N-Acetylcysteine Promotes Helicobacter Pylori Eradication
A biofilm is a complex bacterial ecosystem that allows bacteria to survive in unfavorable environments by enclosing themselves in a polysaccharide matrix. Biofilm-producing bacteria are more resistant to antibiotics than other bacteria, presumably because the protective matrix that they produce blocks the penetration of the antibiotics. Helicobacter pylori is known to be capable of forming a biofilm.

Gastric biopsy specimens were obtained from 10 patients who had had at least four unsuccessful attempts to eradicate H. pylori. Specimens from five of the patients were cultured in the presence of N-acetylcysteine (NAC; 2 mg/ml), and the other five specimens were cultured without NAC. None of the five H. pylori isolates cultured with NAC developed a biofilm, whereas a biofilm did develop in all five isolates cultured without NAC. In the cultures that developed a biofilm, the addition of NAC resulted in a progressive decrease and eventual disappearance of the biofilm.

In a second study, 40 patients with a history of at least four unsuccessful attempts to eradicate H. pylori were randomly assigned to receive, in open-label fashion, NAC (600 mg once a day) or no NAC for one week, followed by a one-week culture-guided H. pylori eradication regimen that included two antibiotics and a proton pump inhibitor. At baseline, electron microscopy revealed the presence of a biofilm in all patients. H. pylori eradication was assessed by urea breath testing at least two months after the end of antibiotic treatment. H. pylori was eradicated in 13 (65%) of 20 patients who received NAC and in 4 (20%) of 20 patients who did not receive NAC (p < 0.01). The biofilm disappeared in all patients in whom eradication was successful, but persisted in an unspecified number of patients in whom eradication was unsuccessful.

Comment: H. pylori infection is an important cause of peptic ulcer and may also contribute to the pathogenesis of gastric cancer. Conventional treatment of H. pylori infection typically consists of two antibiotics plus a proton pump inhibitor. While this treatment is usually successful, up to one-third of patients have failed to respond in some studies. The results of the present study indicate that, in patients in whom H. pylori eradication has been unsuccessful, administration of NAC prior to a culture-guided antibiotic regimen can frequently overcome H. pylori antibiotic resistance. NAC presumably works by breaking disulfide bonds in the biofilm, thereby having a depolymerizing effect. Considering its low cost and relative safety, pretreatment with NAC might be considered for all patients undergoing H. pylori eradication, in order to reduce the probability that a repeat course of treatment will be needed.

Cammarota G et al. Biofilm demolition and antibiotic treatment to eradicate resistant Helicobacter pylori: a clinical trial. Clin Gastroenterol Hepatol. 2010;8:817–820.e3.

N-Acetylcysteine and Glycine Prevent Glutathione Deficiency in the Elderly
The mean concentrations of glutathione, glycine, and cysteine in erythrocytes were significantly lower in healthy elderly subjects (aged 60–75 years) than in healthy younger subjects (aged 30–40 years). The decrease in glutathione levels was associated with a lower rate of glutathione synthesis and higher plasma levels of oxidative stress and oxidant damage (measured as F2-isoprostane and lipid peroxides). Daily oral administration of N-acetylcysteine (NAC; 0.81 mmol/kg of body weight per day [132 mg/kg/day]) and glycine (1.33 mmol/kg/day [100 mg/kg/day]) for 14 days increased the mean erythrocyte glutathione concentration in the elderly subjects by 95% (p < 0.01), increased the glutathione synthesis rate by 231% (p < 0.01), and significantly decreased plasma oxidative stress and oxidant damage.

Comment: NAC is converted to cysteine in vivo. Cysteine and glycine are precursors to glutathione, one of the body's key antioxidants. The results of the present study indicate that glutathione deficiency occurs in healthy elderly people because of a reduction in glutathione synthesis. Supplementation with NAC and glycine restored glutathione synthesis and glutathione concentrations to the levels seen in younger subjects, and lowered levels of oxidative stress and oxidant damage. The doses of NAC and glycine used in this study were relatively large. Further research is needed to determine whether more moderate doses (such as 600 mg/day for NAC and a few grams per day for glycine) taken for a longer period of time would have a similar effect.

Sekhar RV et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011;94:847–853.

