2D and 3D MRI features of classic bladder exstrophy.

The bladder exstrophy-epispadias complex (EEC) represents a spectrum of rare and surgically correctable congenital anomalies. Classic bladder exstrophy (CBE) stands between epispadias and cloacal exstrophy (CE) in the severity spectrum, and is the most commonly encountered type. CBE involves congenital defects of the bladder, abdominal wall, pelvic floor, and bony pelvis. With the growing understanding of the detrimental effects of radiation in children, magnetic resonance imaging (MRI) is progressively been utilized in the preoperative work-up and post-surgical follow-up of these patients. MRI provides valuable information for planning and evaluating the optimal surgical techniques for closure of CBE. The aim of this paper is to provide a review of the two- (2D) and three-dimensional (3D) MRI features of CBE including a detailed analytical description of the anatomy of the pelvic floor in affected patients.

Efficacy of topical benzydamine hydrochloride gel on oral mucosal ulcers: an in vivo animal study.

The aim of this study was to investigate the effect of benzydamine hydrochloride bioadhesive gel on healing of oral mucosal ulceration in an animal model. For in vivo determination of the effects of the bioadhesive gel, 36 rabbits were separated into three groups: the first group was treated with the gel formulation without active agent, the second group with the gel formulation containing benzydamine, and the third group received no treatment. Clinical healing was established by measuring the area of the ulcer in each test group on days 3, 6, 9 and 12. Histological healing was determined on the same days. Benzydamine containing gel applications resulted in a decrease in the ulcer area in 12 days (p=0.000). Histological evaluation showed that the benzydamine group had a higher mean histological score than the base and the control groups during the whole test period, and the difference between the benzydamine group and the control group was significant (p=0.04). The bioadhesive gel formulation of benzydamine hydrochloride showed a statistically significant increased rate of mucosal repair in this experimental standard mucosal wound animal study. It is a candidate for the topical treatment of oral mucosal ulcerative lesions.

Cerebellar abnormality in children and young adults with tuberous sclerosis complex: MR and diffusion weighted imaging findings.

OBJECTIVES: The goal of our study was to: determine the incidence of cerebellar lesions in a cohort of children and young adults with TSC, and analyze the magnetic resonance imaging (MRI) findings of cerebellar TSC lesions including their contrast behavior and diffusion characteristics. MATERIAL AND METHODS: MRI studies of 27 TSC patients (mean age, 10.6 years) were evaluated for: cortical/subcortical tubers, white matter lesions, subependymal nodules, and giant cell astrocytomas. Patients with cerebellar involvement were further analyzed for the imaging and diffusion characteristics. ADC measurements of the cerebellar tubers were performed and compared with the contralateral normal appearing cerebellum. The clinical charts were revisited for symptoms suggesting cerebellar involvement. RESULTS: Cerebellar tubers were seen in 8/27 patients, cerebellar atrophy in 1/27 patients. Cerebellar tubers showed a pyramidal/wedge appearance with a broad base reaching the cortex. The majority of the cerebellar tubers (11/12, 92%) showed a "zebra-like" contrast enhancement. All cerebellar tubers had increased ADC values (mean ADC 1472×10(-6) mm(2)/s). None of the patients had "typical" cerebellar symptoms. CONCLUSION: Thirty-three percent of TSC patients had cerebellar lesions, most of them being cerebellar tubers. Cerebellar tubers differ from supratentorial tubers both concerning shape and contrast behavior. The exact etiology of contrast enhancement remains unclear. Future studies have to determine the impact of cerebellar lesions on neurocognitive development.

MRI with diffusion-weighted imaging in children and young adults with simultaneous supra- and infratentorial manifestations of Sturge-Weber syndrome.

