Life Extension Magazine®

Issue: Nov 2013

Raft alginate

Efficient topical delivery of chlorogenic acid by an oil-in-water microemulsion to protect skin against UV-induced damage.

We examined the intradermal delivery of a hydrophilic polyphenol chlorogenic acid by in vitro study using excised guinea pig dorsal skin and Yucatan micropig skin. Skin accumulation as well as the solubility of chlorogenic acid in aqueous vehicles was much greater than for other polyphenols such as quercetin and genistein. However, since enhancement of skin delivery seemed to be necessary to exhibit its protective effects against oxidative damage of skin, we examined the effects of microemulsions as vehicles. Using microemulsions consisting of 150 mM NaCl solution, isopropyl myristate, polyoxyethylene sorbitan monooleate (Tween 80) and ethanol, skin accumulation as well as solubility of chlorogenic acid further increased. Enhancement effect of an oil-in-water (o/w-type) microemulsion was greater than that of a water-in-oil (w/o-type) microemulsion possibly due to the greater increase in solubility. This finding was quite different from previous findings on relatively hydrophobic polyphenols such as quercetin and genistein. Pretreatment of guinea pig dorsal skin with chlorogenic acid containing microemulsion gel prevented erythema formation induced by UV irradiation. These findings indicate the potential use of hydrophilic chlorogenic acid with o/w-type microemulsion as a vehicle to protect skin against UV-induced oxidative damage.

Chem Pharm Bull (Tokyo). 2011;59(6):793-6

Protection from photodamage by topical application of caffeine after ultraviolet irradiation.

BACKGROUND: Characterization of mechanisms that can reverse residual damage from prior skin exposure to ultraviolet (UV) would be of considerable biological and therapeutic interest. Topical caffeine application to mouse skin that had previously been treated with UV has been shown to inhibit the subsequent development of squamous cell carcinomas. OBJECTIVES: We used an established mouse photodamage model to investigate other possible effects of topical caffeine application after UV. METHODS: SKH-1 hairless mice were treated with ultraviolet B (UVB) followed immediately by topical application of caffeine or vehicle three times weekly for 11 weeks. RESULTS: Caffeine applied topically after UV treatment resulted in a significant decrease in UV-induced skin roughness/transverse rhytides as assessed by treatment-blinded examiners. Histologically, topical caffeine application after a single dose of UVB more than doubled the number of apoptotic keratinocytes as evaluated by sunburn cell formation, caspase 3 cleavage and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) staining. A trend towards decreased solar elastosis was noted in the caffeine-treated group although this was not statistically significant. Other histological parameters including epidermal hyperplasia, solar elastosis and angiogenesis were increased in mice treated with UV but topical application of caffeine did not alter these particular UV effects. CONCLUSIONS: These findings support the concept that topical application of caffeine to mouse skin after UV irradiation promotes the deletion of DNA-damaged keratinocytes and may partially diminish photodamage as well as photocarcinogenesis.

Br J Dermatol. 2007 May;156(5):957-64

Effect of green Coffea arabica L. seed oil on extracellular matrix components and water-channel expression in in vitro and ex vivo human skin models.

BACKGROUND: Green Coffea arabica L. seed oil is being widely
used in cosmetic formulations, although its effects on human skin cells are not clear and most observations are unpublished. AIMS: In this study, we evaluated the in vitro effects of green coffee (C. arabica L.) oil (GCO) on the synthesis of collagen, elastin, and glycosaminoglycans (GAG) and in the release of transforming growth factor-beta1 (TGF-beta1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by human skin fibroblasts. We also investigated the ability of GCO to increase aquaglycerolporins-3 (AQP-3) mRNA expression in cultured keratinocytes and human skin explants. METHODS: Human fibroblasts were incubated for 48 h with several GCO concentrations (3.12, 6.25, 12.5, 25.0 and 50.0 mg/mL). The levels of growth factors and extracellular matrix compounds in the culture supernatant were measured using commercial kits. To evaluate AQP-3 relative expression, using real-time reverse transcription polymerase chain reaction, keratinocytes were incubated for 3-6 h with the GCO optimal concentration of 25.0 mg/mL. Histological sections of human skin were also incubated with GCO (25.0 mg/mL) and immunostained by antiserum against AQP-3. RESULTS: Our results demonstrated that incubation with GCO produces a dose-dependent stimulation in the synthesis of collagen, elastin, and GAG, in addition to increasing the release of the growth factors TGF-beta1 and GM-CSF. GCO also induced the expression of AQP-3 mRNA, which reached levels up to 6.5-fold higher than those of the control cultures. CONCLUSION: The findings presented herein suggest that GCO might improve physiological balance in the skin, thus allowing the formation of new connective tissue, and preventing epidermis dryness by increasing AQP-3 levels. Taking into account the limitations of in vitro studies, it is encouraging in this context to consider CGO as an adjuvant to be used in dermocosmetic formulations. Clinical studies are in progress in our laboratory aiming to further investigate the protective effects of CGO in the skin.

J Cosmet Dermatol. 2009 Mar;8(1):56-62

Mechanisms of photoaging and chronological skin aging.

