Study on the Mechanism Responsible for the Incompatibility of Enalapril Maleate with Sodium Starch Glycolate

Enalapril maleate (EM) is known to suffer from incompatibilities in the solid state. This study investigates the destabilizing effect of sodium starch glycolate (SSG) on EM. This was done by varying the mixing ratio and moisture content of binary mixtures. Differential scanning calorimetry and microscopy show a loss of crystallinity of EM at the contact surface with SSG. It is shown that this is followed by decomposition of E to diketopiperazine (DKP). These phenomena are modulated by moisture. The environmental pH turned out to be crucial; when the zwitterion is formed at the appropriate pH, ring closure into DKP is promoted.     

Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie.

The scrapie-associated form of the prion protein (PrPSc) accumulates in the brain and lymphoid tissues of sheep with scrapie. In order to assess whether detecting PrPSc in lymphoid tissue could be used as a diagnostic test for scrapie, we studied the localization and distribution of PrPSc in various lymphoid tissues collected at necropsy from 55 sheep with clinical scrapie. Samples collected from the spleen, palatine tonsil, ileum, and five different lymph nodes were immunohistochemically stained for PrPSc. PrPSc was found to be deposited in a reticular pattern in the center of both primary and secondary lymphoid follicles. In addition, granules of PrPSc were seen in the cytoplasm in macrophages associated with the lymphoid follicles. In 54 (98%) of the 55 scrapie-affected sheep, PrPSc was detected in the spleen, retropharyngeal lymph node, mesenteric lymph node, and the palatine tonsil. However, only in the palatine tonsils was PrPSc present in a consistently high percentage of the lymphoid follicles. PrP was not detected in any of the lymphoid tissues of 12 sheep that had no neurohistopathological signs of a scrapie infection. We conclude that the tonsils are the best-suited lymphoid tissue to be biopsied for the detection of PrPSc in the diagnosis of clinical scrapie in living sheep.     

The Multidimensional Loss Scale: validating a cross-cultural instrument for measuring loss

The Multidimensional Loss Scale (MLS) represents the first instrument designed specifically to index Experience of Loss Events and Loss Distress across multiple domains (cultural, social, material, and intrapersonal) relevant to refugee settlement. Recently settled Burmese adult refugees (N = 70) completed a questionnaire battery, including MLS items. Analyses explored MLS internal consistency, convergent and divergent validity, and factor structure. Cronbach alphas indicated satisfactory internal consistency for Experience of Loss Events (0.85) and Loss Distress (0.92), reflecting a unitary construct of multidimensional loss. Loss Distress did not correlate with depression or anxiety symptoms and correlated moderately with interpersonal grief and trauma symptoms, supporting divergent and convergent validity. Factor analysis provided preliminary support for a five-factor model: Loss of Symbolic Self, Loss of Interdependence, Loss of Home, Interpersonal Loss, and Loss of Intrapersonal Integrity. Received well by participants, the new scale shows promise for application in future research and practice.     

In vivo induction of aryl hydrocarbon hydroxylase in human scalp hair follicles by topical application of a commercial coal tar preparation

Five low-dose applications of a commercial coal tar preparation on a small scalp skin region resulted in an induction of aryl hydrocarbon hydroxylase (AHH) activity in freshly isolated human hair follicles. Large but reproducible interindividual differences in AHH-inducibility could be detected. The method offers the opportunity to measure AHH-inducibility, which has been correlated to the risk of developing chemical-induced cancer, in vivo in normal epithelium, a cell-type highly relevant for chemical carcinogenesis. Smoking habits did not have any effect on AHH-activity in freshly isolated hair follicles. Therefore the method potentially permits the identification of persons with high and low genetically determined AHH-inducibility.     

Rectal absorption of metronidazol from polyethylene glycol suppositories

The rectal absorption of metronidazol from an aqueous suspension, a fatty suppository and three different polyethylene glycol suppositories was studied in healthy volunteers and compared with absorption from an oral solution. Rectal absorption was found to be rather slow for all suppositories. Of all rectal dosage forms, the polyethylene glycol suppositories gave the highest peak plasma levels and the highest relative bioavailability. Compared with oral administration, a relative bioavailability of 80% could be obtained.     

Qualitative proof of liquid dispersion and penetration-involved granule formation in a high shear mixer.