BACKGROUND AND PURPOSE: Patients with Sturge-Weber syndrome (SWS) may present with neurological symptoms or neurocognitive deficits that cannot always be explained by the supratentorial findings seen on conventional MRI. Purpose of our study was to determine (a) what percentage of children with SWS have simultaneous supra- and infratentorial involvement and (b) what kind of infratentorial lesions are seen. In addition, we used DWI data to measure the ADC-values of normal appearing white matter (NAWM) to rule out impaired or delayed white matter maturation. MATERIAL AND METHODS: Fifteen SWS patients who underwent MRI/DWI between January 2000 and August 2008 were studied. Images were retrospectively reviewed by two experienced pediatric neuroradiologists. ADC measurements of the NAWM were performed at multiple locations within the brain. ADC-values were compared with normative data and with 18 matched normal controls from our hospital. RESULTS: Infratentorial involvement was seen in six out of 15 patients (40%). Cerebellar lesions included leptomeningeal enhancement, atrophy and developmental venous anomaly. ADC-values were increased in the NAWM of the frontal, parietal and occipital lobes of both hemispheres and in the pons. The ADC-values of the cerebellar white matter were increased in six out of eight affected cerebellar lobes. CONCLUSION: Infratentorial involvement of SWS is more frequently than previously thought. ADC analysis of the NAWM reveals impaired/altered white matter maturation distant from the area of leptomeningeal angiomatosis. This may explain neurocognitive deficits. ADC analysis of the NAWM may serve as biomarker of tissue injury and therefore guide treatment options.

The preparation and evaluation of sustained release suppositories containing ketoprofen and Eudragit RL 100 by using factorial design.

The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 3(2) x 2(1) factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250-500, 500-710, and 710-1000 microm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t50 and t80 was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.

Dissolution and vaginal absorption characteristics of metronidazole and ornidazole.

The aim of this study was to investigate and compare the dissolution and vaginal absorption characteristics of metronidazole (MTZ) and ornidazole (ONZ) vaginal suppositories. The formulations were prepared by a simple fusion method using Witepsol H15. The solubility, partitioning and dissolution characteristics of these drugs were investigated in phosphate (pH 7) and lactate buffer (pH 4.5) solutions. MTZ and ONZ were labeled with Technethium-99m (99mTc) and their suppositories were applied to carry out the vaginal absorption and biodistribution studies in rabbits. Scintigraphic images were collected using Sophy DST and DSX gamma cameras. The dissolution of ONZ from the vaginal suppository was slower than that of MTZ at phosphate buffer and similar in lactate buffer. 49% of the administered ONZ dose remained in the rabbit's vagina after 2 h, while this value was calculated as 38% for MTZ. Total activity calculated in uterus and urinary bladder was found as 16% and 22% for MTZ and ONZ, respectively. The biodistribution studies showed that the radioactivity of MTZ in urine and blood was higher than ONZ. The radioactivity of ONZ detected in all organs, especially in uterus, kidneys and urinary bladder, was greater than MTZ. This study determined that the two labeled 5-nitroimidazole derivatives had a high absorbability performance in vagina. MTZ to a large extent transferred to blood and ONZ gathered in lipoid tissues, due to their partition characteristics.

Azathioprine-induced shock in a patient suffering from undifferentiated erosive oligoarthritis.

Shock due to a hypersensitivity response to azathioprine is unpredictable, occurs seldom and bears a potentially fatal outcome. Azathioprine is widely used in the treatment of autoimmune diseases and in solid organ transplantation. Here, we present a patient who suffered from undifferentiated erosive oligoarthritis and was treated with azathioprine. This patient developed anaphylactic shock which was interpreted as a side effect of azathioprine. Although rare, similar cases were described since 1980.

Improving of the accuracy of in vitro-in vivo linear correlation using kinetic models for ultra sustained release theophylline tablets.

