AdcAII of Streptococcus pneumoniae Affects Pneumococcal Invasiveness.

Across bacterial species, metal binding proteins can serve functions in pathogenesis in addition to regulating metal homeostasis. We have compared and contrasted the activities of zinc (Zn2+)-binding lipoproteins AdcA and AdcAII in the Streptococcus pneumoniae TIGR4 background. Exposure to Zn2+-limiting conditions resulted in delayed growth in a strain lacking AdcAII (ΔAdcAII) when compared to wild type bacteria or a mutant lacking AdcA (ΔAdcA). AdcAII failed to interact with the extracellular matrix protein laminin despite homology to laminin-binding proteins of related streptococci. Deletion of AdcA or AdcAII led to significantly increased invasion of A549 human lung epithelial cells and a trend toward increased invasion in vivo. Loss of AdcAII, but not AdcA, was shown to negatively impact early colonization of the nasopharynx. Our findings suggest that expression of AdcAII affects invasiveness of S. pneumoniae in response to available Zn2+ concentrations.

Methotrexate for the Management of Crohn's Disease in Children.

OBJECTIVE: To review the literature evaluating methotrexate as a treatment option for Crohn's disease (CD) in pediatric patients. DATA SOURCES: A search of PubMed electronic database (1966 to August 2015) and secondary resources was performed using the terms methotrexate, Crohn's, and inflammatory bowel disease. Other relevant articles cited within identified articles were also utilized. STUDY SELECTION AND DATA EXTRACTION: Data sources were limited to English-language studies that included children less than 18 years of age. In total, 10 clinical studies met the criteria. DATA SYNTHESIS: Awareness of the risk of hepatosplenic T-cell lymphoma associated with anti-tumor necrosis factor and thiopurine therapies has renewed interest in methotrexate to treat CD in children. According to data from 10 predominantly retrospective studies, children treated with oral or subcutaneous methotrexate once weekly had remission rates of 25% to 53% at 1 year. Adverse effects most often included nausea and vomiting, elevated liver function tests, headache, and hematological toxicity. The evidence to support methotrexate is limited by inconsistent study design and poorly described dosage regimens. It has been most frequently evaluated in patients with prior thiopurine exposure and has not been thoroughly evaluated as first-line therapy. CONCLUSIONS: Based on results of retrospective studies, methotrexate is useful in the treatment of pediatric CD in those who fail thiopurine therapy. Remission rates with methotrexate are similar to those for thiopurine therapy, although no studies directly compare these agents. Although preliminary results are promising, prospective studies are needed to assess the use of methotrexate as initial first-line therapy in the pediatric CD population.

Impact of an Intravenous Magnesium Shortage on Potassium Doses in Adult Surgical Patients Receiving Parenteral Nutrition.

BACKGROUND: Shortages of parenteral nutrition (PN) components have been common in recent years. Effects on patient management and outcomes have not been well documented. This study aimed to determine the effect of a parenteral magnesium shortage, and an institutional decision to omit magnesium from adult PN, on magnesium and potassium doses and serum concentrations. MATERIALS AND METHODS: This was a retrospective cohort study of adult surgical patients during two 6-month periods: prior to the magnesium shortage (2011) and during the shortage (2012). The relation between study period and electrolyte doses was evaluated by unadjusted and adjusted mixed models, while the relation between study period and hypokalemia and hypomagnesemia exposure was evaluated by Student's t tests and multiple linear regression. RESULTS: During the shortage, patients received more supplemental magnesium (0.11-0.12 mEq/kg/d, P < .0001) but received less total daily magnesium (0.08-0.09 mEq/kg/d, P < .0001) and had greater exposure to hypomagnesemia (9.6-14.2 h·mcg/dL/h, P < .05 for all comparisons except multivariate analysis in a matched subpopulation). Patients received similar amounts of potassium in PN (0.06-0.08 mEq/kg/d less, P < .05 for full cohort but P > .05 for matched cohort), in supplemental doses (0.01-0.05 mEq/kg/d less, P > .05), and in total (0.07-0.14 mEq/kg/d less, P > .05), and they had similar exposure to hypokalemia. CONCLUSION: Daily magnesium doses were lower and hypomagnesemia exposure was greater during the shortage, but the differences were numerically small and their clinical significance was questionable. Potassium doses and hypokalemia exposure were not higher during the shortage. This supports the strategy of omitting magnesium from PN of select patients and supplementing as clinically necessary.