Probiotic Prevents Infections in Athletes
Eighty-four highly active individuals (mean age, 27 years) were randomly assigned to receive, in double-blind fashion, fermented milk that contained 6.5 × 109 live Lactobacillus casei Shirota organisms or fermented milk without probiotics (control), twice a day during 16 weeks of winter training. The mean number of weeks during which symptoms of upper respiratory tract infection were present was significantly lower by 46% in the probiotic group than in the placebo group (1.9 vs. 3.5; p < 0.01). The mean number of upper respiratory tract infection episodes was significantly lower by 43% in the probiotic group than in the placebo group (1.2 vs. 2.1; p < 0.01). The mean salivary IgA concentration was significantly higher in the probiotic group than in the placebo group (p = 0.03).

Comment: This study demonstrated that supplementation with a particular probiotic preparation reduced the frequency of upper respiratory tract infections in training athletes during the winter. The beneficial effect was associated with higher salivary concentrations of IgA, an immunoglobulin that plays a role in defense against infection. In addition to enhancing immune function, probiotics may help prevent infections by competing with pathogenic organisms for nutrients and colonization sites, and by producing antimicrobial compounds

Gleeson M et al. Daily probiotic's (Lactobacillus casei Shirota) reduction of infection incidence in athletes. Int J Sport Nutr Exerc Metab. 2011;21:55–64.

Probiotics Prevent Antibiotic-Associated Diarrhea and Clostridium Difficile Infection
A meta-analysis was conducted on eight randomized controlled trials that examined the effect of probiotics on the incidence of antibiotic-associated diarrhea and Clostridium difficile-associated disease in adult hospitalized patients. In the pooled analysis, administration of probiotics significantly decreased the incidence of antibiotic-associated diarrhea by 44% and of C. difficile-associated disease by 71%.

Comment: Diarrhea is a common side effect of antibiotic therapy. C. difficile is a gram-positive bacterium that is a common cause of antibiotic-associated diarrhea and pseudomembranous colitis. C. difficile infection usually manifests as mild-to-moderate diarrhea, but severe colitis culminating in colectomy or death may also occur. Since around the year 2000, there has been a progressive increase in the incidence of C. difficile infection. While C. difficile can be effectively treated with vancomycin or metronidazole, the infection recurs in approximately 20% of patients; and in patients who have a recurrence, subsequent recurrences are even more frequent. The results of the present study indicate that most episodes of antibiotic-induced diarrhea and antibiotic-induced C. difficile infection can be prevented by administration of probiotics.

Avadhani A, Miley H. Probiotics for prevention of antibiotic-associated diarrhea and Clostridium difficile-associated disease in hospitalized adults – a meta-analysis. J Am Acad Nurse Pract. 2011;23:269–274.

Omega-3 Fatty Acids for Juvenile Rheumatoid Arthritis
Twenty-seven Egyptian children (mean age, 12.8 years) with juvenile rheumatoid arthritis (mean disease duration, 5.9 years) received a supplement providing daily 300 mg of eicosapentaenoic acid and 200 mg of docosahexaenoic acid for 12 weeks. All patients were receiving conventional therapy. After 12 weeks, the mean active-joint count decreased by 86% (from 4.15 at baseline to 0.59; p < 0.001), the mean disease activity score decreased (improved) by 55% (p < 0.001), the mean functional status score improved by 84% (p < 0.001), and the mean erythrocyte sedimentation rate decreased significantly by 47%.

Comment: Eicosapentaenoic acid, an omega-3 fatty acid present in fish oil, has demonstrated anti-inflammatory activity, and has been shown in numerous studies to be of value in the treatment of rheumatoid arthritis in adults. The results of the present study suggest that omega-3 fatty acids, when given as an adjunct to conventional therapy, are also beneficial in children with juvenile rheumatoid arthritis. However, since there was no control group, the possibility of a placebo effect or of a delayed benefit of conventional therapy cannot be ruled out.

Gheita T et al. Omega-3 fatty acids in juvenile idiopathic arthritis: effect on cytokines (IL-1 and TNF-alpha), disease activity and response criteria. Clin Rheumatol. 2012;31:363–366.

Vitamin D Status Not Associated with Type 1 Diabetes Risk
Since 1993, the Diabetes Autoimmunity Study in the Young (Denver, Colorado) has followed children who were at increased risk of type 1 diabetes (because of a particular HLA type or because a first-degree relative had type 1 diabetes). As of February 2011, 198 of 2644 children developed autoimmunity against pancreatic islet cells. Vitamin D intake and plasma 25-hydroxyvitamin D levels were measured longitudinally. Higher intake of vitamin D, as compared with lower intake, was associated with a nonsignificantly higher risk of developing islet cell autoimmunity and a nonsignificantly higher risk of progression of islet cell autoimmunity to type 1 diabetes. Higher plasma 25-hydroxyvitamin D levels, as compared with lower levels, were associated with a nonsignificantly higher risk of developing islet cell autoimmunity and a nonsignificantly lower risk of progression of islet cell autoimmunity to type 1 diabetes.

