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Enzyme-responsive release of encapsulated proteins from biodegradable hollow capsules.

Biodegradable hollow capsules encapsulating proteins were prepared via layer-by-layer assembly of chitosan and dextran sulfate on protein-entrapping mesoporous silica particles and the subsequent removal of the silica. The enzymatic degradation of the capsules in the presence of chitosanase was explored by scanning electron microscopy (SEM). With increasing time, the chitosan component was degraded by chitosanase, and the capsules began to deform and were finally destroyed. Sustained release of the encapsulated proteins was attained by using the enzymatic degradation of the hollow capsules. The release behavior was successfully manipulated by altering the charge of capsule surface.

Animals↗

Solvent-stabilized molecular capsules.

Pyrrogallolarenes 2 were prepared by acid-catalyzed condensation of pyrrogallol with aldehydes. Compound 2a crystallizes from a methanol solution of quinuclidine hydrochloride to give a dimeric molecular capsule surrounding one disordered quinuclidinium cation. The molecules of 2a are connected by direct hydrogen bonds and by bridging methanol and water molecules. The chloride anion is positioned outside the capsule and is hydrogen bonded to the hydroxy groups of 2a. The shortest distance between the cation and anion was found to be 6.7 A. Crystallization of 2b from aqueous acetonitrile resulted in a dimeric capsule linked by a polar belt of 16 hydrogen bonding water molecules. Four acetonitrile molecules occupy the cavity of this dimeric capsule and assume two binding sites that differ in hydrogen bonding and electronic environment. Compounds 2 also form hydrogen-bonded dimeric molecular capsules in alcohols and aqueous acetonitrile solutions. These assemblies readily encapsulate tetramethylammonium, tetramethylphosphonium, quinuclidinium, and tropylium cations to give complexes stable on the NMR time scale at 233 K.

Capsules↗

Determination of extent of formaldehyde-induced crosslinking in hard gelatin capsules by near-infrared spectrophotometry.

PURPOSE: To predict the degree of crosslinking from formaldehyde-stressed hard gelatin capsules (HGCs) using near-infrared spectrophotometry (NIR). METHODS: HGCs were exposed to a 150 ppb atmosphere of formaldehyde for 2.25, 4.60, 9.42, 16.0 and 24.0 hours. The capsules were filled with fresh amoxicillin, placed in a 90 degrees conical reflector cone, and scanned in a NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the intact capsules. Dissolution profiles were then obtained for each experimental group. RESULTS: The dissolution of amoxicillin from the capsules at pH 1.2 was found to decrease with increasing time of exposure to the formaldehyde atmosphere. A set of principal components (PCs) was formed by a linear combination of the absorbance values at each wavelength scanned. A good correlation was established (r2 = 0.963) when PC values from the NIR spectra of the HGCs were regressed against percentage of amoxicillin dissolved at 45 minutes, at pH 1.2. Water content of the capsules was found to be the largest determinant in the variation between HGC spectra at each exposure time. CONCLUSIONS: NIR spectrophotometry, combined with PCR, was successful at not only predicting dissolution of HGCs exposed to formaldehyde, but also at determining which wavelengths contributed most to spectral variation of these stressed HGCs.

Amoxicillin↗

In vivo and in vitro diclofenac sodium evaluation after rectal application of soft gelatine capsules enabling application induced transformation (AIT) into a semisolid system of liquid crystals (SSLC) for controlled release.

PURPOSE: Reverse micellar solutions of diclofenac sodium were encapsulated in soft gelatine capsules. On contact with aqueous media they exhibited an application induced transformation (AIT) into a semisolid system of liquid crystals (SSLC) which slows down drug release. The aim of the present paper was to study in vitro and in vivo drug release from these systems after rectal application. METHODS: In vitro drug release was determined in a self-constructed dissolution apparatus to simulate rectal application. For in vivo bioavailability studies rabbits were used as animal models. In vitro release and in vivo bioavailability of the capsules was compared to Voltaren suppositories. RESULTS: The release profiles of the in vitro experiments show zero-order kinetics. The in vivo bioavailability studies show bioequivalence in terms of AUC for both formulations (capsules and Voltaren suppositories). The mean residence time (parameter of sustained release) of the capsules is three time longer in comparison to Voltaren suppositories. CONCLUSIONS: Rectal administration of capsules provides an appropriate route for controlled release via AIT-SSLC which could be clearly verified in rabbits.