A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures.

Pharmacokinetics and pharmacodynamics of intravenous baclofen in dogs: a preliminary study.

UNLABELLED: Abrupt discontinuation of baclofen therapy is associated with a clinically serious withdrawal syndrome. Current treatment modalities are often ineffective. Intravenous (IV) baclofen is a potential method for preventing or treating baclofen withdrawal syndrome. OBJECTIVES: To complete a preliminary study of IV baclofen in dogs. METHODS: Single bolus IV doses (0.5, 2 and 3 mg/kg) as well as multiple dose regimens were evaluated. Sedation and clinical tolerability was assessed by modified Glasgow Coma Scale and Discomfort and Behaviour Scale. KEY FINDINGS: Baclofen concentration-time profiles following single IV boluses were best fit by a two-compartment model which was used to predict plasma concentrations for the multiple dose regimens. The mean distribution and elimination half-lives were 11 min and 222 min, respectively. Maximum clinical effect did not occur until approximately 120 min. The discomfort score increased proportionately with increased single IV bolus doses. Multiple dose regimens resulted in greater than proportionate discomfort scores based on total dose and were generally not as well tolerated. CONCLUSIONS: If projected for human use, our data suggests that initial IV baclofen doses will need to be reduced by approximately one-third of the usual oral dose, and clinicians should observe patients for several hours before administering subsequent doses.

Clinical tolerance and toxicity of intravenous baclofen: a pilot study in a canine model.

OBJECTIVE: Assess safety and tolerance of intravenous (IV) baclofen using a dog model. DESIGN: Prospective pharmacokinetic study involving 6 adult dogs. Two dogs received baclofen 10 mg oral and IV bolus doses. Subsequent 4 dogs were given IV boluses of 0.5, 1.0 and 1.5 mg/kg followed by constant infusion of baclofen (rates of 0.1, 0.2 and 0.4 mg/kg/hour). Also, dogs were given single IV 2 and 3 mg /kg bolus doses. Outcome measures included clinical observation scales and baclofen levels. RESULTS: Oral bioavailability was 0.66 and 0.69 in 2 dogs. Following IV baclofen, terminal phase half-lives were 3.3 and 3.6 hours. Single bolus doses of 2 and 3 mg/kg caused mild to moderate clinical changes which were delayed at least 2 hours after peak blood levels. Boluses of 0.5 and 1.0 mg/kg with constant infusion between boluses were tolerated, however within 30 minutes of beginning constant infusion of 0.2 mg/kg/hr after the second bolus (1.0 mg/kg), dogs showed progressive sedation and ataxia. Clinical improvement occurred within 7 hours of stopping baclofen. Dogs appeared normal by the next morning. CONCLUSIONS: IV baclofen bolus doses of 0.5 to 3 mg/kg were well tolerated. Maximum clinical effect was delayed for at least 2 hours after peak plasma levels.

Pharmacogenetics of the organic anion transporting polypeptide 1A2.

The solute carrier, human organic anion transporting polypeptide 1A2 (OATP1A2, OATP-A, OATP1 and OATP) is highly expressed in the intestine, kidney, cholangiocytes and the blood-brain barrier. This localization suggests that OATP1A2 may be vitally important in the absorption, distribution and excretion of a broad array of clinically important drugs. Several nonsynonymous polymorphisms have been identified in the gene encoding OATP1A2, SLCO1A2 (SLC21A3), with some of these variants demonstrating functional changes in the transport of OATP1A2 substrates.