Enteric-coating of pulsatile-release HPC capsules prepared by injection molding.

Capsular devices based on hydroxypropyl cellulose (Klucel® LF) intended for pulsatile release were prepared by injection molding (IM). In the present work, the possibility of exploiting such capsules for the development of colonic delivery systems based on a time-dependent approach was evaluated. For this purpose, it was necessary to demonstrate the ability of molded cores to undergo a coating process and that coated systems yield the desired performance (gastric resistance). Although no information was available on the coating of IM substrates, some issues relevant to that of commercially-available capsules are known. Thus, preliminary studies were conducted on molded disks for screening purposes prior to the spray-coating of HPC capsular cores with Eudragit® L 30 D 55. The ability of the polymeric suspension to wet the substrate, spread, start penetrating and initiate hydration/swelling, as well as to provide a gastroresistant barrier was demonstrated. The coating of prototype HPC capsules was carried out successfully, leading to coated systems with good technological properties and able to withstand the acidic medium with no need for sealing at the cap/body joint. Such systems maintained the original pulsatile release performance after dissolution of the enteric film in pH 6.8 fluid. Therefore, they appeared potentially suitable for the development of a colon delivery platform based on a time-dependent approach.

Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease.

RATIONALE: Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects. OBJECTIVES: We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy. METHODS: An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased. CONCLUSIONS: Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.

On understanding the role of need thwarting in the association between athlete attachment and well/ill-being.

Grounded in attachment theory and basic psychological needs theory, the current study aimed to examine the mediating role of basic psychological need thwarting between perceptions of athlete attachment to the coach and indexes of athlete well/ill-being. A sample of athletes (N = 241) participating in various organized sports completed a multisection questionnaire assessing the main study variables. Bootstrap mediation analysis revealed that the perceived psychological needs of thwarted autonomy and competence within the coach relational context mediated the associations between athletes' perceptions of insecure attachments to the coach and experiences of life satisfaction and negative affect. Analysis also revealed that the perceived psychological needs of thwarted competence and relatedness within the sport context mediated the associations between athletes' attachment style and experiences of performance satisfaction, life satisfaction, depression, and negative affect. Overall, the findings of the study highlight that the examination of negative aspects of sport participation may facilitate a more complete understanding of athletes' psychological functioning.

"What do coaches do" and "how do they relate": their effects on athletes' psychological needs and functioning.

Grounded in self-determination theory, this study aimed to examine the links of the social environment, as defined by coach interpersonal behaviors and coach-athlete relationships, with athletes' psychological need satisfaction and indexes of well-being. Athletes (N = 300) completed a multi-section questionnaire assessing the study variables. Bootstrap mediation analysis highlighted significant indirect effects whereby the competence need mediated associations between the social environment of coaching and athletes' vitality, negative affect, and physical self-concept (defined as skillfulness and performance). Findings support theoretical assumptions and highlight that athletes' perceptions of what coaches do, and how they relate, are important to their psychological needs satisfaction and optimal functioning.

Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines.

Systemic inflammation impacts on the brain and gives rise to behavioral changes, often referred to as 'sickness behavior'. These symptoms are thought to be mainly mediated by pro-inflammatory cytokines. We have investigated the communication pathways between the immune system and brain following sub-pyrogenic inflammation. Low grade systemic inflammation was induced in mice using lipopolysaccharide (LPS); 1-100 microg/kg to mimic aspects of bacterial infection. Changes in fever, open-field activity, burrowing and consumption of glucose solution were assessed and immune activation was studied in the periphery and brain by measuring cytokine production, and immunohistochemistry to study changes in immune cell phenotype. Sub-pyrogenic inflammation resulted in changes in a species-typical, untrained behavior (burrowing) that depends on the integrity of the hippocampus. Increased expression of cytokines was observed in the periphery and selected regions of the brain which coincided with changes in behavior. However, peripheral neutralization of LPS-induced pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha did not abrogate the LPS-induced behavioral changes nor affect CNS cytokine synthesis. In contrast, pretreatment of mice with indomethacin completely prevented LPS-induced behavior changes, without affecting cytokine levels. Taken together, these experiments suggest a key role for prostaglandins, rather than cytokines, in communicating to the brain.

Brain cytokine synthesis induced by an intraparenchymal injection of LPS is reduced in MCP-1-deficient mice prior to leucocyte recruitment.