Administration, Rectal↗

Sulfamethizole capsules containing contrast medium for assessment of gastric emptying in functional dyspepsia patients.

The usefulness of sulfamethizole capsules containing contrast medium in gastric emptying tests for functional dyspepsia was evaluated in five healthy volunteers and nine patients with dysmotility-like symptoms. Each subject swallowed 15 capsules with a liquid, food, and at 0, 15, 30, 45, 60, 90, and 120 min, the capsule position and size were monitored fluoroscopically for 30 sec and radiograms were obtained. Blood sulfamethizole concentrations were also measured at the same time. Visualized capsule movement from the proximal to distal stomach up to 60 min was faster in the patients, whereas in the later digestion period, proximal stomach emptying in the patients was delayed significantly (P < 0.05), and the number of capsules remaining in the distal stomach at 120 min was significantly larger in the patients (P < 0.05). This test method was evaluated as being useful in monitoring solid emptying in normal and pathophysiologic conditions.

Adult↗

The effect of anthelmintic capsules on the egg output and larval viability of drug-resistant parasites.

Challenge with an equal mix of drug-resistant and drug-susceptible larvae of Teladorsagia circumcincta resulted in infections in groups of lambs (n = 6) either untreated or given controlled-release capsules, containing either albendazole or ivermectin. Lambs treated with albendazole capsules contained similar numbers of adult worms at necropsy to the other groups but had no detectable faecal egg count. Animals treated with ivermectin capsules had similar worm burdens and faecal egg counts to the control group but the worms had significantly higher numbers of eggs in utero. These results provide evidence for suppression of egg production by both anthelmintic treatments. The observation that albendazole caused a significant reduction in the developmental success of parasite eggs also has implications for the use of faecal egg count as an indicator for pasture contamination with resistant parasites. In two further groups of lambs, either untreated or given albendazole capsules, treatment caused a significant reduction in egg count and adult worm burden of Trichostrongylus colubriformis. No significant effects were observed on in utero egg counts or egg viability and the apparent effect on the number of eggs produced in faeces per adult female was not significant (p = 0.077). There was, therefore, no evidence that albendazole controlled-release capsules caused suppression of egg output in this species.

Albendazole↗

Effect of sodium lauryl sulfate in dissolution media on dissolution of hard gelatin capsule shells.

PURPOSE: Sodium lauryl sulfate (SLS) is a commonly used surfactant in dissolution media for poorly water soluble drugs. However, it has occasionally been observed that SLS negatively impacts the dissolution of drug products formulated in gelatin capsules. This study investigated the effect of SLS on the dissolution of hard gelatin capsule shells. METHODS: The USP paddle method was used with online UV monitoring at 214 nm (peptide bond). Empty size #0 capsule shells were held to the bottom of the dissolution vessel by magnetic three-prong sinkers. RESULTS: SLS significantly slowed down the dissolution of gelatin shells at pH < 5. Visually, the gelatin shells transformed into some less-soluble precipitate under these conditions. This precipitate was found to contain a higher sulfur content than the gelatin control sample by elemental analysis, indicating that SLS is part of the precipitate. Additionally, the slowdown of capsule shell dissolution was shown to be dependent on the SLS concentration and the ionic strength of the media. CONCLUSIONS: SLS interacts with gelatin to form a less-soluble precipitate at pH < 5. The use of SLS in dissolution media at acidic pH should be carefully evaluated for gelatin capsule products.

Capsules↗

Construction of ectopic xenogeneic bone marrow structure associated with persistent multi-lineage mixed chimerism by engraftment of rat bone marrow plugs into mouse kidney capsules.