The objective of the current study was to establish and evaluate a new technique to increase the accuracy of the in vitro/in vivo linear correlation of single and multiple dose ultra-sustained release theophylline (USRT) preparation (Xantium) in hospitalized patients. In vitro dissolution data for theophylline were collected for 24 h using a USP I (basket) and USP II (paddle) methods. In vivo plasma concentration data were obtained from 8 patients after administration of either single or multiple doses of theophylline. Both in vitro and in vivo results were evaluated by zero-order, first-order, RRSBW, Hixson-Crowell, Higuchi, Hopfenberg, Langenbucher, modified Langenbucher and (Bt)a kinetic models. The individual linear correlations between each in vitro and in vivo percent results and their kinetic distributions were established and regression equations were obtained. The determination coefficient results of the linear kinetic correlations were found to be 0.994 and 0.997 for single and multiple doses by basket method and 0.992 and 0.998 for single and multiple doses by paddle method, respectively. Furthermore, the results of the linear correlations were found as 0.953 and 0.950 for single and multiple doses by basket method and 0.963 and 0.962 for single and multiple doses by paddle method respectively. Therefore, this study suggested that the accuracy of the linear correlation could be improved signilicantly by using linear kinetic correlation.

Sustained release bioadhesive effervescent ketoconazole microcapsules tabletted for vaginal delivery.

Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxymethylcellulose as a coating material. The microcapsules were mixed with effervescent granules and were tabletted. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out with a new basket method (horizontal rotating basket). A good sustained action was obtained with tablets. Micromeritic investigations were carried out on microcapsules in order to standardize the microcapsule product and to optimize the pilot production of the dosage forms prepared with these microcapsules. Bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, relative deviation, particle size distribution, density and porosity values of the microcapsules were determined. In addition, to evaluate whether some kind of glidant will be needed during tabletting of microcapsules, the Hausner ratio o and consolidaton index were also calculated and it may be concluded that microcapsules do not need any glidant.

A new in vitro/in vivo kinetic correlation method for nitrofurantoin matrix tablet formulations.

The kinetic distributions of in vitro percentage release and in vivo percentage urinary excretion rates of nitrofurantoin from matrix tablets were plotted using a kinetic program. In vitro release rates were determined using the USP paddle and half-change methods. Urinary excretion curves of the drug were characterized by means of the statistical moments. The individual linear correlations between each in vitro and in vivo kinetic distribution were established, and regression equations were calculated. The application results of the best correlations obtained were evaluated according to in vivo results. A reversed kinetic procedure was applied for transformation of the correlated kinetic values to the drug percentage release rates. The modified Langenbucher kinetic showed excellent linear correlation (r = .9985). The method that is proposed in this study, the kinetic correlation program, is simple, independent of time, and suggests that it is possible to use kinetic distributions in the in vitro/in vivo correlation. This study also suggests using kinetic correlation to investigate the suitability of the in vitro dissolution methods with the in vivo drug dissolution.

Modeling of theophylline release from different geometrical erodible tablets.

The aim of this study is to reveal statistically how various geometrical shapes such as triangle, cylinder, half-sphere affect the release rate of the active substance called theophylline in erodible hydrogel matrix tablets. We have tried to indicate these changes in the release rate of theophylline by supporting our aim with the mathematical equations developed by Hopfenberg and Katzhendler et al. The model developed by Hopfenberg assumes that drug release occurs from the primary surface area of the device but Katzhendler et al. (I. Katzhendler, A. Hoffman, A. Goldberger, M. Friedman, Modelling of drug release from erodible tablets, J. Pharm. Sci. 86 (1997) 110-115), described a situation where the erosion rates of the tablet are different in the radial and axial directions. Hydrogel matrix tablets were prepared with hydroxypropylmethylcellulose (HPMC E(50)) possessing different geometrical shapes as triangular, cylindrical and half-spherical using experimental design. When the dissolution results have been evaluated, it has been observed theophylline release from different geometrical erodible tablets fitted with that of the Katzhendler et al., equation. This equation which was suggested for cylindrical tablets was also used to interpret half-spherical and triangular tablets. According to the above stated equation, n has been determined as 4 for triangular tablets and 1.5 for half-spherical tablets and we have also suggested that, these n values could be used in the kinetic programs.

The effect of the type and the concentration of the lipophilic surfactant on the stability and release kinetics of the W/O/W multiple emulsions.