Human skin, like all other organs, undergoes chronological aging. In addition, unlike other organs, skin is in direct contact with the environment and therefore undergoes aging as a consequence of environmental damage. The primary environmental factor that causes human skin aging is UV irradiation from the sun. This sun-induced skin aging (photoaging), like chronological aging, is a cumulative process. However, unlike chronological aging, which depends on the passage of time per se, photoaging depends primarily on the degree of sun exposure and skin pigment. Individuals who have outdoor lifestyles, live in sunny climates, and are lightly pigmented will experience the greatest degree of photoaging. During the last decade, substantial progress has been made in understanding cellular and molecular mechanisms that bring about chronological aging and photoaging. This emerging information reveals that chronological aging and photoaging share fundamental molecular pathways. These new insights regarding convergence of the molecular basis of chronological aging and photoaging provide exciting new opportunities for the development of new anti-aging therapies. This article reviews our current understanding and presents new data about the molecular pathways that mediate skin damage by UV irradiation and by the passage of time.

Arch Dermatol. 2002 Nov;138(11):1462-70

Efficacy of anti-aging products for periorbital wrinkles as measured by 3-D imaging.

BACKGROUND: The periorbital area is a key wrinkle-prone region, where the first signs of aging usually appear. AIMS: To demonstrate the ability of new anti-aging moisturizing products to improve overall smoothness and wrinkle depth appearance in the periorbital region via the Fast Optical in vivo Topometry of Human Skin (FOITS). METHODS: Two double-blind, randomized, controlled, split-face studies (n = 42, Study 1; n = 35, Study 2) were conducted in women 30-70 years old with moderate to distinct periorbital wrinkles. Subjects applied 0.5 g of individual products to half their face twice daily for 4 weeks. Four test products containing niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine were used and included a daytime SPF 30 lotion also containing antioxidants, a night cream, an eye cream also containing caffeine, and a wrinkle treatment containing retinyl propionate. The wrinkle treatment was only tested in Study 2. The FOITS technique was used to measure changes in periorbital R(a) (mean roughness) and R(z) (average maximum roughness) at 2 and 4 weeks. RESULTS: In Study 1, the daytime SPF 30 lotion, night cream, and eye cream significantly improved crow’s feet smoothness after 4 weeks relative to no treatment. After 4 weeks, the daytime SPF 30 lotion and night cream, but not the eye cream, were significantly better than no treatment at improving R(z). In Study 2, the night cream, eye cream, and wrinkle treatment, but not the daytime SPF 30 lotion, significantly improved both R(a) and R(z) after 4 weeks. To increase power and precision of estimates, a meta-analysis was performed; the pooled data showed all three products were significantly better than no treatment at improving R(a) and R(z) after 4 weeks. CONCLUSIONS: Four weeks of treatment with these products was shown to improve the smoothness of periorbital skin and to reduce the apparent depth of larger wrinkles.

J Cosmet Dermatol. 2009 Sep;8(3):228-33

Effects of caffeine and siloxanetriol alginate caffeine, as anticellulite agents, on fatty tissue: histological evaluation.

BACKGROUND: Cellulite is a physiological condition that presents etiologic plurality. Caffeine and its derivatives are used in anticellulite cosmetics due to their lipolytic activity on fatty cells. Siloxanetriol alginate caffeine (SAC) is a silanol derived from organic silicon. Radicals primarily from SAC are caffeine and the mannuronic acid. AIMS: This study aims to analyze the effects of caffeine and siloxanetriol alginate caffeine on fatty tissue by histological evaluation. METHODS: Formulations were developed with caffeine, caffeine + sodium benzoate or SAC and were applied topically for 21 days on Wistar female mice. The study regarded the histological aspects by determination of diameter and number of fatty cells with a light microscope. RESULTS: Emulsion with caffeine caused a reduction of 17% on the diameter of the fatty cells compared with the control. The emulsion with caffeine + sodium benzoate did not cause alterations on cell diameter. Emulsion with SAC provoked reduction on fatty cell diameters of 16%. No significant alterations were observed on the diameter of the fatty cells treated with gels, although it was noticed that gel with SAC promoted a reduction of 26% on the number of fatty cells. CONCLUSIONS: Emulsion with SAC was considered more indicated to promote the lipolytic action on fatty tissue, acting as a complement to treat cellulite. When sodium benzoate was added to the preparations, it inhibited the caffeine efficiency. Gel was not an adequate vehicle to be incorporated with caffeine and SAC.

J Cosmet Dermatol. 2008 Mar;7(1):23-9


Among harmful environmental factors that contribute to extrinsic aging, long-term effects of repeated exposure to ultraviolet light are the most significant and are referred to as photoaging. Photoaging is a multisystem degenerative process that involves the skin and skin support system. It is a cumulative process and depends primarily on the degree of sun exposure and skin pigment. The epidermis and dermis are both affected by UVB, but the dermis is also affected to a significant extent by UVA. It has long been thought that the majority of human photo-lesions due to UVB rays, now it is believed that UVA play a substantial role in photoaging. Photoaging affects the sun-exposed areas and is characterized clinically by fine and coarse wrinkling, roughness, dryness, laxity, teleangiectasia, loss of tensile strength and pigmentary changes. There is also an increase in development of benign and malignant neoplasms on photoaged skin. During the years the progress has been made in understanding the photoaging in human skin. UV irradiation invokes a complex sequence of specific molecular responses that damage skin connective tissue. Restriction of UV irradiation and the use of high-protection, broad-spectrum sunscreens may slow progression of photoaging.

Coll Antropol. 2008 Oct;32 Suppl 2:177-80

A double-blind, randomized, controlled clinical trial evaluating the efficacy and tolerance of a novel phenolic antioxidant skin care system containing Coffea arabica and concentrated fruit and vegetable extracts.