Poor bone marrow (BM) engraftment in a xenogeneic combination results at least in part from the limited engraftment capacity of BM-derived stromal cells, which support hematopoietic repopulation in a species-specific fashion. We attempted to construct a BM stromal microenvironment by engraftment of BM plug fragments into kidney capsules in a rat-to-mouse combination. BM plugs from F344/N Jcl-rnu/rnu (F344 nu) rats were transplanted into the kidney capsules of C.B-17 scid/scid (C.B-17 scid) mice treated with rabbit anti-asialo-GM1 serum to deplete natural killer (NK) cells and then with 3 Gy of whole body irradiation. As a conventional control, an equivalent amount of F344 nu bone marrow cells (BMCs) was intravenously injected into C.B-17 scid mice treated with a similar conditioning regimen. In both mouse recipients of rat BM plug engraftment in the kidney capsules and recipients of intravenous injection of rat BMC suspension, comparable extents of donor rat class I+ cells were persistently detected in the peripheral blood. However, the differentiation of rat-derived B cells in the mouse recipients of rat BM plugs was more rapid than that in the recipients of rat BMC suspension. In the late phase (10 weeks after BM transplantation), the percentage of rat-derived T cells (CD4+ cells) in the mouse recipients of rat BM plugs was significantly higher than that in the recipients of rat BMC suspension. At this time point, ectopic BM structure consisting of bone, mesenchymal cells, and hematopoietic progenitors was constructed in the kidney capsules of mice that received rat BM plugs. Most of the cells in the ectopic BM were derived from the donor rat. Thus, engraftment of BM plugs into the kidney capsules results in the construction of a donor-derived BM microenvironment, facilitating multilineage mixed xenogeneic chimerism.

Animals↗

Effect of metoclopramide on digoxin absorption from tablets and capsules.

The effect of metoclopramide, a drug that increases gut motility, on the consistency of digoxin absorption was examined in 16 healthy men. Each received the following four single-dose digoxin treatments in complete crossover fashion: two 0.25-mg digoxin tablets, alone, and two 0.2-mg digoxin capsules with metoclopramide. Mean serum AUCs over 24 hr (AUC-24) and cumulative urinary digoxin excretion over 48 hr (CUE-48) were of the same order for the tablets and capsules alone treatments. Metoclopramide reduced the mean AUC-24 for tablets from 12.26 +/- 2.70 to 9.38 +/- 3.78 ng X hr/ml (P less than 0.001) and the CUE-48 from 119.0 +/- 22.4 to 97.6 +/- 22.2 micrograms (P less than 0.01). There were no significant differences in mean AUC-24 (12.94 +/- 3.16 and 13.45 +/- 2.33 ng X hr/ml) and mean CUE-48 (117.8 +/- 23.4 and 109.7 +/- 25.0 micrograms) when capsules alone were compared to capsules with metoclopramide. Metoclopramide reduced the time to reach peak concentration for both digoxin dosage forms. The effect of metoclopramide on digoxin absorption is minimized by administration of digoxin in capsules.

Absorption↗

Influence of single and multiple doses of oral ranitidine on the gastric transit of an indigestible capsule in humans.

The effect of single and multiple doses of ranitidine on the gastric residence time of an indigestible pH-sensitive radiotelemetric device, the Heidelberg capsule, was evaluated in 12 healthy men (mean age, 29 +/- 8 years) in a placebo-controlled, randomized, crossover study. Each subject received 150 mg ranitidine or placebo orally 2 hours before administration of the Heidelberg capsule. A 500 kcal standardized breakfast was served 1/2 hour before the capsule was administered. Gastric pH was monitored at 15-minute intervals, until pyloric passage (pH increase greater than or equal to 3 U) of the Heidelberg capsule was observed. Blood samples (n = 12) were collected 0 to 8 hours after administration of drug or placebo. The subjects continued to receive ranitidine or placebo b.i.d. for 7 days and returned on day 8 for a similar evaluation. After a 1-week washout period, the subjects received the alternative treatment. The mean (+/- SD) gastric residence time of the Heidelberg capsule was significantly decreased after both single and multiple doses of ranitidine compared to placebo (3.1 +/- 0.9 versus 3.8 +/- 1.1 hours, p less than 0.02; and 2.9 +/- 0.74 versus 3.9 +/- 0.9 hours, p less than 0.005, n = 9). Gastric residence time was not determined in three subjects who showed unusually slow gastrointestinal motility after both placebo and ranitidine. Mean AUC(0-8 hr) and AUC(0-infinity) were significantly increased, whereas Cmax, tmax, and t1/2 remained unchanged after 7 days of ranitidine b.i.d. treatment. No ranitidine double-peak profile or linear pharmacokinetic-pharmacodynamic relationship was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

Phacoemulsification in true exfoliation of the lens capsule: a case series.

