Avoidance of “First-Pass” Elimination of Rectally Administered Propranolol in Relation to the Site of Absorption in Rats

The extent of first-pass elimination of racemic propranolol and dextropropranolol in doses of 0.25 or 0.50 mg was investigated in relation to the site of drug administration in the rectum of rats. The compounds were given orally, i.v., and rectally at distances of 2 and 1 cm from and directly at the anus by low volume zero-order 30 min infusion. Unchanged propranolol was determined in blood, and propranolol and three metabolites were measured in urine. The systemic availability of propranolol after oral administration was approximately 6 %. Rectal administration at 2 cm, at 1 cm and directly at the anus (0.2 cm) gave two, three and six times higher values, respectively. The more distal application site produced urinary metabolite profiles that were comparable to those observed after oral administration, while application directly at the anus was similar to i.v. dosing. In all experiments log-linear elimination phases with comparable elimination half-lives (range 12–18 min) were found, except with the 0.50 mg dose after i.v. and rectal administration close to the anus which showed a non-linear profile. The mean systemic availability after rectal administration of 0.25 mg dextro-propranolol close to the anus was 50 and 64 % as compared to a 0.25 and 0.125 mg i.v. dose, respectively. The rectal route may be used for propranolol to partially prevent hepatic first-pass metabolism. However, avoidance of presys-temic elimination is maximal only in the immediate vicinity of the anus as the venous blood supply of the upper part of the rectum of rats appears to be connected to the portal system and the lower part to the general circulation.     

Engineered NS1 for Sensitive,Specific Zika Virus Diagnosis from Patient Serology

Dengue virus (DENV) and Zika virus (ZIKV) belong to the Flaviviridae family of viruses spread by Aedes aegypti mosquitoes in tropical and subtropical areas. Accurate diagnostic tests to differentiate the 2 infections are necessary for patient management and disease control. Using characterized ZIKV and DENV patient plasma in a blind manner, we validated an ELISA and a rapid immunochromatographic test for ZIKV detection. We engineered the ZIKV nonstructural protein 1 (NS1) for sensitive serologic detection with low cross reactivity against dengue and developed monoclonal antibodies specific for the ZIKV NS1 antigen. As expected, the serologic assays performed better with convalescent than acute plasma samples; the sensitivity ranged from 71% to 88%, depending on the performance of individual tests (IgM/IgG/NS1). Although serologic tests were generally less sensitive with acute samples, our ZIKV NS1 antibodies were able to complement the serologic tests to achieve greater sensitivity for detecting early infections.     

Mitigating disparity in children with acute appendicitis: Impact of patient-driven protocols

PurposePrevious reports in the literature demonstrate racial and ethnic disparities for children diagnosed with acute appendicitis, with minorities experiencing worse outcomes. At our institution, we have developed an evidence based patient driven protocol for children following laparoscopic appendectomy. However, the influence of such protocol on mitigating racial and ethnic disparities in outcomes remains unknown. The purpose of our study is to assess the impact of our protocol by evaluating the influence of race and ethnicity on surgical outcomes among children treated for acute appendicitis.Material and methodsA retrospective review of prospectively collected data was conducted. Children undergoing a laparoscopic appendectomy at our freestanding children's hospital between December 2015 and July 2017 were included. Demographic data, post-operative length of stay, same day discharge rates and hospital readmission rates were abstracted from patient medical records. Patients were classified by their race and ethnic background. Comparative analysis was performed in STATA with a p value < .05 determined as significant.ResultsA total of 786 children were included, with the majority being either White (70%, n = 547), Black (8%, n = 62) or Hispanic (17%, n = 133); 569 patients (72%) were found to have non-perforated appendicitis. There was no statistically significant difference in the rates of same day discharge among White, Black or Hispanic children respectively (88% vs. 77% vs. 86%, p = .126). Of the 217 children with perforated appendicitis, Hispanic children had increased rates of perforation (41%, n = 55) compared to White and Black children respectively (23%, n = 128 and 29%, n = 18, p = .001). However, average post-operative length of stay were similar among White, Black and Hispanic children (96 h vs. 95 h vs. 98 h, p = .015). On multivariate analysis, the only significant risk factor for an elevated post-operative length of stay was the presence of a perforation.ConclusionOur evidence based patient driven protocol effectively mitigates racial and ethnic disparities found in children with acute appendicitis. Further prospective investigation into the role of such patient-driven protocols to mitigate healthcare disparities is warranted.Levels of EvidenceTherapeutic study; Level 3.     