OBJECTIVE: This 12-week, double-blinded, randomized, controlled clinical usage study was conducted to evaluate the efficacy and tolerance of a novel topical, multi-ingredient, polyphenol, high antioxidant skin care system (facial wash, day lotion, night crème and eye serum) to reduce the appearance of photoaging. METHODS: A total of 40 Caucasian female participants were randomly assigned to apply the test regimen or control regimen for 12 weeks. One group washed with the test antioxidant facial wash twice daily, applied the test antioxidant day lotion each morning and the test antioxidant night creme and eye serum each evening. The second group washed with a control facial wash twice daily and applied a control moisturizer each morning and evening. Clinical evaluations for efficacy were made by a board-certified dermatologist at baseline and after six and 12 weeks of product use. Efficacy was also measured by subjects’ self-assessments and via photography and instrumentation. RESULTS AND CONCLUSION: Overall, the results of the study showed that the test regimen produced statistically significant improvements in the appearance of photodamaged skin. Most impressive was the significantly greater improvements produced by the test regimen over the control regimen for nearly every grading parameter. The results from this study demonstrate that this high Total ORACsc scoring antioxidant skin care system was well tolerated, with no adverse events reported by the participants during the course of the study, and improved, significantly greater than a control regimen, the appearance of wrinkles, firmness, hyperpigmentation, blotchy redness, tactile roughness and clarity in photodamaged skin. Post-baseline clinical grading scores, silicone replica parameters, cutometer and corneometer scores were statistically compared to baseline using a paired t test at the P?0.05 significance level.

J Drugs Dermatol. 2010 Dec;9(12):1480-7

Lactose and milk intolerance: clinical implications.

We studied 166 hospitalized male patients to determine the clinical importance of tolerance-test-determined “lactose intolerance,” assumed to affect most of the world’s adults. Abnormal lactose tolerance tests were found in 81% of 98 blacks, 12% of 59 whites of Scandinavian or Northwestern European extraction, and three of nine non-European whites. Seventy-two per cent of the “lactose-intolerant” subjects had previously realized that milk drinking could induce abdominal and bowel symptoms. Two hundred and forty milliliters of low-fat milk produced gaseousness or cramps in 59% of 44 “lactose-intolerant” men, and 68% were symptomatic with the equivalent amount of lactose. None of 18 “lactose-tolerant” men noted symptoms with milk or lactose. Refusal to drink 240 ml of low-fat milk served with meals correlated significantly with “lactose-intolerance”: 31.4% versus 12.9% among “lactose-tolerant” patients. “Lactose intolerance” is common in adults and is a clinically relevant problem.

N Engl J Med. 1975 May 29;292(22):1156-9

Review article: lactose intolerane in clinical practice­—myths and realities.

BACKGROUND: Approximately 70% of the world population has hypolactasia, which often remains undiagnosed and has the potential to cause some morbidity. However, not everyone has lactose intolerance, as several nutritional and genetic factors influence tolerance. AIMS: To review current clinical practice and identify published literature on the management of lactose intolerance. METHODS: PubMed was searched using the terms lactose, lactase and diet to find original research and reviews. Relevant articles and clinical experience provided the basis for this review. RESULTS: Lactose is found only in mammalian milk and is hydrolysed by lactase in the small intestine. The lactase gene has recently been identified. ‘Wild-type’ is characterized by lactase nonpersistence, often leading to lactose intolerance. Two genetic polymorphisms responsible for persistence have been identified, with their distribution concentrated in north Europeans. Symptoms of lactose intolerance include abdominal pain, bloating, flatulence and diarrhoea. Diagnosis is most commonly by the lactose hydrogen breath test. However, most people with hypolactasia, if given appropriate advice, can tolerate some lactose-containing foods without symptoms. CONCLUSION: In clinical practice, some people with lactose intolerance can consume milk and dairy foods without developing symptoms, whereas others will need lactose restriction.

Aliment Pharmacol Ther. 2008 Jan 15;27(2):93-103

A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance.

BACKGROUND: Ingestion of a large dose of the milk sugar lactose--for example, the 50-g load in 1 liter of milk--causes symptoms such as abdominal pain, diarrhea, bloating, and flatulence in the majority of people with lactose malabsorption. It is uncertain whether the ingestion of more common doses of lactose, such as the amount in 240 ml (8 oz) of milk, causes symptoms. Some people insist that even smaller quantities of milk, such as the amount used with cereal or coffee, cause severe gastrointestinal distress. METHODS: In a randomized, double-blind, crossover trial, we evaluated gastrointestinal symptoms in 30 people (mean age, 29.4 years; range, 18 to 50) who reported severe lactose intolerance and said they consistently had symptoms after ingesting less than 240 ml of milk. The ability to digest lactose was assessed by measuring the subjects’ end-alveolar hydrogen concentration after they ingested 15 g of lactose in 250 ml of water. Subjects then received either 240 ml of lactose-hydrolyzed milk containing 2% fat or 240 ml of milk containing 2% fat and sweetened with aspartame to approximate the taste of lactose-hydrolyzed milk; each type of milk was administered daily with breakfast for a one-week period. Using a standardized scale, subjects rated the occurrence and severity of bloating, abdominal pain, diarrhea, and flatus and recorded each passage of flatus. RESULTS: Twenty-one participants were classified as having lactose malabsorption and nine as being able to absorb lactose. During the study periods, gastrointestinal symptoms were minimal (mean symptom-severity scores for bloating, abdominal pain, diarrhea, and flatus between 0.1 and 1.2 [1 indicated trivial symptoms; and 2, mild symptoms]). When the periods were compared, there were no statistically significant differences in the severity of these four gastrointestinal symptoms. For the lactose-malabsorption group, the mean (+/- SEM) difference in episodes of flatus per day was 2.5 +/- 1.1 (95% confidence interval, 0.2 to 4.8). Daily dietary records indicated a high degree of compliance, with no additional sources of lactose reported. CONCLUSIONS: People who identify themselves as severely lactose-intolerant may mistakenly attribute a variety of abdominal symptoms to lactose intolerance. When lactose intake is limited to the equivalent of 240 ml of milk or less a day, symptoms are likely to be negligible and the use of lactose-digestive aids unnecessary.