Comment: The biologically active form of vitamin D (1,25-dihydroxyvitamin D) has been shown to prevent the development of type 1 diabetes in experimental animals. In addition, a prospective cohort study conducted in Finland found that supplementation of infants with vitamin D was associated with a reduced risk of developing type 1 diabetes. However, since vitamin D supplementation is widely recommended in Finland, the results of that study may have been due to compliance bias (i.e., people who comply with recommendations have better outcomes than people who do not comply). In the present study, higher vitamin D intake was associated with a nonsignificant trend toward increased risk of type 1 diabetes. There was no significant association between plasma 25-hydroxyvitamin D levels and diabetes risk. However, if there were an association, it would be difficult to interpret, since islet cell autoimmunity is an inflammatory process, and circulating 25-hydroxyvitamin D levels fall in response to inflammation.

Simpson M et al. No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia. 2011;54:2779–2788.

Vitamin D for COPD? Only If You Are Deficient
One hundred eighty-two patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) and a history of recent exacerbations were randomly assigned to receive, in double-blind fashion, 100,000 IU of vitamin D (vitamin D3, according to a personal communication from the study author) or placebo every four weeks for one year (equivalent to about 3600 IU/day). There was no significant difference between groups with respect to exacerbation rate, pulmonary function (FEV1), or rates of hospitalization or death. In post hoc analysis of 30 patients with severe vitamin D deficiency at baseline (serum 25-hydroxyvitamin D < 10 ng/ml), vitamin D supplementation significantly reduced the exacerbation rate by 43% compared with placebo (p < 0.05). Among the 152 patients who did not have severe vitamin D deficiency at baseline, the mean exacerbation rate was 8% higher in the vitamin D group than in the placebo group (p value not stated). Among the 142 patients who were not taking vitamin D supplements at baseline, the mean exacerbation rate per patient-year was nonsignificantly lower by 10% in the vitamin D group than in the placebo group (p = 0.3). Among the 40 patients who were taking 400 to 880 IU/day of vitamin D at baseline for osteoporosis, the mean exacerbation rate per patient-year was 41% higher in the group assigned to receive additional vitamin D than in the placebo group (p value not stated).

Comment: These data indicate that high-dose vitamin D supplementation did not decrease the incidence of exacerbations in patients with COPD. Vitamin D supplementation may reduce exacerbations in patients with severe vitamin D deficiency. However, the data are also consistent with the possibility that high-dose vitamin D increases exacerbations in patients who do not have severe vitamin D deficiency. The findings of this study are similar to those of other research that I have cited in the past few issues of the Townsend Letter. Taken as a whole, these studies suggest that, for the average person, supplementation with a modest dose of vitamin D (such as 800–1200 IU/day) may be beneficial, but that that taking doses substantially higher than 800–1200 IU/day might negate those benefits.

Lehouck A et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2012;156:105–114.

Ginkgo Biloba for Tardive Dyskinesia
One hundred fifty-seven Chinese schizophrenic inpatients with tardive dyskinesia were randomly assigned to receive, in double-blind fashion, Ginkgo biloba extract EGb 761 (ginkgo; 240 mg/day) or placebo for 12 weeks. Eighty-two percent of the patients were taking clozapine, and the other patients were taking other neuroleptic (antipsychotic) drugs. The mean score on the Abnormal Involuntary Movement Scale (AIMS) improved by 30.3% in the ginkgo group and worsened by 1.5% in the placebo group (p < 0.0001 for the difference in the change between groups). The proportion of patients who had at least a 30% improvement of their AIMS score was significantly greater in the ginkgo group than in the placebo group (51.3% vs. 5.1%; p < 0.001). Ginkgo had no effect on symptoms of schizophrenia or on cognitive function.

Comment: Tardive dyskinesia is characterized by involuntary movements of the tongue, lips, extremities, and other parts of the body. In most cases, it occurs as a side effect of dopaminergic antagonists, particularly neuroleptic drugs. There is evidence that oxygen-derived free radicals play a role in the pathogenesis of this condition. Vitamin E, an antioxidant, has been reported in several controlled trials to decrease the severity of tardive dyskinesia. Since ginkgo has antioxidant activity, it may also be useful. The results of this study indicate that treatment with ginkgo can improve tardive dyskinesia in schizophrenic patients, although it did not improve symptoms of schizophrenia.

Zhang WF et al. Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72:615–621.

Alan R. Gaby, MD
drgaby@earthlink.net