

OBJECTIVE: Kefir is a fermented milk beverage that contains different cultures than yogurt. The objective of this study was to determine whether kefir improves lactose digestion and tolerance in adults with lactose maldigestion. DESIGN: Randomized block design. SUBJECTS: Fifteen healthy, free-living adults with lactose maldigestion. MAIN OUTCOME MEASURES: Breath hydrogen excretion and lactose intolerance symptoms were monitored hourly for 8 hours after each test meal. INTERVENTION: Subjects were fed test meals consisting of 20 g lactose portions of milk (2% reduced fat), plain and raspberry flavored kefir, and plain and raspberry flavored yogurt, each following an overnight (12 hour) fast. STATISTICAL ANALYSIS: Mixed model ANOVA was performed on raw or transformed data, followed by Tukey HSD post hoc tests (when appropriate). Significance was defined as P<.05. RESULTS: The breath hydrogen area under the curve (AUC) for milk (224+/-39 ppm x h) was significantly greater than for the plain yogurt (76+/-14 ppm x h, P<.001), the plain kefir (87+/-37 ppm x h, P<.001), and the flavored yogurt (76+/-14 ppm x h, P=.005). The flavored kefir had an intermediate response (156+/-26 ppm x h). The yogurts and kefirs all similarly reduced the perceived severity of flatulence by 54% to 71% relative to milk. Abdominal pain and diarrhea symptoms were negligible among the five treatments. APPLICATIONS/CONCLUSION: Because kefir improved lactose digestion and tolerance in this study, its use may be another potential strategy for overcoming lactose intolerance. Further studies of other types of kefir for improving lactose digestion are warranted.

Adult↗

Long-term follow-up after Billroth I and II partial gastrectomy. Gastrointestinal tract function and changes in bone metabolism.

Late results of Billroth I (BI) partial gastrectomy for peptic ulcer in 19 patients were compared with those in 19 patients who had undergone Billroth II (B II) operation. The groups were matched for age and sex and were re-examined 21 to 27 years postoperatively. The study included notation of abdominal symptoms and haematologic status and tests of calcium metabolism with serum D-vitamin concentrations [S-25(OH)D2 and S-25(OH)D3], A-vitamin absorption, lactose and d-xylose tolerance and barium meal transit time to assess intestinal function, gastroscopy with biopsies, and measurement of bone mineral density, using the 241Am gamma ray attenuation method. In the paired comparisons of B I and B II patients, no significant difference was found in haematologic status or results of intestinal function tests. The serum alkaline phosphatase activity was significantly higher after B II than after B I, whereas S-25(OH)D2 and S-25(OH)D3 were significantly higher in the B I group. Other data for calcium metabolism showed no significant intergroup difference. Bone mineral density likewise was not significantly different in the two groups, but in both of them the values were significantly lower than in healthy control subjects. Most patients in both Billroth groups had atrophic mucosal gastritis.

Aged↗

Tolerance to small amounts of lactose in lactose maldigesters.

In this study we examined whether small doses of lactose induced symptoms in 39 lactose maldigesters and 15 lactose digesters in a randomized, crossover, double-blind design. The test doses were 200 mL fat-free, lactose-free milk to which 0, 0.5, 1.5, and 7 g lactose was added. Every third day of a lactose-free diet, after an overnight fast, the subjects drank one of the test milks in random order and registered the occurrence and severity of gastrointestinal symptoms in the next 12 h. During the study, the maldigesters reported significantly more abdominal bloating (P = 0.0003) and abdominal pain (P = 0.006) than the digesters. There was no difference in the mean severity of the reported symptoms between the test milks and the lactose-free milk in the group of lactose maldigesters, of whom one-third did not experience any symptoms from any of the test doses. The same proportion (64%) of the maldigesters experienced symptoms after both the lactose-free milk and the milk with 7 g lactose. However, the symptoms occurred inconsistently with the different test doses in 59% of the maldigesters. Thus, it can be concluded that the gastrointestinal symptoms in most lactose maldigesters are not induced by lactose when small amounts (0.5-7.0 g) of lactose are included in the diet.

Abdominal Pain↗

[Strategies for investigating non-assimilation. A critical status].

This review reevaluates the rational basis for choice of diagnostic strategies in patients with suspected malassimilation. Prospective evaluation of diagnostic tests must fulfil several requirements for a correct assessment of their clinical value. Very few studies meet such requirements, resulting in unnecessary investigations as well as overlooked cases with a negative impact on patients and society. This problem includes evaluation of assimilation of macronutrients (carbohydrate, fat, protein) as well as micronutrients (e.g. vitamin B12), and it is further complicated by the occurrence of conditions with occult (compensated) malassimilation. Malassimilation of carbohydrates may be physiological (starch, fructose, sugar alcohols etc., in certain ethnic groups lactose) as well as pathological. In both instances chronic gastro-intestinal distress may arise in sensitive individuals. The diagnosis is based on tolerance tests, combined with blood tests or breath tests (hydrogen excretion). The latter is considered the most reliable, but the available evidence for choice of tests is not solid. Similar reservations apply to conditions of bacterial overgrowth of the small intestine, which may lead to diffuse malassimilation. The frequency and clinical importance of this condition is in all probability underestimated. Screening for coeliac disease may be achieved by several serological tests (reticulin-, gliadin-, endomysial antibodies), of which IgA-endomysial antibodies seem superior. Comparative studies are often flawed in design, however, and permeability tests may also eventually find their place in the test battery. There is thus a strong need for more evidence-based diagnostic strategies in patients with suspected malassimilation.