N Engl J Med. 1995 Jul 6;333(1):1-4

Management and treatment of lactose malabsorption.

Lactose malabsorption is a very common condition characterized by intestinal lactase deficiency. Primary lactose malabsorption is an inherited deficit present in the majority of the world’s population, while secondary hypolactasia can be the consequence of an intestinal disease. The presence of malabsorbed lactose in the colonic lumen causes gastrointestinal symptoms. The condition is known as lactose intolerance. In patients with lactase nonpersistence, treatment should be considered exclusively if intolerance symptoms are present. In the absence of guidelines, the common therapeutic approach tends to exclude milk and dairy products from the diet. However, this strategy may have serious nutritional disadvantages. Several studies have been carried out to find alternative approaches, such as exogenous beta-galactosidase, yogurt and probiotics for their bacterial lactase activity, pharmacological and non pharmacological strategies that can prolong contact time between enzyme and substrate delaying gastrointestinal transit time, and chronic lactose ingestion to enhance colonic adaptation. In this review the usefulness of these approaches is discussed and a therapeutic management with a flow chart is proposed.

World J Gastroenterol . 2006 Jan 14;12(2):187-91

Enzyme replacement therapy for primary adult lactase deficiency. Effective reduction of lactose malabsorption and milk intolerance by direct addition of beta-galactosidase to milk at mealtime.

The addition of microbial beta-galactosidases directly to milk at mealtime represents a potential “enzyme replacement therapy” for primary lactase deficiency. We used the hydrogen breath test as the index of incomplete carbohydrate absorption to assess the efficacy of two enzymes--one from yeast, Kluyveromyces lactis (LactAid), and the other from the fungus Aspergillus niger (Lactase N)--to assist in the hydrolysis of 18 g of lactose in 360 ml (12 oz) of whole milk when consumed by an adult lactose malabsorber. Graded amounts of Lactase N produced, at best, a 53% relative reduction in breath hydrogen excretion, whereas quantitative elimination of excess hydrogen excretion was produced by 1 and 1.5 g of LactAid. A double-blind, controlled, crossover trial was subsequently performed in 50 healthy, unselected Mexican adults, to whom 360 ml of cow’s milk was presented in the three forms in a randomized order: intact milk, prehydrolyzed milk, and milk to which 1 g of LactAid was added immediately before consumption. Among the 25 subjects with incomplete carbohydrate absorption with intact milk, adding enzyme 5-min before consumption produced a 62% reduction in breath hydrogen excretion, and symptoms of intolerance were significantly reduced. The feasibility of effective enzyme replacement therapy with a beta-galactosidase from K. lactis is demonstrated.

Gastroenterology. 1984 Nov;87(5):1072-82

Cow’s milk allergy versus cow milk intolerance.

BACKGROUND: Although cow’s milk allergy (CMA) and cow’s milk intolerance (CMI) are two different terms, they are often used interchangeably, resulting in confusion both in clinical practice and in research reports. OBJECTIVE: To promote the appropriate differential use of the terms CMA and CMI. METHODS: Highlighting the differences in clinical and laboratory findings between CMA and CMI. Information was derived from reviewing the literature on these two topics, supplemented by the clinical experience of the author. RESULTS: CMA is an immunologically mediated reaction to cow’s milk proteins that may involve the gastro-intestinal tract, skin, respiratory tract, or multiple systems, ie, systemic anaphylaxis. Its prevalence in the general population is probably 1 to 3%, being highest in infants and lowest in adults. Even though it can cause severe morbidity and even fatality, dietary elimination is associated with good prognosis. However, CMI should refer to nonimmunologic reactions to cow’s milk (CM), such as disorders of digestion, absorption, or metabolism of certain CM components. The most common cause of CMI is lactase deficiency, which is mostly acquired during late childhood or adulthood. It has high racial predilection, being highest in dark-skinned populations and lowest in northern Europeans. Lactose intolerance is generally a benign condition, with symptoms limited to the gastro-intestinal tract, yet the primary acquired type lasts for a lifetime. Symptoms can be well ameliorated by reducing the intake of CM or using lactose-hydrolyzing agents. CONCLUSIONS: Adverse reactions to CM should be differentiated into immunologic (CMA) and nonimmunologic (CMI). The latter is still a general term that comprises several conditions and requires further differentiation.

Ann Allergy Asthma Immunol. 2002 Dec;89(6 Suppl 1):56-60

Structural basis of specificity in tetrameric Kluyveromyces lactis b-galactosidase.

b-Galactosidase or lactase is a very important enzyme in the food industry, being that from the yeast Kluyveromyces lactis the most widely used. Here we report its three-dimensional structure both in the free state and complexed with the product galactose. The monomer folds into five domains in a pattern conserved with the prokaryote enzymes of the GH2 family, although two long insertions in domains 2 and 3 are unique and related to oligomerization and specificity. The tetrameric enzyme is a dimer of dimers, with higher dissociation energy for the dimers than for its assembly. Two active centers are located at the interface within each dimer in a narrow channel. The insertion at domain 3 protrudes into this channel and makes putative links with the aglycone moiety of docked lactose. In spite of common structural features related to function, the determinants of the reaction mechanism proposed for Escherichia coli b-galactosidase are not found in the active site of the K. lactis enzyme. This is the first X-ray crystal structure for a b-galactosidase used in food processing.