The origination of granules in the early seconds is an important aspect of high shear granulation. To elucidate these mechanisms, a substandard amount (1.5% w/w) of an aqueous hydroxypropyl cellulose solution was added to four different lactose mixtures: (1) lactose 100 M (d(4,3) approximately 170 microm), (2) lactose 200 M (d(4,3) approximately 50 microm), and (3, 4) 10% magnesium stearate/lactose 100 or 200 M. Between 1 and 15 s after binder addition samples were taken, which were immediately frozen in liquid nitrogen. The frozen sample was sieved into granular (> 280 microm) and non-granular-material (< 280 microm). The binder distribution in these fractions was determined. The observed binder distribution behaviour revealed that three different nucleation mechanisms can occur: (I) For lactose 100 M holds that all the binder is initially located in the granules. These granules are subsequently broken again. (II) The lactose 200 M granules also contain 100% of the added binder liquid. Contrary to lactose 100 M the lactose 200 M granules remain intact during the process. It is argued that in both cases liquid penetration is responsible for the accumulation of all liquid in the granules. A theoretical evaluation also confirmed that liquid penetration leads to the formation of the primary granules (III) No liquid penetration is possible in the hydrophobic magnesium stearate/lactose mixtures and the binder is completely dispersed in the non-granular material.     

Immunohistochemical distinction between preclinical bovine spongiform encephalopathy and scrapie infection in sheep

Sheep are susceptible experimentally to bovine spongiform encephalopathy (BSE), the clinical signs being indistinguishable from those of scrapie. Because of the possibility of natural ovine BSE infection, laboratory tests are needed to distinguish between scrapie and BSE infection. The objectives of this study were to determine whether (1) PrPSc accumulates in biopsy samples of the tonsil or third eyelid, or both, of BSE-infected sheep before the appearance of clinical disease, and (2) such samples from BSE- and scrapie-infected sheep differ in respect of PrPSc accumulations. Homozygous ARQ sheep (n = 10) were dosed orally at 4-5 months of age with a brain homogenate from BSE-infected cattle. Third eyelid and tonsillar biopsy samples were taken at < or = 6 monthly intervals post-infection and examined immunohistochemically for PrPSc. Third eyelid protuberances were difficult to identify, resulting in many unsuitable samples; however, third eyelid samples shown to contain lymphoid follicles were invariably negative for PrPSc. In contrast, tonsillar biopsy samples became positive for PrPSc from 11 to 20 months post-infection. Consistent differences in the morphology of PrPSc granules in tingible body macrophages (TBMs) between BSE- and scrapie-infected sheep were detected with anti-peptide antibodies directed towards amino acids 93-106 of the ovine prion protein: thus, PrPSc appeared as single granules in TBMs of tonsillar sections from BSE-infected sheep, whereas clusters of PrPSc granules were observed within TBMs in the tonsils of scrapie-infected sheep. In contrast, antibodies against epitopes situated N- and C-terminally from the 93-106 region of the ovine prion protein revealed no differences between BSE- and scrapie-infected sheep in terms of PrPSc granules in TBMs.     

The effect of crystal imperfections on particle fracture behaviour

Micronisation of active pharmaceutical ingredients is a process which is sometimes difficult to control. The main purpose of this study was to assess the effect of the pre-existing flaws in the material to be milled. The rate of breakage of four samples of a model compound (sodium chloride), originating from different sources, was determined in a jet mill. It appeared that each type of sodium chloride has a distinct particle rate of breakage and breakage pattern. The numbers of flaws in the different types of sodium chloride have been determined by immersing the sodium chloride particles in a liquid with the same refractive index. This makes the cracks better visible. Microphotographs were made and flaws were counted manually. The study shows that the flaw density has an impact on the fracture behaviour of particles. The degree of fracture tends to increase with increasing flaw density. The paper shows however that the mechanical properties of the material as well as the starting particle size dominate the significance of the impact of flaws on fracture behaviour.     

Biowaivers for oral immediate-release products: implications of linear pharmacokinetics

Bioequivalence of drug formulations plays an important role in drug development. Recently, the Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using the rationale of the BCS, it can be argued that biowaivers can, however, also be granted on the basis of standard pharmacokinetic data. If a drug exhibits dose-linear pharmacokinetics and a sufficiently fast dissolution profile, it can be concluded that this drug appears to pose no problem with respect to absorption. It should be noted that a change of an immediate-release tablet formulation can only lead to a deviating rate and/or extent of absorption when release of the drug from the formulation is altered. Logically, the dissolution profiles of the different formulations should be equal to guarantee bioequivalency. Thus, both BCS and the alternative linear pharmacokinetics approach require an evaluation of dissolution profiles. The justification of BCS is found in the permeability classification of the compound, while those of the linear pharmacokinetics lie in the apparent lack of a permeability problem. For example, in this context P-glycoprotein-transported drugs form an interesting class of compounds, which may be treated likewise when complying to the aforementioned requirements. Furthermore, poorly soluble compounds may be less troublesome than expected. It is shown that linear kinetics can be explained by the solubilising activity of, for example, bile salts. In this instance, linear pharmacokinetics shows that elevated doses do not appear to exhibit a limiting role on the dissolution. Hence, a change in formulation without any effect on the dissolution profile is not expected to cause a change in availability. It is clear that the formulations to be compared should not contain excipients that display an effect on (presystemic) drug metabolism.