Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is an under-recognised diagnosis with important clinical implications when untreated. However, the optimal treatment regimen remains unclear. AIM: To perform a systematic review and meta-analysis comparing the clinical effectiveness of antibiotic therapies in the treatment of symptomatic patients with documented SIBO. METHODS: Four databases were searched to identify clinical trials comparing effectiveness of: (i) different antibiotics, (ii) different doses of the same antibiotic and (iii) antibiotics compared with placebo. Data were independently extracted according to predetermined inclusion and exclusion criteria. Study quality was independently assessed. The primary outcome was normalisation of post-treatment breath testing. The secondary outcome was post-treatment clinical response. RESULTS: Of 1356 articles identified, 10 met inclusion criteria. Rifaximin was the most commonly studied antibiotic (eight studies) with overall breath test normalisation rate of 49.5% (95% confidence interval, CI 44.0-55.1) (44.0%-55.1%) then (46.7%-55.5%), then (4.6%-17.8%). Antibiotic efficacy varied by antibiotic regimen and dose. Antibiotics were more effective than placebo, with a combined breath test normalisation rate of 51.1% (95% CI 46.7-55.5) for antibiotics compared with 9.8% (95% CI 4.6-17.8) for placebo. Meta-analysis of four studies favoured antibiotics over placebo for breath test normalisation with an odds ratio of 2.55 (95% CI 1.29-5.04). Clinical response was heterogeneously evaluated among six studies, but tended to correlate with breath test normalisation. CONCLUSIONS: Antibiotics appear to be more effective than placebo for breath test normalisation in patients with symptoms attributable to SIBO, and breath test normalisation may correlate with clinical response. Studies were limited by modest quality, small sample size and heterogeneous design. Additional higher quality clinical trials of SIBO therapy are warranted.

Sequences of the bovine and yeast ADP-ribosylation factor and comparison to other GTP-binding proteins.

The ADP-ribosylation factor (ARF) is a 21-kDa GTP-binding protein that serves as the cofactor in the cholera toxin-catalyzed activation of the stimulatory guanine nucleotide-binding protein of adenylate cyclase (Gs). An oligonucleotide probe based on the partial amino acid sequence was used to clone ARF from a bovine adrenal chromaffin cDNA library. The yeast (Saccharomyces cerevisiae) ARF gene was then cloned from a YCp50 genomic library by cross-species hybridization by using the coding region of the bovine gene. RNA gel blots of poly(A)+ RNA indicate that only one ARF message size (900 and 2000 base pairs) is present in yeast and cows, respectively. Comparison of the cDNA-derived amino acid sequences of ARF to other GTP-binding proteins reveals a structural relationship between ARF and the ras family of proteins. A slightly better structural relationship is detected when ARF is compared to the alpha subunits of the trimeric GTP-binding proteins, including Gs alpha. All of the biochemical characteristics of the purified ARF, including the lack of GTPase activity and the posttranslational myristoylation, are consistent with the derived sequences. Comparison of the ARF sequences to that of the chicken processed pseudogene (CPS-1), previously reported as a ras homologue, reveals that CPS-1 is actually an ARF-derived gene. These results demonstrate that ARF is a GTP-binding protein with structural features of both the ras and the trimeric GTP-binding protein families.

Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers.

A radioactive photoactive dihydropyridine calcium channel blocker, [3H]azidopine, was used to photoaffinity label plasma membranes of multidrug-resistant Chinese hamster lung cells selected for resistance to vincristine (DC-3F/VCRd-5L) or actinomycin D (DC-3F/ADX). Sodium dodecyl sulfate-polyacrylamide gel electrophoretic fluorograms revealed the presence of an intensely radiolabeled 150-180-kDa doublet in the membranes from drug-resistant but not from the drug-sensitive parental (DC-3F) cells. A similar radiolabeled doublet was barely detected in a drug-sensitive partial revertant (DC-3F/ADX-U) cell line. The 150-180-kDa doublet exhibited a specific half-maximal saturable photolabeling at 1.07 X 10(-7) M [3H]azidopine. The dihydropyridine binding specificity was established by competitive blocking of specific photolabeling with nonradioactive azidopine as well as with nonphotoactive calcium channel blockers nimodipine, nitrendipine, and nifedipine. In addition, [3H]azidopine photolabeling was blocked by verapamil and diltiazem but was stimulated by excess prenylamine and bepridil suggesting a cross-specificity for up to four different classes of calcium channel blockers. The 150-180-kDa calcium channel blocker acceptor co-electrophoresed exactly with the 150-180-kDa surface membrane glycoprotein (gp150-180 or P-glycoprotein) Vinca alkaloid acceptor from multidrug-resistant cells and was immunoprecipitated by polyclonal antibody recognizing gp150-180. [3H]Azidopine photolabeling of the 150-180-kDa component in the presence of excess vinblastine was reduced over 90%, confirming the identity or close relationship of the calcium channel blocker acceptor and the gp150-180 Vinca alkaloid acceptor. The [3H]azidopine photolabeling of gp150-180 also was reduced by excess actinomycin D, adriamycin, or colchicine, demonstrating a broad gp150-180 drug recognition capacity. The ability of gp150-180 to recognize multiple natural product cytotoxic drugs as well as calcium channel blockers suggests a direct function for gp150-180 in the multidrug resistance phenomenon and a role in the circumvention of that resistance by calcium channel blockers.