We have previously shown that ischaemic lesions are smaller in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice than in wild-type (wt) controls. In addition to its role as a monocyte chemoattractant, monocyte chemoattractant protein-1 (MCP-1) has been proposed to contribute to lesion progression after focal ischaemia by driving local cytokine synthesis by resident glia. To investigate this hypothesis we injected lipopolysaccharide (LPS) into the brain parenchyma of MCP-1(-/-) mice and compared the resulting inflammatory response and production of proinflammatory cytokines to those in wt mice. Microglial and astrocyte morphological activation was the same in the two strains, but MCP-1(-/-) mice showed significantly lower levels of proinflammatory cytokine synthesis; interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) levels were up to 50% lower than in wt controls after 6 h. This reduced synthesis of proinflammatory cytokines occurred well before leucocyte recruitment to the central nervous system (CNS) is observed in this model of acute inflammation and thus cannot be attributed to lower numbers of recruited monocytes at the site of injury. We propose that MCP-1 contributes to acute CNS inflammation by pleiotropic mechanisms. In addition to being a potent chemoattractant for monocytes, we provide evidence here that MCP-1 can modify the responsiveness of CNS glia to acute inflammatory stimuli prior to leucocyte recruitment, thereby acting as a priming stimulus for cytokine synthesis in cells such as microglia.

A nondestructive technique to determine the rate of oxygen permeation into solid dosage forms.

The current study investigated the use of electron paramagnetic resonance (EPR) spectroscopy as a nondestructive method to quantify the partial pressure of oxygen (PO2) in tablets and hard shell capsules. Lithium phthalocyanine crystals (LiPC) were placed inside the dosage forms. The peak-to-peak linewidth of the first derivative of the LiPC EPR spectra was measured and, by calibration tables, the oxygen partial pressure, pO2, within the dosage form was determined. The intra-dosage form pO2 was followed as a function of time after changing the exterior gas stream composition. Results showed initial oxygen concentrations comparable to atmospheric levels in all tablets and capsules investigated. Oxygen rapidly permeated into unsealed gelatin and cellulosic hard shell capsules. Banding at the cap/body joint significantly reduced the oxygen permeation rate. Oxygen also rapidly permeated into tablet compacts, regardless of the compressional force used during tableting, while application of a polymeric film significantly decreased the rate of oxygen permeation. This EPR technique was shown to be a suitable nondestructive method to study oxygen permeation kinetics in solid dosage forms.

MCP-1 and murine prion disease: separation of early behavioural dysfunction from overt clinical disease.

Prion diseases are chronic, fatal neurodegenerative conditions of the CNS. We have investigated the role of monocyte chemoattractant protein-1 (MCP-1) in the ME7 model of murine prion disease. MCP-1 expression increased in the CNS throughout disease progression and was positively correlated with microglial activation. We subsequently compared the inflammatory response, pathology and behavioural changes in wild-type (wt) mice and MCP-1 knockout mice (MCP-1-/-) inoculated with ME7. Late-stage clinical signs were delayed by 4 weeks in MCP-1-/- mice, and survival time increased by 2-3 weeks. By contrast, early changes in affective behaviours and locomotor activity were not delayed in onset. There was also no difference in microglial activation or neuronal death in the hippocampus and thalamus of wt mice and MCP-1-/- mice. These results highlight an important dissociation between prolonged survival, early behavioural dysfunction and hippocampal/thalamic pathology when considering therapeutic intervention for human prion diseases and other chronic neurodegenerative conditions.

Influence of curing on the adhesive and thermomechanical properties of an applied acrylic polymer.

The objective of the current study was to investigate the relationship between polymer adhesion and post-coating thermal treatment. A novel adhesion technique was used to quantify the adhesive properties of applied acrylic films. Differential scanning calorimetry was used to determine the glass transition temperature of the applied polymer. Post-coating thermal treatment, or curing, was found to significantly influence the adhesive and thermomechanical properties of the applied film coating. Adhesion of triethyl citrate-plasticized films to tablets increased during storage at elevated temperatures, equilibrating within four hours. The glass transition temperature of the applied triethyl citrate-plasticized coatings also increased during curing. Equilibration of polymer properties was found to be dependent on the hydrophobicity of the plasticizer incorporated into the coating formulation, with longer curing times required for films containing the hydrophobic plasticizer tributyl citrate. The curing temperature was shown to influence polymer properties, with stronger film-tablet adhesion and higher glass transition temperatures resulting when the coated tablets were stored at higher temperatures. Substrate hydrophobicity was also found to influence the curing process, suggesting that the mechanisms involved in film formation and polymer-substrate adhesion may contribute to the internal stresses within the film.

Influence of surfactants in aqueous-based polymeric dispersions on the thermomechanical and adhesive properties of acrylic films.

Good adhesion between a polymeric film and the surface of a solid substrate is critical to the performance of coated pharmaceutical products. Previous research has shown that tablet wettability by an organic-based cellulosic solution could predict the extent of film-tablet adhesion. Using an aqueous-based acrylic polymeric dispersion, the current study investigated the relationship between film adhesion and tablet wettability. Up to 10% (w/w based on dry polymer weight) polysorbate 80 or sorbitan monooleate was incorporated into the film-coating formulations. While the contact angle between the polymeric dispersion and the tablet surface was dependent on the type and concentration of surfactants added to the coating formulation, no correlation between tablet wettability and polymer adhesion could be established. The addition of surfactants to formulations containing the hydrophobic plasticizer tributyl citrate (TBC) caused lowering of the glass transition temperature of the polymer. Increased force of adhesion, elongation at adhesive failure, and adhesive toughness, however, were noted only in the TBC-plasticized films containing polysorbate 80. These findings demonstrate that our understanding of the mechanisms involved in film-tablet adhesion is still quite limited.