Cardiopulmonary bypass

The purpose of cardiopulmonary bypass is to maintain perfusion and oxygenation of the vital organs in the absence of heart and lung function, usually to facilitate surgery on the heart, but occasionally in other situations. Although the intricacies of the modern extracorporeal circuit and the conduct of cardiopulmonary bypass are the domain of the clinical perfusion scientist (‘perfusionist’), safe surgery mandates a good understanding of some fundamentals by the anaesthetist and the surgeon. This review is aimed at the anaesthetist. First, we will systematically examine the main components of the extracorporeal circuit, travelling in the direction that blood travels, from the venous cannula to the arterial cannula. Then we will describe the process of preparing for bypass, ‘going on’, conducting a bypass run, and weaning and separation from bypass. It is crucial to have clear communication between the surgeon, perfusionist and anaesthetist. This can be difficult for the novice because a quite specific language has evolved in cardiac operating theatres to signal key events in the cardiopulmonary bypass sequence. As we go through this article, we will highlight commonly used terminology and expressions used.     

How do women interpret abortion information they find online?

ObjectiveWe sought to assess how women interpret the information they find online about the overall safety and risk of infertility associated with abortion and cesarean delivery (CD).MethodsWe conducted an exploratory, prospective study tracking the internet searches of 100 reproductive-aged individuals who identify as women. We directed participants to search for information about either (1) whether surgical abortion or CD is safe or (2) the risk of infertility following surgical abortion or CD. Our data collection had 3 phases: baseline survey, directed internet search, and a postsearch survey. We analyzed participants’ pre- and postsurvey responses using bivariate tests and analyzed within-subject changes. We evaluated the sites they visited based on expert ratings of site content based on trustworthiness and slant.ResultsWomen perceived abortion as safer and less likely to cause infertility after their web searches than before (70% perceived abortion in the United States as very/completely safe presearch vs 92% postsearch; p < 0.02). Women's perceptions about CD did not change. Participants sought information from web pages that experts largely deemed trustworthy and lacking in slant.ConclusionsWomen's perceptions about abortion safety and risk can be influenced by information they find online; perceptions about CD safety and risk may be less influenced by online information.ImplicationsDisseminating high quality, user-friendly abortion information on highly ranked and easily findable websites can help women find evidence-based information and influence knowledge about abortion.     

Use of Stable Isotopes for Evaluation of Drug Delivery Systems: Comparison of Ibuprofen Release in Vivo and in Vitro from Two Biphasic Release Formulations Utilizing Different Rate-Controlling Polymers

