Which model of small bowel capsule endoscopy has a better diagnostic yield? A systematic review and meta-analysis.

Background and study aims: Small-bowel capsule endoscopy (SBCE) is a safe and efficient method for diagnosis of small-bowel diseases. Since its development, different models have appeared. The aim of this study was to analyze which of the different models of SBCE has the best diagnostic yield. Patients and methods: Extensive medical literature research was reviewed, using MESH terms, searching studies comparing different SBCE types. We analyzed the diagnostic yield of all the comparisons and when there were 2 or more studies that compared the same model of SBCEs, a meta-analysis was performed. Results: Ten eligible studies including 1065 SBCEs procedures were identified. The main indication was occult gastrointestinal bleeding in 9/10 studies. Two of them included anemia, chronic diarrhea and/or chronic abdominal pain. The indication in one article was celiac disease. In 9 studies, different types of SBCEs (MiroCam, Endocapsule, OMOM and CapsoCam) were compared with PillCam (SB, SB2 and SB3). Three studies compared MiroCam vs PillCam and CapsoCam vs PillCam, while two studies contrast Endocapsule vs PillCam. None of the SBCEs show superiority over PillCam [OR 0.78 (95%CI;0.60-1.01)]. One study compared SBCEs other than Pillcam (MiroCam vs Endocapsule). Nine studies did not find statistical differences between SBCEs, one showed better diagnostic yield of Mirocam compared with PillCam SB3 (p=0.02). The difference between these SBCE was not replayed in the metaanalysis [OR 0.77 (95%CI;0.49-1.21)]. Conclusions: Despite the appearance of new SBCE models, there are no differences in diagnostic yield; therefore, SBCE endoscopist's performance should be based on experience and availability.

Double-balloon enteroscopy: Indications, approaches, diagnostic and therapeutic yield, and safety. Early experience at a single center. / Enteroscopia de doble balón: indicaciones, abordajes, eficacia diagnóstica y terapéutica y seguridad. Experiencia temprana de un solo centro.

INTRODUCTION AND AIMS: Double-balloon enteroscopy has been improving the visualization of the entire intestine for more than a decade. It is a complementary method in the study of intestinal diseases that enables biopsies to be taken and treatments to be administered. Our aim was to describe its main indications, insertion routes, diagnostic/therapeutic yield, and complications. MATERIALS AND METHODS: All patients referred to our unit with suspected small bowel pathology were included. The insertion route (oral/anal) was determined through diagnostic suspicion. The variables measured were: insertion route, small bowel examination extent, endoscopic diagnosis/treatment, biopsy/histopathology report, complications, and surgical findings. RESULTS: The study included 28 double-balloon enteroscopies performed on 23 patients, of which 10 were women and 13 were men (mean age of 52.95 years). The oral approach was the most widely used (n=21), the main indication was overt small bowel bleeding (n=16), and the general diagnostic yield was 65.21%. The therapeutic intervention rate was 39.1% and the procedure was effective in all the cases. The most widely used treatment was argon plasma therapy (n=7). The complication rate was 8.6%; one patient presented with low blood pressure due to active bleeding and another had deep mucosal laceration caused by the argon plasma. CONCLUSIONS: Double-balloon enteroscopy is a safe and efficacious method for the study and management of small bowel diseases, with an elevated diagnostic and therapeutic yield.

Liquid chromatographic determination of CPZEN-45, a novel anti-tubercular drug, in biological samples.

CPZEN-45 is a new drug candidate being considered for the treatment of tuberculosis (TB). The aim of this study was to develop and validate a reverse-phase high-performance liquid chromatographic (HPLC) method suitable to determine CPZEN-45 concentrations in biological samples. CPZEN-45 was extracted from biological fluids and tissues (plasma, lung and spleen from guinea pig) by sequential extraction with acetonitrile and quantified by a Waters HPLC Alliance System coupled with a ZORBAX Bonus-RP column, guard column and UV detection at 263nm. The mobile phase was 20:80 acetonitrile:ultrapure-water with 0.05% TFA. The CPZEN-45 peak was eluted at 5.1min with no interference from the inherent peaks of plasma, bronchoalveolar lavage (BAL), lung or spleen tissues. Recovery of CPZEN-45 from biological samples was >96% of the spiked amount. The limit of detection was 0.05µg/ml and the limit of quantitation was 0.29µg/ml which was more than 5 and 21 times lower than the reported minimal inhibitory concentration of CPZEN-45 (MIC=1.56µg/ml for Mycobacterium tuberculosis and 6.25µg/ml for MDR-TB, respectively). Thus, HPLC method was deemed reliable, sensitive, reproducible and accurate for the determination of CPZEN-45 concentrations in plasma, BAL, lung and spleen tissues. Therefore, this method was used in subsequent studies in the guinea pig model to determine the disposition of CPZEN-45 after administration of solutions by the IV and SC routes.