Adhesion of polymeric films to pharmaceutical solids.

The two major forces influencing polymer adhesion include the strength of the interfacial bonds between the polymeric film and the surface of the solid and the internal stresses within the film coating. While good adhesion between the polymer and the substrate is desirable for pharmaceutical products, the small size of the dosage form and the non-uniform surface roughness have created difficulties in assessing polymer adhesion. In this review, the experimental devices and procedures used to quantitate polymer adhesion are addressed. The affects of the physical and chemical properties of the substrate, including surface roughness and tablet hydrophobicity, on adhesion of a polymer to either tablets or capsules are discussed. The influence of the plasticizers, pigments, and solvents in film coating formulations on polymer adhesion, and the effects of aging of the coated solids on adhesion of polymers to tablets and capsules are also discussed.

Influence of pigment concentration and particle size on adhesion of an acrylic resin copolymer to tablet compacts.

The effects of the particle size and the concentration of pigments in aqueous polymeric dispersions on the adhesive properties of an acrylic resin copolymer were investigated. Aqueous polymeric dispersions containing up to 20% (v/v) pigment were coated onto hydrophilic and hydrophobic tablet compacts, and polymer adhesion was assessed using a novel butt adhesion technique. An inverse relationship was found between the particle size of the pigment present in the aqueous polymeric dispersion and film-tablet adhesion. As the particle size of the pigment increased, the adhesive strength of the polymer to the tablet compact decreased. Increased concentrations of the opacifying agent titanium dioxide in the acrylic dispersion resulted in stronger film-tablet adhesion. No clear relationship could be established between the wettability of the tablet compact by the pigmented polymeric dispersion and the strength of film-tablet adhesion. The hydrophobicity of the tablet compact was found to affect the glass transition temperature of the polymeric film to a greater extent than the particle size, morphology, or concentration of the pigment incorporated into the acrylic dispersion.

Influence of tablet hardness and hydrophobicity on the adhesive properties of an acrylic resin copolymer.

The adhesive properties--including the force of adhesion, elongation at adhesive failure, the modulus of adhesion, and the adhesive toughness--of an acrylic resin copolymer were determined using the butt adhesion technique. Flat-faced tablets containing up to 30% hydrogenated castor oil were coated with an aqueous dispersion of Eudragit L30D-55. Using data obtained from a Chatillon digital force gauge attached to a motorized test stand, force-deflection profiles, similar to stress-strain curves generated in the tensile testing of free films, were constructed. The surface characteristics of the tablets significantly influenced polymer-substrate interaction. The force of adhesion, the elongation at adhesive failure, and the adhesive toughness decreased as the surface of the tablet became more hydrophobic through the addition of wax to the tablet formulation. Lower adhesive properties were found with increasing tablet hardness, due to a decrease in the effective area of contact between the film coating and the tablet surface. Increased polymer loading resulted in stronger adhesion, indicating a relationship between the mechanical and adhesive properties of the polymer. The present study demonstrated that the area under the force-deflection profile in conjunction with the force of adhesion was more representative of the adhesive properties of the polymer.

Infection in inguinal hernia repair considering biomaterials and antibiotics.

Synthetic biomaterials have been incriminated for promoting wound infection. Perioperative antibiotics have received praise for reducing the rate of infection after certain operations. These claims were tested in a cooperative multicenter prospective study of 2,493 inguinal hernia repairs. This study was done to examine the effect of prophylactic antibiotics in primary and recurrent inguinal hernia repaired with synthetic biomaterials. Clinical signs and symptoms of wound infection and the results of each infected repair are reported. The rate of infection was about 1 percent, whether or not biomaterials or antibiotics were used. More than 70 percent of wound infections occurred in patients 60 years of age or older. Removal of biomaterials from the infected wounds was not necessary and generally is not recommended. Recurrence has not occurred in any of the infected repairs. With or without prosthetic repair, the treatment of infected inguinal hernia wounds was relatively simple, of reasonable cost and concluded with a good result. The expense incurred for routine prophylactic antibiotic treatment in inguinal hernia operation could not be reconciled by any benefits obtained.

Intracavitary irradiation of renal pyelocalyceal transitional cell carcinoma with iridium-192.

A case of multicentric urothelial transitional cell carcinoma is presented, in which the patient underwent a left ureteronephrectomy and in the remaining right kidney recurrent transitional cell carcinoma was found in the inferior calyx. Because this area was accessible via a cutaneous nephrostomy, it is treated with a combination of external beam radiation and intracavitary implantation with iridium-192. The iridium was placed in the vicinity of the tumor using an angiographic procedure. The technique successfully preserved remaining renal parenchyma. The case illustrates how angiography skills and procedures can be applied in a novel brachytherapy application.