Stable multiple emulsions that contain different lipophilic surfactants in the internal aqueous phase have been formulated. The multiple systems were assessed by evaluating several parameters such as macroscopic aspect, droplet size, percent release and accelerated stability under centrifugation or elevated temperature. The effect of polymeric and monomeric surfactants on the release mechanism and stability was examined. An excess of monomeric surfactant in the oil phase enhances the release rate and decreases stability. The release rate can be decreased by an increase of the lipophilic surfactant concentration. It appears that the more the oil globule swells, the less hydrosoluble drug is released. As a result a high swelling capacity is associated with better stability.

Sustained-release microcapsules of nitrofurantoin and amoxicillin; preparation, in-vitro release rate, kinetic and micromeritic studies.

In this work, nitrofurantoin and amoxicillin trihydrate microcapsules were prepared by complex coacervation at pH 3.5 using carboxymethylcellulose-gelatin at a weight ratio of 3:7. Release rates were studied as a function of core:wall ratios of microcapsules. Dissolution tests of microcapsules and their tabletted microcapsules were studied in artificial gastric and intestinal media without enzyme using the USP XXII basket method. Release rates were examined kinetically and the ideal kinetic models were estimated for drug release. In addition, the micromeritics of these microcapsules were investigated. In order to standardize the drug powder and the microcapsule product for industrial application, the micromeritic properties of microcapsules were studied by determining their bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, particle size distribution, density and porosity. Hausner ratio and consolidation index were also calculated to understand flowability rates of microcapsules when tableting or filling into gelatin capsules. The results indicated that the nitrofurantoin microcapsules need appropriate glidant but the amoxicillin trihydrate microcapsules did not. Moreover, it was observed that the microencapsulation changed the micromeritic properties of the drugs significantly.

Release characteristics of implantable cylindrical polyethylene matrices.

The geometrical relationship between a hemisphere and a cylinder has been investigated for controlled-release systems. The relationship was tested by comparing dissolution results with results from mathematical calculation based on the principles of diffusion for matrix systems. A procedure has been developed for producing implantable, cylindrical, low-density polyethylene matrices, uncoated or coated with a thin impermeable film and a thick paraffin layer except for a hole on the flat faces of the cylinder. Drug matrices were prepared from a blend of sodium salicylate and polymer compressed in an appropriately designed stainless-steel mould at 150 degrees C. Differential scanning calorimetry revealed that no decomposition product was formed in the matrix. When the surface area and the number of holes is increased, drug release also increases. When density is increased, however, drug release decreases significantly. Zero-order drug release was obtained from high-density covered one-hole and two-hole matrices. The diffusion coefficient was calculated as 0.067 day-1. The study suggested that true zero-order drug release could be obtained by drug diffusion from a hole, rather than from geometric shapes in the matrix systems. In addition, for constant release the diffusion area has to increase by approximately 25 mm2 every day, compared to the area of the previous day, because the diffusion distance increases logarithmically.

In vivo/in vitro correlations of nitrofurantoin matrix tablet formulations.

In our recent study, a new sustained release dosage form of nitrofurantoin (nft) as matrix tablets by 2(2) factorial design has been prepared by using different drug:polymer ratios. The effect of the polyvinylpyrolidone contents of nft matrix tablets on dissolution rate and bioavailability of the drug have been evaluated. The ideal formulation which fitted at USP XXII dissolution norms was tested by in vivo experiments. The satisfactory correlation was also obtained between the in vivo and the in vitro results. This study suggested that the amounts of nft excreted in urine can be calculated by using in vitro dissolution results and sampling time.

3(3) factorial design-based optimization of the formulation of nitrofurantoin microcapsules.