Certain delivery systems are intended to release the active ingredient in different phases to obtain the desired therapeutic effect. For these formulations, such as a bilayer tablet, it is desirable to distinguish and measure the release of drug from the different phases simultaneously. Mass spectrometric methods were developed to measure three ibuprofen isotopomers in serum and two in dissolution fluid. The analytical methods were linear (r 0.992) over the concentration range of interest and recovery was greater than 99.2% for all isotopomers. Coadministration of [²H₀]ibuprofen, [²H₄]ibuprofen, and [²H₇]ibuprofen to male beagles demonstrated that the isotopomers were bioequivalent and verified the absence of any kinetic isotope effect due to deuterium incorporation (p = 0.286). These methods were then used to evaluate a bilayer tablet formulation composed of an immediate release layer of 100 mg [²H₄]ibuprofen and a sustained release layer with a drug load of 300 mg [²H₀]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro dissolution profiles were compared in the sustained release phase, while the immediate release formulation remained the same. In male beagles, the HPMC matrix delivered a significantly greater amount of ibuprofen (p < 0.05). The AUC was threefold greater for HPMC (1067 ± 437 nmole * h/ml) versus EUDRAGIT^® (320 ± 51), and C_max was nearly four times greater (145 ± 62.1 nmole/ml for HPMC versus 37.9 ± 14.4 for EUDRAGIT^®). Although T_max for HPMC (3.4 ± 1.9 h) lagged behind EUDRAGIT^® (2.0 ± 0.82 h), the difference was not significant (p > 0.05). The immediate release layer was absorbed to the same extent as an oral solution (containing [²H₇]ibuprofen) that was administered concomitantly with the bilayer tablet. Using the stable isotope markers also demonstrated that the release rates of the two layers were independent of each other, both in vivo and in vitro. Stable isotope techniques are a useful tool in the development of biphasic release formulations since they can be used to determine proper drug load of each phase as well as the appropriate rate of release.     

Serum and salivary antiendomysium antibodies in the screening of coeliac disease

BACKGROUND: Antiendomysium antibodies (EMA) detection in serum is the best screening test for coeliac disease (CD): in saliva it has not yet been assayed. Aims of this study are: to verify the presence of EMA in saliva collected with a not invasive technique; to evaluate the validity of serum and salivary EMA in CD screening. METHODS: We investigated 130 subjects divided into 3 groups: "A": 45 untreated CD patients (mean age 6.11); "B": 18 CD patients treated with a gluten free diet (mean age 13.2); "C": 67 controls (mean age 8.9). We performed the EMA test using the indirect immunofluorescence technique, in serum and in saliva concentrated samples. RESULTS: Our results show: sensitivity EMA serum 100%; specificity EMA serum 96.5%; sensitivity EMA saliva 46.5%; specificity EMA saliva 100%; pos. pred. value EMA serum 93.5%; neg. pred. value serum 100%; pos. pred. value EMA saliva 100%; neg. pred. value saliva 78.7%. CONCLUSIONS: Conclusion indicates a high specificity of salivary EMA and a high sensitivity of serum EMA, anyway biopsy is still recommended for diagnosis of CD.     

Third-generation assays for hepatitis C antibodies: a four-year study of pattern changes in patients with chronic and past infection

BACKGROUND: Many advances have been made in the sensitivity of assays for hepatitis C virus antibodies (HCV-Ab). Nevertheless, polymerase chain reaction (PCR) is still the best method to establish if infection has become chronic. In this study we utilised third-generation assays for HCV-Ab in a four-year follow-up to determine the trend in antibody levels in currently and past infected patients. METHODS: Seventy-two multitransfused subjects were enrolled. All the patients were reactive at the first test with third-generation screening and confirmatory assays (ELISA-3 and RIBA-3) for HCV-Ab. They were subsequently retested in a follow-up ranging from 41 to 47 months. Viraemia was investigated with a standardised PCR kit; negative samples were reevaluated with nested PCR. Differences in antibody trend were calculated with the Wilcoxon signed-rank test. RESULTS: No statistical variation in antibody titre was found in the 41 HCV-RNA positive patients, although some of these showed a decrease in anti-c100p level. In contrast, anti-c22p, anti-c33c and anti-c100p levels decreased significantly in the 19 past infected patients. Twelve patients were HCV-RNA negative or intermittently positive with commercial PCR test, and consistently or intermittently positive in nested PCR: in these patients, antibody trend varied. CONCLUSIONS: Although resolving hepatitis is associated with a decrease in antibody titre, the trend should be observed for a long period to distinguish between chronic and past infection. However, the evaluation in a single patient can be unreliable. Since a doubtful response for HCV-RNA is in some cases obtained, further improvements in the diagnosis of chronic HCV infection are needed.