Pharmacokinetics of sequential doses of capreomycin powder for inhalation in guinea pigs.

The global control of tuberculosis (TB) is at risk by the spread of multidrug-resistant TB (MDR TB). Treatment of MDR TB is lengthy and involves injected drugs, such as capreomycin, that have severe side effects. It was previously reported that a single daily dose of inhaled capreomycin had a positive effect on the bacterial burden of TB-infected guinea pigs. The modest effect observed was possibly due to a dose that resulted in insufficient time of exposure to therapeutic systemic and local levels of the drug. In order to determine the length of time that systemic and local drug concentrations are above therapeutic levels during the treatment period, the present study investigated the disposition of capreomycin powders after sequential pulmonary administration of doses of 20 mg/kg of body weight. Capreomycin concentrations in bronchoalveolar lavage fluid and lung tissue of animals receiving a series of one, two, or three doses of capreomycin inhalable powder were significantly higher (50- to 100-fold) at all time points than plasma concentrations at the same time points or those observed in animals receiving capreomycin solution by intramuscular (i.m.) injection (10- to 100-fold higher). Notably, at the end of each dosing period, capreomycin concentrations in the lungs were approximately 100-fold higher than those in plasma and severalfold higher than the MIC, suggesting that sufficient capreomycin remains in the lung environment to kill Mycobacterium tuberculosis. No accumulation of capreomycin powder was detected in the lungs after 3 pulmonary doses. These results indicate that the systemic disposition of capreomycin after inhalation is the same as when injected i.m. with the advantage that higher drug concentrations are present at all times in the lungs, the primary site of infection.

Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model.

Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.

Evaluation of dosing regimen of respirable rifampicin biodegradable microspheres in the treatment of tuberculosis in the guinea pig.

OBJECTIVES: The efficacy of rifampicin-loaded polymeric microspheres (RPLGA) delivered to guinea pigs infected with Mycobacterium tuberculosis (H37Rv) was compared with a daily dose of nebulized rifampicin suspension. METHODS: Aerosol-infected animals were subjected to multiple dose or single dose treatment with RPLGA, PLGA microspheres or micronized rifampicin suspension aerosols. For comparison with treatment with suspensions of microspheres, additional groups received daily doses of rifampicin-only suspensions for 20 (20-RIF) and 10 (10-RIF) days. RESULTS: Drug and polymer treated multiple dose groups exhibited significantly lower wet lung weights than untreated animals. Spleen wet weights and viable bacterial counts (VBCs) were much lower for drug microsphere treated animals than for all other groups. In multiple dose studies with rifampicin-only suspensions, wet lung weights for 10-RIF and 20-RIF treated animals were much smaller than controls. Likewise, wet spleen weights of 10-RIF and 20-RIF treated animals were much smaller than controls, consistent with reduced inflammation. Spleen VBC of 20-RIF treated animals was much smaller than controls. No statistical differences were observed in the lung VBC among single dose groups. However, a trend similar to that of the wet weights was observed. CONCLUSIONS: Aerosolized RPLGA reduced most measures of tuberculosis (TB) infection. These studies are further evidence for the potential of inhaled aerosol therapy for the treatment of TB. However, additional studies are required to elucidate underlying mechanisms of action and optimize this route of drug delivery.

Immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs: relevance to humans.

The effects of xenobiotics on the lungs have been studied for many years. In the past 50 years, delivery of drugs to the lungs has been adopted to achieve local effects, specifically for the treatment of asthma. Recently, due to the proximity of the circulating blood supply and to their large surface area, the lungs have been proposed as the port of entry for drugs to obtain systemic effects, particularly for macromolecular compounds of biological origin. Numerous studies regarding drug formulation, delivery systems, and related pharmacokinetics have been reported; however, the concurrent effects of pulmonary delivery of drugs on the physiology of the lung has not been evaluated early in the development process. The prospect of using the lungs for the delivery of biological molecules such as proteins, peptides, and nucleic acids raises the question of the local toxicity of these compounds. Therefore, criteria must be established to study the initial impact of pulmonary drug delivery on the physiology of the lungs. This relates particularly to subtle local and systemic implications of those effects on the transport phenomena that may be contrasted with conventional toxicity studies focused on gross effects.

Immediate and short-term cellular and biochemical responses to pulmonary single-dose studies of insulin and H-MAP.