PURPOSE: We report five cases (seven eyes) of true exfoliation during an 18-month period. Of the two bilateral cases, the first was identified immediately before cataract surgery and the second spontaneously developed a split in the anterior capsule just before capsulorrhexis, mimicking a partial capsulorrhexis. In the three unilateral cases, true exfoliation was noted during the first examination. METHODS: Vision blue aided uneventful capsulorrhexis differentiating its edge from the true exfoliation edge, and in the first two cases, the anterior capsule was sent for histopathology and ultrasound of the fellow eye was requested. RESULTS: Ultrasound and histopathology demonstrated lamellar separation of the anterior portion of the lens capsule, confirming the diagnosis of true exfoliation. Cataract surgery by phacoemulsification was uneventful in all cases. CONCLUSION: True exfoliation of the lens capsule can masquerade as a partial capsulorrhexis and should be looked for before surgery and immediately before capsulorrhexis to avoid creating a partial thickness capsulorrhexis and its related surgical complications. No zonule weakness was appreciated in our cases. To our knowledge, the spontaneous occurrence of a curvilinear lamellar capsular dehiscence with a flap before capsulorrhexis has not been reported before. This series highlights that cataracts associated with true exfoliation of the lens capsule can be safely operated, with the help of vision blue, by routine phacoemulsification without having to convert to the extracapsular technique.

Aged↗

Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis.

The two major virulence factors of Bacillus anthracis are the tripartite toxin and the polyglutamate capsule, which are encoded by genes on the large plasmids, pXO1 and pXO2, respectively. The genes atxA, located on pXO1, and acpA, located on pXO2, encode positive trans-acting proteins that are involved in bicarbonate-mediated regulation of toxin and capsule production, respectively. A derivative strain cured of pXO1 produced less capsular substance than the parent strain harbouring both pXO1 and pXO2, and electroporation of the strain cured of pXO1 with a plasmid containing the cloned atxA gene resulted in an increased level of capsule production. An acpA-null mutant was complemented by not only acpA but also the atxA gene. The cap region, which is essential for encapsulation, contains three genes capB, capC, and capA, arranged in that order. The atxA gene stimulated capsule synthesis from the cloned cap region. Transcriptional analysis of cap by RNA slot-blot hybridization and primer-extension analysis revealed that atxA activated expression of cap in trans at the transcriptional level. These results indicate that cross-talk occurs, in which the pXO1-located gene, atxA, activates transcription of the cap region genes located on pXO2. We identified two major apparent transcriptional start sites, designated P1 and P2, located at positions 731 bp and 625 bp, respectively, upstream of the translation-initiation codon of capB. Transcription initiated from P1 and P2 was activated by both atxA and acpA, and activation appeared to be stimulated by bicarbonate. Deletion analysis of the upstream region of the cap promoter revealed that activation by both atxA and acpA required a DNA segment of 70 bp extending upstream of the P1 site. These results suggest that cross-talk by atxA to the genes encoding capsule synthesis is caused by the interaction of the atxA gene product with a regulatory sequence upstream of cap.

Antigens, Bacterial↗

Capsule endoscopy for the evaluation of patients with chronic abdominal pain.

BACKGROUND AND STUDY AIMS: Chronic abdominal pain is a common complaint and in many patients even an extensive work-up does not reveal the cause for the pain. Given Imaging wireless capsule endoscopy is a new method for visualization of the entire small bowel. The aim of our study was to determine the role of capsule endoscopy in the evaluation of patients with unexplained chronic abdominal pain. PATIENTS AND METHODS: 20 patients with chronic abdominal pain of 6 - 96 months' duration were enrolled in the study. They had had an extensive diagnostic work-up which was negative. Capsule endoscopy was performed in all patients. RESULTS: Imaging of the small intestine was excellent and the colon was reached in 16 patients. In 14 patients the study was completely normal; in six patients the procedure revealed findings which were considered to be clinically insignificant. All patients tolerated the capsule well and had no adverse effects. CONCLUSION: Capsule endoscopy did not seem to have any significant clinical value in the evaluation of our patients with obscure chronic abdominal pain.