A microcapsule form of nitrofurantoin was prepared by a simple coacervation method with carboxymethylcellulose and aluminium sulfate. 3(3) factorial design was performed for three independent variables, namely, the particle size of the drug, the size of the microcapsules and the pH of the dissolution medium. The dissolution tests with the formulated microcapsules were carried out according to the United States Pharmacopeia XXII rotating basket method at pH 1.2, 5, and 7.5, which represent the pH of gastrointestinal fluids. Release data were examined kinetically and the ideal kinetic models were estimated and t(63.2) values obtained from RRSBW distribution were used in the factorial design experiment. The influence of the independent variables on the dissolution of nitrofurantoin microcapsules could be expressed as the pH of the dissolution medium > particle size of the microcapsule > particle size of nitrofurantoin. The other aim of this study was to evaluate microcapsule formulation in terms of the United States Pharmacopeia criteria with a minimum of experiments. Our findings suggest that dosage forms which comply with the pharmacopoeia criteria for dissolution can be prepared and selected by factorial design.

The release of isoconazole nitrate from different suppository bases: in-vitro dissolution, physicochemical and microbiological studies.

The influence of the suppository base on the in-vitro release of isoconazole nitrate was studied by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. Vaginal suppository formulations containing 25 mg isoconazole nitrate for local treatment of vaginitis were prepared by a fusion method, using different hydrophilic and lypophilic suppository bases (PEG 6000, PEG 4000, PEG 1500, Witepsol H15, Novata BD and Cremao). In-vitro release rates were examined by dissolution, physicochemical diffusion and microbiological disk-diffusion methods. In the physicochemical investigations the pH indicators (pH 1-14) erythrosin B, thymol blue, bromocresol green, chlorophenol red, phenol red, and alkali blue were added to agar gels. The discs were placed onto the agar gels and 21 h later, the coloured zone diameters were measured. In the microbiological investigations, the discs were put on the inoculated plates with the suspension of Candida albicans (Institute Pasteur 628). The inoculated plates were incubated at 37 degrees C for 3 days, then the diameters of inhibition zones were measured. In the dissolution investigations release rates were in the order PEG 6000 > PEG 4000 > PEG 1500 > > Witepsol H15 > Cremao > Novata BD. The diffusion distance of isoconazole nitrate in the physicochemical investigation was in the order polyethylene glycols > Witepsol H15 > Novata BD. In the microbiological studies release rates were found with polyethylene glycols > Witepsol H15 > Novata BD > Cremao. The findings in the in-vitro studies suggested that polyethylene glycols are suitable bases for vaginal suppositories.

The release of isoconazole nitrate from different suppository bases: in-vivo release of drug labelled with 99mTc in rabbits.

The influence of the suppository bases on the in-vivo release of 99mTc-labelled isoconazole nitrate was investigated. The single-dose vaginal suppository formulations for local treatment of vaginitis were prepared by a fusion method using polyethylene glycols, Witepsol H15, Novata BD and Cremao. Prepared vaginal suppositories containing solid-labelled substance were applied to the vagina of rabbits and at 0, 2 and 24 h after administration, the amounts of radioactivity in the vagina were detected by the SPECT Gamma Camera and the release rates of the drug were calculated. The percent released was found to be in the following order; polyethylene glycol (PEG) 6000 > PEG 4000 > Witepsol > PEG 1500 > Novata BD > Cremao. The results obtained in both in-vitro and in-vivo studies indicated that the vaginal suppository of isoconazole nitrate prepared with polyethylene glycols could confidently be used in therapy.

Sustained-release dosage form of nitrofurantoin. Part 1. Preparation of microcapsules and in vitro release kinetics.

A new sustained-release dosage form of nitrofurantoin as microcapsules was prepared by carboxymethylcellulose-aluminium sulphate simple coacervation technique. In vitro release studies for microcapsules and their formulated hard gelatin capsule and tablet forms were performed. Release rates were studied as functions of core: wall ratios and the particle sizes of the microcapsules. Dissolution tests of microcapsules and their dosage forms were studied in simulated gastric and intestinal media without enzyme using the USP XXI basket method. Release data were examined kinetically and the ideal kinetic models were estimated for drug release. In addition, optical and electron scanning microscopic works were carried out on the microcapsules.