Celiac Disease↗

Self-reported milk intolerance in irritable bowel syndrome: what should we believe?

BACKGROUND & AIMS: The real importance of lactose malabsorption in irritable bowel syndrome (IBS) is still controversial. The aim is to define the relationship between patient perception of milk tolerance/intolerance, lactose malabsorption and abdominal symptoms in IBS. METHODS: A hydrogen breath test (HBT) after an oral load of lactose was carried out in 475 consecutive IBS patients, diagnosed according to the Rome criteria. Data were analyzed in 201 age- and sex-matched pairs of IBS patients, classified according to self-reported milk tolerance/intolerance. Hydrogen peak and excretion, predominant presenting symptom and the occurrence of symptoms during the test, were evaluated. RESULTS: The prevalence of positive HBT and the occurrence of symptoms during the test was similar in milk "tolerant" (68.6%, 40.7% respectively) and "intolerant" patients (75.6%, 42.7% respectively), as well as peak (76.4 vs 75.2 ppm) and amount of H2 excreted (57.8 vs. 53.2 ppm/h). The positive predictive value for self-reported milk intolerance was 0.75, and the negative predictive value in regular milk users was 0.31, reflecting the prevalence of lactose malabsorption in the general population more than the awareness of milk tolerance. CONCLUSIONS: In IBS patients, self-reported milk intolerance does not help in identifying lactose malabsorbers. The opposite does not rule out the occurrence of symptoms after a lactose load. Lactose is, indeed, responsible for symptoms in some IBS patients, however, these patients can only be identified by the occurrence of symptoms during the test, and not on the individual perception of milk intolerance.

Adult↗

Urinary excretion by dogs of intravenously administered simple sugars.

Seven simple sugars, commonly used in intestinal function tests, were simultaneously administered intravenously to dogs and their urinary excretion was measured to assess their potential for metabolic degradation. Lactose, lactulose and 3-O-methyl-D-glucose were excreted unchanged, but small proportions of palatinose and sucrose were not, and were assumed to have been metabolised. More than half of the administered D-xylose and a quarter of L-rhamnose was not excreted and was assumed to have been metabolised. These findings may be significant for the interpretation of differential sugar absorption tests and the D-xylose tolerance test.

3-O-Methylglucose↗

Effects of indigestible dextrin on glucose tolerance in rats.

A recently developed indigestible dextrin (IDex) was studied for its effects on glucose tolerance in male Sprague-Dawley rats. IDex is a low viscosity, water-soluble dietary fibre obtained by heating and enzyme treatment of potato starch. It has an average molecular weight of 1600. An oral glucose tolerance test was conducted with 8-week-old rats to evaluate the effects of IDex on the increase in plasma glucose and insulin levels after a single administration of various sugars (1.5 g/kg body weight). The increase in both plasma glucose and insulin levels following sucrose, maltose and maltodextrin loading was significantly reduced by IDex (0.15 g/kg body weight). This effect was not noted following glucose, high fructose syrup and lactose loading. To evaluate the effects of continual IDex ingestion on glucose tolerance, 5-week-old rats were kept for 8 weeks on a stock diet, a high sucrose diet or an IDex-supplemented high sucrose diet. An oral glucose (1.5 g/kg body weight) tolerance test was conducted in week 8. Increases in both plasma glucose and insulin levels following glucose loading were higher in the rats given a high sucrose diet than in the rats fed a stock diet. However, when IDex was included in the high sucrose diet, the impairment of glucose tolerance was alleviated. Moreover, IDex feeding also significantly reduced accumulation of body fat, regardless of changes in body weight. These findings suggest that IDex not only improves glucose tolerance following sucrose, maltose and maltodextrin loading but also stops progressive decrease in glucose tolerance by preventing a high sucrose diet from causing obesity.

Animals↗

Malabsorption of different lactose loads in children with human immunodeficiency virus infection.

Thirty children infected with human immunodeficiency virus (HIV) (18 P1 and 12 P2, according to the classification system of the Centers for Disease Control) and 54 noninfected children were evaluated for lactose malabsorption with use of the hydrogen breath test after different lactose loads. Lactose malabsorption after load of 2 g/kg occurred in 75% of P2, 67% of P1, and in 46% of noninfected children. With a lower lactose load (1 g/kg), the prevalence of malabsorption was significantly higher among P2 children than P1 and noninfected cases. A similar figure was obtained after the lowest load (0.5 g/kg). Infected children with lactose malabsorption were significantly younger than noninfected malabsorbers (mean age +/- SD; 50.3 +/- 22 vs. 63.5 +/- 20.9 months) when the load of 2 g/kg was used. The use of lower lactose loads seems to be helpful in finding the dose that can be tolerated. This finding could have nutritional importance and could lead to better dietary management.

Breath Tests↗