Abdominal Pain↗

Wireless capsule endoscopy for evaluation of phenotypic expression of small-bowel polyps in patients with Peutz-Jeghers syndrome and in symptomatic first-degree relatives.

BACKGROUND AND STUDY AIMS: Peutz-Jeghers syndrome (PJS) is an inherited gastrointestinal hamartomatous polyposis disorder. Small-bowel intussusception and bleeding are the most common complications, and malignancy may also occur. Survey of the gastrointestinal tract, particularly of the small bowel, is difficult and current recommendations for management syndrome are ambiguous. We evaluated the feasibility of capsule endoscopy for identifying phenotypic expression of small-bowel polyps in patients with full-blown PJS and a previous diagnosis of gastrointestinal polyposis, and in symptomatic kindred of PJS patients with no previous diagnosis of gastrointestinal polyposis. PATIENTS AND METHODS: Two groups were studied: group A consisted of 14 patients with gastrointestinal polyposis, eight of whom had undergone previous small-intestine surgery; group B consisted of six symptomatic first-degree relatives of PJS patients; these patients had previous negative gastrointestinal endoscopic examinations. RESULTS: Numerous polyps were detected in all patients in group A. Most polyps were sessile, but the larger polyps tended to be pedunculated. Polyp density was highest in the jejunum (greater than in the ileum and duodenum). Seven patients had at least one large polyp (> 11 mm) and five of these patients subsequently underwent enteroscopy, which revealed that capsule endoscopy had correctly identified all the patients with large polyps, but had missed 20 % of the total number of large polyps in these patients. No polyps were detected by capsule endoscopy in group B patients, despite the excellent visualization of the small intestine. In all patients, the capsules were expelled within 24 hours, without complications, and the procedure was well tolerated. CONCLUSIONS: Capsule endoscopy is an effective and well-tolerated method for evaluating small-bowel pathology in patients with PJS.

Adolescent↗

Video capsule endoscopy for investigation of obscure gastrointestinal bleeding: feasibility, results, and interobserver agreement.

BACKGROUND AND STUDY AIMS: The aim of the study was to assess the feasibility, diagnostic yield, and interobserver agreement of capsule endoscopy in the investigation of patients with obscure or occult gastrointestinal bleeding. PATIENTS AND METHODS: A total of 64 consecutive patients with occult bleeding (31 %) or overt bleeding (69 %) were assessed using capsule endoscopy after negative upper and lower endoscopy and small-bowel radiology. The quality of visualization of the small-bowel mucosa was scored from 1 (poor) to 4 (excellent). Thirty video capsule recordings with normal or abnormal findings were blindly assessed by four independent endoscopists. Interobserver agreement was evaluated using the kappa index. RESULTS: The small bowel was completely visualized in 57/64 patients (89 %). Incomplete small-bowel transit was most commonly due to prolonged gastric retention (five patients). The mucosa visualization scores (means) for the proximal, middle, and distal thirds of the small bowel were 3.7, 3.3, and 2.2 respectively. Visualization of the distal ileum was good (> or = 3) in 38 % and a bleeding site was found in 45 % of patients. Push-enteroscopy was also performed in 56 patients. The results of the two techniques were similar in 37 patients, capsule endoscopy was superior in 12 patients, and push-enteroscopy was superior in seven patients. Interobserver agreement was good for bleeding and for angiodysplasia, but poor for ulcers and tumors. Mean interobserver agreement was better among experienced endoscopists than among junior endoscopists. CONCLUSIONS: Capsule endoscopy allowed the whole small intestine to be explored in 89 % of patients, with good visualization of the mucosa, except distally. Interobserver agreement was better among the experienced endoscopists and was better for red-colored abnormalities (bleeding and angiodysplasia) than for ulcers and tumors.

Adult↗

Nonendoscopic transnasal placement of a wireless capsule for esophageal pH monitoring: feasibility, safety, and efficacy of a manometry-guided procedure.

