Comparison of Drug Release and Adsorption under Supersaturating Conditions for Ordered Mesoporous Silica with Indomethacin or Indomethacin Methyl Ester.

Incomplete drug release from mesoporous silica systems has been observed in several studies. This work aims to increase the understanding of this phenomenon by investigating the mechanism of drug-silica interactions and adsorption behavior from supersaturated aqueous solutions of two similar drug molecules with different hydrogen bonding capabilities. Drug-silica interactions between indomethacin or its methyl ester and SBA-15 were investigated using spectroscopic techniques (infrared, fluorescence and X-ray photoelectron) and adsorption experiments. The results demonstrate that the predominant mechanism of interaction of both drugs with silica is hydrogen bonding between drug acceptor carbonyl groups with donor groups on the silica surface. The presence of a drug hydrogen bond donor group did not enhance drug adsorption. No evidence was obtained for drug adsorption through nonspecific hydrophobic interactions. Drug adsorption onto the silica surface was investigated under supersaturating conditions through the generation of adsorption isotherms. Similar adsorption isotherms were observed for each compound when the concentration scale was normalized to the drug amorphous solubility. In other words, the equilibrium between the drug adsorbed on the silica surface and free drug in solution was related to the drug activity in solution. The high tendency of the drug to adsorb when the solution is supersaturated was, in turn, found to limit the extent of drug release during dissolution under nonsink conditions. Thus, adsorption provides an explanation for incomplete drug release.

Role of Drug Adsorption onto the Silica Surface in Drug Release from Mesoporous Silica Systems.

Factors contributing to incomplete drug release from a number of mesoporous silica formulations are not well understood. This study aims to address this gap in knowledge by exploring the role of drug adsorption onto silica substrates during the drug release process in dissolution media. Adsorption isotherms were generated to understand drug adsorption behavior onto the silica surface. Two silica materials were selected (SBA-15 (mesoporous) and Aerosil 200 (nonporous)) to investigate the influence of porous architecture on the adsorption/dissolution processes. The ability of the dissolution medium to wet the silica surface, particularly the porous network, was investigated by the addition of a surfactant to the dissolution medium. The results demonstrated that a larger amount of drug was bound/m2 to the nonporous surface than to the mesoporous material. Adsorption isotherms proved useful in understanding drug adsorption/release behavior for the nonporous silica formulation. However, the quantity of drug remaining on the mesoporous silica surface after dissolution was significantly higher than the amount predicted using adsorption isotherm data. These results suggest that a fraction of loaded drug molecules were tightly bound to the silica surface or attached to sites which are inaccessible for the dissolution media. The presence of surfactant, sodium dodecyl sulfate, in the media enhanced drug release from the silica surface. This behavior can be attributed to both the improved wetting characteristics of the media and adsorption of the surfactant to the silica surface. The findings of this study reinforce the significance of the role that silica porous architecture plays in the dissolution process and indicates that accessible surface area is an important parameter to consider for mesoporous systems in relation to drug release.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series.

OBJECTIVE: The goal was to describe herpes simplex virus (HSV) disease in neonates whose mothers received suppressive acyclovir therapy for HSV infection. STUDY DESIGN: A multicenter case series of 8 infants who developed neonatal HSV disease following maternal antiviral suppressive therapy during pregnancy. RESULTS: Eight infants were identified from New Jersey (5), Maine (1), New York (1), and Texas (1) between 2005 and 2009. All 6 mothers of infants infected with HSV who were screened prenatally for group B Streptococcus were positive; 1 mother was not tested and the other had bacterial vaginosis and genital human papillomavirus infection. Six mothers had a first clinical episode of genital HSV infection during this pregnancy; mothers with a prior history of genital HSV had no clinically recognized outbreak during the pregnancy. Perinatal transmission of HSV occurred in 7 infants (despite suppressive therapy until the day of delivery in 5 instances). Seven of 8 patients were born at term; 6 infants were male. In 7 of 8 cases, HSV was diagnosed by 8 days of age. Five infants had skin, eye, and mucous membrane disease, 2 had central nervous system disease (without and with disseminated disease), and one had intrauterine/disseminated disease. CONCLUSIONS: Although maternal antiviral suppressive therapy is an increasingly wide practice, physicians caring for neonates should be aware that suppressive therapy does not prevent neonatal HSV disease, which can have an atypical clinical presentation and drug resistance.

Cardiac Manifestations of Lyme Disease.

Lyme carditis is an uncommon manifestation of Lyme disease. Most cases present with heart block of varying degrees, but the spectrum of disease includes other transient arrhythmias and structural manifestations, such as myopericarditis or cardiomyopathy. Antibiotics hasten the resolution of Lyme carditis, and cardiac pacing can be an adjunctive therapy. Outcomes are generally good, but there are rare fatalities associated with Lyme carditis. The latter underscores the continued need for improved modes of prevention of Lyme disease and the importance of its early recognition and treatment.

Lyme Disease in Children.