J Struct Biol. 2012 Feb;177(2):392-401

Dietary manipulation of postprandial colonic lactose fermentation: II. Addition of exogenous, microbial beta-galactosidases at mealtime.

The feasibility and efficacy of adding microbial beta-galactosidase enzymes directly to milk at the time of consumption was explored in adult lactose-malabsorbers. The hydrogen breath test, and on one occasion, the rise in blood glucose, were used as indices of the completeness of intraintestinal hydrolysis and absorption of milk lactose. When added to 360 ml of cow milk containing 18 g of lactose, empirical dosages of three beta-galactosidases--one from Kluyveromyces (yeast) and two from Aspergillus (fungal)--had some effectiveness in reducing postprandial H2 excretion, although no in vivo treatment at the dosages chosen was as effective as pre-incubation of the milk in vitro. The yeast enzyme also reduced symptom frequency as compared to intact milk and enhanced postprandial rises in blood glucose. The replacement therapy with exogenous, food-grade beta-galactosidases may provide a useful intervention to reduce lactose malabsorption and milk intolerance in individuals with primary lactase deficiency.

Am J Clin Nutr. 1985 Feb;41(2):209-21

The relationship between lactose tolerance test results and symptoms of lactose intolerance.

OBJECTIVE: A standard for the assessment of lactose malabsorption does not exist. As measured by lactose tolerance tests, insufficient increase in blood glucose or increased breath hydrogen (H2) excretion after lactose ingestion is regarded as pathological. In this study, we have tried to elucidate the relationship between lactose tolerance test results and symptoms after a lactose challenge. This relationship might be an indicator for the validity of the test. METHODS: In a prospective study, 309 consecutive patients with suspected lactose malabsorption underwent a lactose tolerance test. After consumption of 50 g of lactose, blood glucose and breath H2 concentrations were measured. During the test (240 min), the severity of bloating, flatulence, abdominal distention, and diarrhea were semiquantitatively scored as 0, 1, or 2. The individual sum of these four scores was calculated and denoted as the total symptom score (TSS). All subjects were classified according to their TSS to compare symptoms with peak breath-H2 concentration and change in blood glucose concentration, respectively. RESULTS: The glucose and breath H2 response were pathological in 51.1 and 39.5% of cases, respectively. A stepwise increase in TSS of 1 point was associated with a significant increase (p < 0.05) in mean peak H2 concentration. However, a significantly lower glucose increment compared with patients with a TSS of 0 was found only in patients with a TSS of 2 or 4. The mean symptom score differed significantly between the positive and negative breath tests (p < 0.001), but did not differ between the positive and negative glucose response results. CONCLUSIONS: This study shows that GI symptoms after a lactose challenge are strongly associated with the amount of H2 excretion. The relationship between the increase in glucose concentration and symptoms after a lactose load is less evident. Thus, the H2 breath test seems to be superior to the measurement of blood glucose increment as a diagnostic tool in lactose malabsorption, although the true predictive value of this test only can be determined after a period of dietary treatment.

Am J Gastroenterol. 1997 Jun;92(6):981-4

The genetically programmed down-regulation of lactase in children.

BACKGROUND & AIMS: Intestinal lactase activity is high in all healthy human babies, but in adults a genetic polymorphism, which acts in cis to the lactase gene, determines high or low messenger RNA (mRNA) expression and activity (lactase persistence and nonpersistence, respectively). Our aim was to investigate the onset of expression of this polymorphism in children. METHODS: Activities were analyzed in relation to age in normal biopsy specimens from a 20-year collection of diagnostic specimens. In a smaller set of 32 samples, aged 2-132 months, RNA was extracted for semiquantitative reverse-transcription polymerase chain reaction. Marker polymorphisms were used to determine the allelic origin of lactase mRNA transcripts. RESULTS: Analysis of 866 children showed evidence that the lactase persistence/nonpersistence polymorphism began before 5 years of age. The 32 children tested had high lactase mRNA and activity. Six children aged 2-16 months showed equal expression of two alleles, 2 children aged 7 and 14 months showed slightly asymmetric expression, and 7 children aged 22-132 months showed very asymmetric expression, the second allele being undetectable in the 11-year-old, as previously seen in lactase-persistent heterozygote adults. CONCLUSIONS: Genetically programmed down-regulation of the lactase gene is detectable in children from the second year of life, although the onset and extent are somewhat variable.

Gastroenterology. 1998 Jun;114(6):1230-6

Effect of alginate and alginate-cimetidine combination therapy on stimulated postprandial gastro-oesophageal reflux.