BACKGROUND AND STUDY AIMS: The aim of the study was to evaluate the safety, feasibility, and efficacy of transnasal placement of the Medtronic Bravo capsule for wireless esophageal pH monitoring. PATIENTS AND METHODS: Forty patients with symptomatic gastroesophageal reflux disease were prospectively evaluated. All patients underwent upper gastrointestinal endoscopy and esophageal manometry. The Bravo capsule was then introduced transnasally and released 5 cm above the upper margin of the lower esophageal sphincter. Serial radiographs were performed weekly until capsule release. RESULTS: Of the 40 patients who were evaluated, 38 (95 %) were eligible to undergo the procedure. Transnasal placement proved impossible in one patient (2.5 %). Overall, a total of 39 procedures were performed in 38 patients (the procedure was repeated in one patient because of accidental intragastric fixation). Esophageal placement was successful in 36/39 procedures (92.3 %). The mean duration of the procedure was 10 minutes (range 5 - 16 minutes). Adverse events were noted in five of the 39 procedures (12.8 %), mild epistaxis in two patients (5.1 %) and pharyngeal irritation in three patients (7.7 %). After the procedure, a slight "foreign body" sensation was reported by 20 of the 36 patients (55.5 %) who had undergone successful esophageal placement; two patients (5.5 %) experienced severe retrosternal pain necessitating endoscopic removal of the capsule. At the end of the study, 34 of the 38 patients (89.5 %) stated that they would be willing to undergo the test again if necessary. CONCLUSIONS: Transnasal placement of the Bravo pH capsule is safe, well tolerated, does not require sedation, and avoids endoscopy and its complications.

Adult↗

[The sono-capsule: a new method for measuring gastrointestinal motility].

PURPOSE: We developed a noninvasive procedure using ultrasound and a specially designed capsule to permit determination of transit times in the gastrointestinal tract. METHODS: The ultrasound capsule consisted of a latex balloon of 1 cm diameter filled with water and containing a solid metal ball. After ingestion the marker was visualised in the gastrointestinal tract at defined intervals using conventional ultrasound machines. The various transit times were determined in 10 healthy volunteers. RESULTS: On account of its artifact-in-artifact structure (cystic configuration and reverberation), the ultrasound capsule was first detected in the stomach without any difficulty. During its further passage through the gastrointestinal tract the location of the capsule in the small and large bowel could be identified on the basis of the surrounding plicae circulares and haustrations. The mean oropyloric transit time was 2.4 hours; passage through the small bowel took 1.5 to 3 hours, and pyloro-anal transit times between 6 and 10 hours. CONCLUSION: the ultrasound capsule is a suitable method for investigating the gastrointestinal transport. It is non-invasive and does not expose the patient to radiation.

Adult↗

[Complications after rupture of the lens capsule with vitreous body prolapse during routine cataract operations].

PURPOSE: To evaluate the rate of complications and visual outcome after vitreous loss due to an unintended rupture of the posterior lens capsule during routine cataract surgery. PATIENTS AND METHODS: The study included 32 consecutive patients who underwent planned cataract surgery by extra-capsular extraction or phacoemulsification during which the posterior lens capsule ruptured and vitreous prolaps occurred. In all patients, the same surgeon was called to continue with the operation. After substantial transpapillary vitrectomy, a posterior chamber lens was implanted in all patients. The pseudophakos was transsclerally fixed in 12 patients. Mean follow-up time was 20.9 months (range, 1.5 to 71.6 months). RESULTS: The list of complications included cystoid macula edema in 2 patients (2/32 or 6.2%), persisting corneal endothelial decompensation in 1 patient (1/32 or 3.1%), and dislocation of the pseudophakos in one patient (1/32 or 3.1%). Rhegmatogenous retinal detachment did not occur. Compared with the preoperative status, visual acuity increased in 26 patients (26/32 or 81%). Visual acuity of equal or better than 20/30 was achieved in 15 eyes (15/32 or 47%). In 5 eyes (5/32 or 16%), visual acuity was equal to or better than 20/25. CONCLUSIONS: In eyes with a ruptured posterior lens capsule during routine cataract surgery eventually requiring vitrectomy, frequencies of complications are relatively low, if all vitreous adherent to the edges of the lens capsule rupture is removed by substantial transpapillary vitrectomy, and if in doubt of a sufficient lens capsule support for the posterior chamber lens, the pseudophakos is fixed by transscleral sutures.

Aged↗