Lyme disease is now the most frequently reported vector-borne disease in the United States. The highest incidence is in children aged 5 to 9 years with a male predominance. The most common manifestation, erythema migrans, is sometimes not recognized, leading to risk of complications. Testing for Lyme disease should only be done if there is a consistent clinical syndrome with exposure in a Lyme-endemic area. Most forms of Lyme disease are successfully treated with short courses of oral therapy. Prevention and management of tick bites is important.

Lyme Carditis in Hospitalized Children and Adults, a Case Series.

BACKGROUND: Lyme carditis is an uncommon manifestation of Lyme disease. This report compares Lyme carditis presentation, management, and outcomes in pediatric and adult populations. METHODS: Charts of pediatric and adult patients with heart block (PR interval >300 ms) and positive Lyme serologies hospitalized in Portland, Maine, between January 2010 and December 2018 were analyzed. Data on medical history, presentation, treatment, and outcomes are described. RESULTS: Ten children and 20 adults were admitted for Lyme carditis between June and October. Ninety percent were male, and 87% had no prior cardiac history. Seventeen had outpatient evaluation before admission. Of these, a minority (41%) had Lyme disease suspected in the outpatient setting, and fewer (12%) were initiated on Lyme disease treatment. The most common alternate diagnoses were viral illness and erythema multiforme. More children than adults had disseminated erythema migrans and fever. First-degree heart block was more prevalent in children, and Mobitz type 2 heart block was more prevalent in adults. Ten patients presented with syncope. Proportionately more adults needed temporary pacing. Children had shorter antibiotic durations compared with adults. Of the 30 cases, 27 had improved heart block, while 3 adults required a pacemaker at discharge. Nine children and 14 adults were discharged with a PR 200-300 ms. There was a single death in this series. CONCLUSIONS: Cases tended to be younger males. Most patients had some heart block on discharge. Of patients evaluated as outpatients, Lyme disease was suspected in 41%. Improved early recognition and treatment of Lyme disease may decrease Lyme carditis.

Renal and miliary tuberculosis in an internationally adopted infant.

Renal tuberculosis is rare in children and particularly in infants. We present a case of miliary tuberculosis with focal renal involvement in a 5-month-old male infant recently adopted from Ethiopia, and review the literature on miliary and renal tuberculosis in infants and children. Salient points regarding tuberculosis screening in internationally adopted patients are also addressed.

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation.

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships, was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations.

Mesoporous silica formulation strategies for drug dissolution enhancement: a review.

INTRODUCTION: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture. AREAS COVERED: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered. EXPERT OPINION: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.

Human parechovirus-3 encephalitis in two neonates: acute and follow-up magnetic resonance imaging and evaluation of central nervous system markers of inflammation.

BACKGROUND: Human parechovirus-3 has been known to cause neonatal sepsis and encephalitis for nearly a decade. However, information about magnetic resonance imaging and cerebrospinal fluid findings as well as outcomes has been limited. PATIENTS: Acute presentations and diagnostic testing of two neonates with Human parechovirus-3 encephalitis are described. Clinical and radiographic follow-up is provided. CONCLUSIONS: Evaluation of central nervous system neurochemistry with inflammatory markers such as neopterin, may be helpful for diagnosis in neonatal encephalitis. The pattern of white matter injury seen in these two patients should raise suspicion for Human parechovirus-3 infection. Testing for this virus should be more routinely considered in neonates presenting with encephalitis and normal cerebrospinal fluid results. The severity of radiographic abnormality may not correlate with long-term findings as the clinical and radiographic follow-up after a year is better than expected in the first patient.

Lyme arthritis: a comparison of presentation, synovial fluid analysis, and treatment course in children and adults.

OBJECTIVE: This case series examines differences in the presentation, management, and outcome of Lyme arthritis between the pediatric and adult population. METHODS: We reviewed charts of pediatric and adult patients evaluated for Lyme arthritis by rheumatologists and pediatric infectious disease specialists in Portland, Maine between January 2002 and July 2008. Patients included for analysis had documented joint swelling and positive Lyme serology. Data on clinical presentation, synovial fluid and peripheral blood results, treatment, and clinical course were analyzed. RESULTS: Twenty-nine adults and 52 children met case criteria for Lyme arthritis. Children were more likely than adults to present acutely (P < 0.0001) and also had higher mean peripheral blood (P = 0.05) and synovial fluid white blood cell counts (P < 0.0001). Lyme arthritis was more frequently suspected in children at presentation (P = 0.04). There was no difference between children and adults with respect to suspicion for septic arthritis, hospitalization, or surgical intervention. Adults received more antibiotic courses (P = 0.007) and were more likely to have intravenous antibiotics in subsequent treatment courses (P = 0.006). Children were more likely to have normal function within 4 weeks of initiating antibiotic treatment (P < 0.0001). CONCLUSION: Children with Lyme arthritis were more likely to present acutely with higher synovial white cell counts than adults. We did not, however, observe a significant difference in hospitalization or surgical management. Children had more prompt resolution of their joint swelling and received less treatment overall.