PURPOSE: It was previously reported that co-administration of H-MAP to the airways of the lungs significantly influenced the absorption, disposition. and effect of insulin in a dose-dependent fashion. Doses of H-MAP (16 mg/kg) and insulin (1.3 U/kg) required to achieve maximum pharmacokinetic and pharmacodynamic responses were determined. The purpose of the present study was to evaluate the effects of insulin and H-MAP spray-instilled (SI) to rats on the physiology of the lung. A short-term, single-dose study of insulin alone and combined with H-MAP was performed. METHODS: Solutions of either insulin (INS), H-MAP, or insulin plus H-MAP (INMA) were SI to the lungs of rats. Lipopolysaccharide solution (LPS) and sodium dodecyl sulfate solution (SDS) were used as positive controls. and normal saline (SAL) was used as negative control. Animals were sacrificed at various time points and bronchoalveolar lavage (BAL) was conducted. BAL fluid was analyzed for local markers of lung injury, such as total cell numbers, differential cell count, total protein content and enzyme activities of lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and N-acetyl glucosaminidase (NAG). RESULTS: SI of any solution, including normal saline, seems to have a minor but detectable effect on the normal physiology of the lung. SI of positive control solutions resulted in most markers of immunity and lung injury being significantly elevated, notably enzyme activity and white cell infiltrate. In contrast, SI of INS produced a response similar to that of SAL. SI of INMA resulted in a small transient response characterized by a slight increase in the proportion of neutrophils at 24 h, which decreased with time and was comparable to that of SAL at 72

Facilitation of pulmonary insulin absorption by H-MAP: pharmacokinetics and pharmacodynamics in rats.

PURPOSE: Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined. METHODS: Aliquots (100 microl) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined. RESULTS: The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (Cmax) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG0-->t) was achieved for H-MAP/insulin combination (66+/-5%) compared to insulin alone (47+/-10 %). CONCLUSION: H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.

Biodegradable cisplatin microspheres for direct brain injection: preparation and characterization.

The objectives of the present study were to prepare cisplatin loaded-PLGA microspheres that are suitable for direct brain injection and to characterize them in terms of their physicochemical properties, in vitro drug release, and self-removal mechanism. The microspheres were prepared by emulsification/solvent evaporation method using PLGA (50:50) as the biodegradable matrix forming polymer. The physicochemical characterization encompassed the following: surface morphology, particle size, entrapment efficiency, surface area, and density. The in vitro release and in vitro degradation studies were performed in phosphate buffer and in 10% rat brain preparation. SEM micrographs revealed that the microspheres have a rough porous surface and a smooth interior. Particle size typically ranged from 180 to 250 microns with an average of 230 T microns. Entrapment efficiency was approximately 70% and was found to be dependent on the particle size. Surface area and density ranged from 0.038 to 0.025 m2/g and from 1.44 to 1.39 g/cm3, respectively. Both were also dependent on particle size. In the in vitro release study in phosphate buffer, approximately 80% of cisplatin was released over 30 days, after which the release rate plateaued. The release profile in 10% rat brain preparation was comparable in shape to that obtained in phosphate buffer. However, the release rate was lower and the total amount released by the end of the study was only 55% of the total cisplatin content. The degradation of PLGA microspheres in phosphate buffer and in rat brain homogenate correlated well with the respective release profiles. Based on the evidence of self-removal and the sustained release of cisplatin for over a month, cisplatin-loaded PLGA microspheres may be useful for local delivery to brain tumors.

Preparation and evaluation of zidovudine-loaded sustained-release microspheres. 2. Optimization of multiple response variables.

The formulation of zidovudine-loaded (AZT-loaded) sustained-release microspheres was prepared and optimized using response surface methodology. The objective was to use this statistical procedure to obtain a formulation with optimized overall properties. The effect of formulation variables (emulsifier concentration, drug to polymer ratio, and composition of the internal phase of the emulsion) on a number of response variables was systemically investigated. The response variables were t85, entrapment efficiency, yield, and percentage of loose surface crystals. A desirability function that combines these four response variables was constructed. A second-order polynomial equation was fitted to the data, and the resulting equation was used to predict the responses in the optimal region. All the investigated response variable were found to be highly dependent on the formulation variables, with strong interactions observed between the formulation variables. It was found that optimum overall desirability of AZT microspheres can be obtained at low levels of SDS and ethyl acetate concentrations and at intermediate levels of drug to polymer ratio. An optimized formulation was prepared under these experimental conditions and evaluated for individual responses and overall desirability. The experimental values of the response variables highly agreed with the predicted values.

Preparation and evaluation of sustained release AZT-loaded microspheres: optimization of the release characteristics using response surface methodology.

The purpose of the study was to prepare and optimize a sustained release formulation of zidovudine (AZT). Ethylcellulose microspheres containing AZT were prepared using an emulsification/solvent evaporation technique. The critical formulation variables were emulsifier concentration, drug to polymer ratio, and ethyl acetate concentration in the internal phase of the emulsion. The time to release 85% of the contents of the microspheres (t85) was used as a measure for the release time. A second-year polynomial equation was fitted to the release data to systemically investigate the effect of the formulation variables on the release rate. This equation was then used to predict t85 in the optimum region. The t85 was found to be dependent on the three formulation variables, with strong interactions observed between these variables. The microspheres were characterized in terms of their particle size and surface morphology. The study indicated no overall correlation between the mean diameter of the microspheres and the t85.