This randomized, single-blind cross-over study compared the effectiveness of a conventional alginate reflux barrier formulation (20 mL single dose of Liquid Gaviscon; sodium alginate, sodium bicarbonate, calcium carbonate) with a 20 mL single dose of an alginate-cimetidine combination formulation (Algitec Suspension; sodium alginate, cimetidine) in the suppression of food and acid reflux into the oesophagus after a test meal in 12 healthy volunteers. Subjects were fasted overnight before the study. A pH electrode and gamma detector were accurately positioned 5 cm above the cardia. The volunteers received a 99mTc-labelled meal designed to provoke reflux and then either remained untreated, or 30 min later were given either Algitec Suspension or Liquid Gaviscon. Reflux of both food and acid into the oesophagus was measured for 3 h. There was a seven day wash-out period between each treatment. Food reflux in the control group was 22,878 +/- 14,385 counts x 10(3) and this was significantly suppressed by both Liquid Gaviscon (174 +/- 128 (s.e.) counts x 10(3); P = 0.003); however, although the reduction of food reflux to 3812 +/- 2322 counts x 10(3) observed after Algitec treatment was considerable, this did not reach statistical significance (P > 0.05) due to the large intersubject variation. Liquid Gaviscon was significantly better at reducing food reflux than Algitec (P = 0.001). Gaviscon also significantly reduced acid reflux when compared with the control group (1.08 +/- 0.73 vs 5.87 +/- 3.27% recording time oesophageal pH < 4, respectively) (P = 0.03). The slight reduction in acid reflux after Algitec treatment (3.25 +/- 1.82% recording time oesophageal pH < 4) also did not reach statistical significance. The difference between Algitec and Gaviscon treatment was also not significant.

J Pharm Pharmacol. 1995 Nov;47(11):879-82

Rapid onset of effect of sodium alginate on gastro-oesophageal reflux compared with ranitidine and omeprazole, and relationship between symptoms and reflux episodes.

The objective of the open, randomised, four-period crossover study was to compare the time of onset of effect of sodium alginate (SA), omeprazole, ranitidine and control, based on oesophageal and intragastric pH and to determine any correlation between reflux symptoms and episodes in volunteers suffering from occasional gastro-oesophageal reflux. SA showed extensive prevention of acid exposure in the oesophagus compared with other treatments during the first hour. Overall, SA was more effective than control or omeprazole and comparable with ranitidine. There was little evidence of association between ‘oesophageal’ symptoms and reflux episodes, but associations between ‘gastric’ symptoms and acidity in the oesophagus, fundus and corpus were apparent. For an immediate reduction in gastro-oesophageal reflux into the oesophagus and gastric acidity during the first hour, SA was significantly superior to control, ranitidine and omeprazole. Ranitidine showed a superior effect from 2 h, consistent with its pharmacological mode of action.

Int J Clin Pract. 2006 Mar;60(3):275-83

Gastroprotective and ulcer-healing mechanisms of ellagic acid in experimental rats.

Ellagic acid (EA), a plant-derived polyphenol, exhibits antioxidant, anti-inflammatory, and gastroprotective effects. Its gastroprotective mechanisms have not been fully elucidated nor have its effects on chronic ulcer previously been described. Toward these ends, the antiulcer activities of EA were evaluated in acute (ethanol and indomethacin) and chronic (acetic acid) ulcer models in Wistar rats. In this study, oral administration of EA significantly prevented the gastric ulceration caused by ethanol, indomethacin, and acetic acid treatments. Its gastroprotective mechanism in ethanol-induced ulcer were partly due to intensification in the endogenous production of nitric oxide, an antioxidant effect by replenishing depletion of endogenous nonprotein sulfhydryls and attenuation of tumor necrosis factor-α increase, whereas in indomethacin ulcer, it is partly due to a reduction in the plasma level of leukotriene B(4). In acetic acid ulcer, promotion of ulcer-healing effects was partly due to attenuation of the elevated levels of the inflammatory cytokines TNF-α, interferon-γ, and interleukins-4 and -6. These findings suggest that ellagic acid exerts its antiulcer activity by strengthening the defensive factors and attenuating the offensive factors.

J Agric Food Chem. 2011 Jul 13;59(13):6957-65

Strawberry polyphenols attenuate ethanol-induced gastric lesions in rats by activation of antioxidant enzymes and attenuation of MDA increase.

BACKGROUND AND AIM: Free radicals are implicated in the aetiology of gastrointestinal disorders such as gastric ulcer, colorectal cancer and inflammatory bowel disease. Strawberries are common and important fruit due to their high content of essential nutrient and beneficial phytochemicals which seem to have relevant biological activity on human health. In the present study we investigated the antioxidant and protective effects of three strawberry extracts against ethanol-induced gastric mucosa damage in an experimental in vivo model and to test whether strawberry extracts affect antioxidant enzyme activities in gastric mucosa. METHODS/PRINCIPAL FINDINGS: Strawberry extracts were obtained from Adria, Sveva and Alba cultivars. Total antioxidant capacity and radical scavenging capacity were performed by TEAC, ORAC and electron paramagnetic resonance assays. Identification and quantification of anthocyanins was carried out by HPLC-DAD-MS analyses. Different groups of animals received 40 mg/day/kg body weight of strawberry crude extracts for 10 days. Gastric damage was induced by ethanol. The ulcer index was calculated together with the determination of catalase and SOD activities and MDA contents. Strawberry extracts are rich in anthocyanins and present important antioxidant capacity. Ethanol caused severe gastric damage and strawberry consumption protected against its deleterious role. Antioxidant enzyme activities increased significantly after strawberry extract intake and a concomitantly decrease in gastric lipid peroxidation was found. A significant correlation between total anthocyanin content and percent of inhibition of ulcer index was also found. CONCLUSIONS: Strawberry extracts prevented exogenous ethanol-induced damage to rats’ gastric mucosa. These effects seem to be associated with the antioxidant activity and phenolic content in the extract as well as with the capacity of promoting the action of antioxidant enzymes. A diet rich in strawberries might exert a beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species.

PLoS One. 2011;6(10):e25878

Inhibition of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus by dietary freeze-dried strawberries.

In the present study, we examined the ability of dietary freeze-dried strawberries to inhibit N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. Initially, we conducted a bioassay to determine the effects of dietary freeze-dried strawberries on esophageal tumor development. Two weeks prior to NMBA treatment, animals were placed on a control diet or diets containing 5 and 10% freeze-dried strawberries. NMBA treatment was once per week for 15 weeks. At 30 weeks, 5 and 10% freeze-dried strawberries in the diet caused significant reductions in esophageal tumor multiplicity of 24 and 56%, respectively. Based on these results, we conducted studies to determine potential mechanisms by which freeze-dried strawberries inhibit tumorigenesis. In a short-term bioassay, we evaluated the effects of dietary freeze-dried strawberries on the formation of O6-methylguanine in the rat esophagus. Animals were placed on control diet or diets containing 5 and 10% freeze-dried strawberries for two weeks. At the end of this period, animals received a single subcutaneous dose of NMBA and were killed 24 h later. A significant decrease in O6-methylguanine levels was observed in the esophageal DNA of animals fed strawberries, suggesting that one or more components in strawberries influence the metabolism of NMBA to DNA-damaging species. Finally, in order to evaluate post-initiation effects, we conducted a study where freeze-dried strawberries were administered in the diet only following NMBA treatment. Animals were placed on control diet and dosed with NMBA three times per week for 5 weeks. Immediately following NMBA treatment, animals were placed on control diet or diets containing 5 and 10% freeze-dried strawberries. At 25 weeks, 5 and 10% freeze-dried strawberries in the diet significantly reduced tumor multiplicity by 38 and 31%, respectively. Our data suggest that dietary freeze-dried strawberries effectively inhibit NMBA-induced tumorigenesis in the rat esophagus.

Carcinogenesis. 2001 Mar;22(3):441-6

Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.

BACKGROUND: The causes of adenocarcinomas of the esophagus and gastric cardia are poorly understood. We conducted an epidemiologic investigation of the possible association between gastroesophageal reflux and these tumors. METHODS: We performed a nationwide, population-based, case-control study in Sweden. Case ascertainment was rapid, and all cases were classified uniformly. Information on the subjects’ history of gastroesophageal reflux was collected in personal interviews. The odds ratios were calculated by logistic regression, with multivariate adjustment for potentially confounding variables. RESULTS: Of the patients interviewed, the 189 with esophageal adenocarcinoma and the 262 with adenocarcinoma of the cardia constituted 85 percent of the 529 patients in Sweden who were eligible for the study during the period from 1995 through 1997. For comparison, we interviewed 820 control subjects from the general population and 167 patients with esophageal squamous-cell carcinoma. Among persons with recurrent symptoms of reflux, as compared with persons without such symptoms, the odds ratios were 7.7 (95 percent confidence interval, 5.3 to 11.4) for esophageal adenocarcinoma and 2.0 (95 percent confidence interval, 1.4 to 2.9) for adenocarcinoma of the cardia. The more frequent, more severe, and longer-lasting the symptoms of reflux, the greater the risk. Among persons with long-standing and severe symptoms of reflux, the odds ratios were 43.5 (95 percent confidence interval, 18.3 to 103.5) for esophageal adenocarcinoma and 4.4 (95 percent confidence interval, 1.7 to 11.0) for adenocarcinoma of the cardia. The risk of esophageal squamous-cell carcinoma was not associated with reflux (odds ratio, 1.1; 95 percent confidence interval, 0.7 to 1.9). CONCLUSIONS: There is a strong and probably causal relation between gastroesophageal reflux and esophageal adenocarcinoma. The relation between reflux and adenocarcinoma of the gastric cardia is relatively weak.

N Engl J Med. 1999 Mar 18;340(11):825-31

Review article: alginate-raft formulations in the treatment of heartburn and acid reflux.

Alginate-based raft-forming formulations have been marketed word-wide for over 30 years under various brand names, including Gaviscon. They are used for the symptomatic treatment of heartburn and oesophagitis, and appear to act by a unique mechanism which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate, forming a gel. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate; in the presence of gastric acid, the bicarbonate is converted to carbon dioxide which becomes entrapped within the gel precipitate, converting it into a foam which floats on the surface of the gastric contents, much like a raft on water. Both in vitro and in vivo studies have demonstrated that alginate-based rafts can entrap carbon dioxide, as well as antacid components contained in some formulations, thus providing a relatively pH-neutral barrier. Several studies have demonstrated that the alginate raft can preferentially move into the oesophagus in place, or ahead, of acidic gastric contents during episodes of gastro-oesophageal reflux; some studies further suggest that the raft can act as a physical barrier to reduce reflux episodes. Although some alginate-based formulations also contain antacid components which can provide significant acid neutralization capacity, the efficacy of these formulations to reduce heartburn symptoms does not appear to be totally dependent on the neutralization of bulk gastric contents. The strength of the alginate raft is dependant on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate, and the presence of aluminium or calcium in the antacid components of the formulation. Raft formation occurs rapidly, often within a few seconds of dosing; hence alginate-containing antacids are comparable to traditional antacids for speed of onset of relief. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that of traditional antacids. Indeed, clinical studies have shown Gaviscon is superior to placebo, and equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginate-based, raft-forming formulations have been used to treat reflux symptoms in infants and children, and in the management of heartburn and reflux during pregnancy. While Gaviscon is effective when used alone, it is compatible with, and does not interfere with the activity of antisecretory agents such as cimetidine. Even with the introduction of new antisecretory and promotility agents, alginate-rafting formulations will continue to have a role in the treatment of heartburn and reflux symptoms. Their unique non-systemic mechanism of action provides rapid and long-duration relief of heartburn and acid reflux symptoms.

Aliment Pharmacol Ther. 2000 Jun;14(6):669-90

The value of a liquid alginate suspension (Gaviscon Advance) in the management of laryngopharyngeal reflux.

Laryngopharyngeal reflux (LPR) refers to the backflow of stomach contents into the laryngopharynx. Increasing evidence has demonstrated that LPR is a contributing factor in some cases of hoarseness, vocal fatigue, voice breaks, cough and globus and chronic throat clearing. However, several randomised placebo-controlled trials of proton pump inhibitors in the treatment of LPR have been reported with the majority showing no significant benefit in patient symptom scores over placebo. The aim of this pilot clinical study was to investigate whether any improvement in LPR-related symptoms, using the Reflux Symptom Index (RSI), and clinical findings, using the Reflux Finding Score (RFS), could be achieved with treatment with a liquid alginate suspension compared to control (no treatment). Patients presenting with the symptoms of LPR to the Otorhinolaryngology Outpatient Department at the Queen’s Medical Centre, Nottingham, UK were considered eligible if they had an RSI of greater than 10 and an RFS greater than 5 based on a fibreoptic examination of the larynx. A total of 49 patients were randomised into the open, parallel group study; 24 patients were randomised to receive 10 ml liquid alginate suspension (Gaviscon Advance) four times daily after meals and at bedtime, and 25 patients into the control group (no treatment). Patients were assessed pre-treatment and at 2, 4 and 6 months post treatment. Mean (SD) RSI and RFS pre-treatment scores were 23.9 (7.0) and 10.4 (3.6) for the treatment group and 24.6 (7.4) and 10.3 (3.3) for the control group, respectively. Significant differences between treatment and control were observed for RSI at the 2-month (11.2 (7.0) vs. 16.8 (6.4), P=0.005) and 6-month (11.2 (8.1) vs. 18.3 (9.4), P=0.008) assessments and for RFS at the 6-month (7.1 (2.8) vs. 9.5 (3.4), P=0.005) assessment. Significant improvement in symptom scores and clinical findings were achieved with liquid alginate suspension (Gaviscon Advance) compared to control and further evaluation for the management of patients presenting with LPR is warranted.

Eur Arch Otorhinolaryngol. 2009 Feb;266(2):243-51

Gaviscon® vs. omeprazole in symptomatic treatment of moderate gastroesophageal reflux. a direct comparative randomised trial.

BACKGROUND: Medical management of GERD mainly uses proton pump inhibitors. Alginates also have proven efficacy. The aim of this trial was to compare short-term efficacy of an alginate (Gaviscon®, 4 × 10 mL/day) and omeprazole (20 mg/day) on GERD symptoms in general practice. METHODS: A 14-day multicentre randomised double-blind double-dummy non-inferiority trial compared Gaviscon® (4 × 10 mL/day) and omeprazole (20 mg/day) in patients with 2-6 day heartburn episodes weekly without alarm signals. The primary outcome was the mean time to onset of the first 24-h heartburn-free period after initial dosing. Secondary outcomes were the proportion of patients without heartburn by D7, pain relief by D7, and reduction in pain intensity by D7 and D14. RESULTS: 278 patients were recruited; 120 were included in the Gaviscon® group and 121 in the omeprazole group for the per protocol non-inferiority analysis. The mean time to onset of the first 24-h heartburn-free period after initial dosing was 2.0 (± 2.2) days for Gaviscon® and 2.0 (± 2.3) days for omeprazole (p = 0.93); mean intergroup difference was 0.01 ± 1.55 days (95% CI = -0.41 to 0.43): i.e., less than the lower limit of the 95% CI of -0.5 days predetermined to demonstrate non-inferiority. The mean number of heartburn-free days by D7 was significantly greater in the omeprazole group: 3.7 ± 2.3 days vs. 3.1 ± 2.1 (p = 0.02). On D7, overall quality of pain relief was slightly in favour of omeprazole (p = 0.049). There was no significant difference in the reduction in pain intensity between groups by D7 (p = 0.11) or D14 (p = 0.08). Tolerance and safety were good and comparable in both groups. CONCLUSION: Gaviscon® was non-inferior to omeprazole in achieving a 24-h heartburn-free period in moderate episodic heartburn, and is a relevant effective alternative treatment in moderate GERD in primary care.

BMC Gastroenterol . 2012 Feb 23;12:18

A comparison between sodium alginate and magaldrate anhydrous in the treatment of patients with gastroesophageal reflux symptoms.

The aims of the present study were to compare effects of sodium alginate and the antacid magaldrate anhydrous in adults with gastroesophageal reflux (GOR) symptoms. Patients with heartburn and/or acid regurgitation for at least 3 days in the week before the study started (n=203) were randomized to receive a single dose of sodium alginate or magaldrate anhydrous at the onset of symptoms during a 3-day run-in period. Patients with symptoms during the run-in (n=191) were rerandomized to receive a 14-day treatment with either drug given as four daily doses. A speed of action < or =30 min was significantly more frequent among patients in the alginate group (49.4% vs. 40.4%; P=0.0074). A trend toward a more prolonged duration of action (median: 16.5 vs. 12.7 hr) and a greater sum of the symptom intensity difference (median: 40.0 vs. 31.0) was observed in the sodium alginate group. Total disappearance of symptoms was reported in 81.6% and 73.9% of patients in the sodium alginate group and magaldrate group, respectively. We conclude that sodium alginate was faster than magaldrate in relieving GRO symptoms and showed a tendency toward a more prolonged duration of action and a higher level of efficacy.

Dig Dis Sci . 2006 Nov;51(11):1904-9.

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