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Respiratory infections represent a major global health problem. They are often treated by parenteral administrations of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation efficiencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to commercialisation, advanced formulation strategies are in high demand for combating respiratory 'super bugs'.

Background Regorafenib is a multi-targeted tyrosine kinase inhibitor approved for use in refractory colorectal cancer. We report the first case of seizures secondary to acute liver failure, shortly after initiation of regorafenib in a patient with advanced rectal carcinoma. Case presentation A 64 year-old Caucasian female presented with confusion and generalized tonic–clonic seizures, 5 days after initiation of regorafenib for advanced rectal cancer. Investigations revealed significant elevations in bilirubin and alanine aminotransferase. No other cause for seizures and liver dysfunction were found. After interruption of regorafenib, no further seizures occurred, the symptoms of confusion resolved and liver function returned to normal. Conclusions We report the first case of regorafenib-induced acute liver failure resulting in seizures. We suggest early monitoring for side effects, both clinically and biochemically after initiation of regorafenib.

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation.

SummaryHead and neck cancer (HNC) is a disease of the upper aerodigestive tract and is one of the most frequently diagnosed cancers worldwide. A high rate of cancers involving the head and neck are reported across the Asian region, with notable variations between countries. Disease prognosis is largely dependent on tumor stage and site. Patients with early stage disease have a 60–95% chance of cure with local therapy. Early diagnosis and appropriate treatment are important to increase the likelihood of cure and survival. However, the majority of patients present with locally advanced disease and require multimodality treatment. This necessitates, a multidisciplinary approach which is essential to make appropriate treatment decisions, particularly with regards to tolerability, costs, available infrastructure and quality of life issues. Unfortunately, majority of the studies that dictate current practice have been developed in the west where diseases biology, patient population and available infrastructure are very different from those in the Asian continent. With this in mind an expert panel of Head and Neck Oncologists was convened in May 2012 to review the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) clinical practice guidelines and develop practical recommendations on the applicability of these guidelines on the management of head and neck cancer for Asian patients. The objective of this review and consensus meeting was to suggest revisions, to account for potential differences in demographics and resources, to the NCCN and ESMO guidelines, to better reflect current clinical management of head and neck cancer within the Asian region for health care providers. These recommendations, which reflect best clinical practice within Asia, are expected to benefit practitioners when making decisions regarding optimal treatment strategies for their patients.

This study applied computational fluid dynamics (CFD) analysis to investigate the role of device design on the aerosolization of a carrier-based dry powder inhaler (DPI). The inhaler device was modified by reducing the inlet size, decreasing the mouthpiece length and increasing the mesh grid voidage. The flow patterns in the inhaler device were examined. It was observed that there was no significant influence on the aerosol performance with the reduced mouthpiece. When the inlet size was reduced to one third of the original one, the fine particle fraction (FPF), defined as mount of inhalable fine particles below 5μm in the aerosol, was improved significantly from 17.7% to 24.3%. The CFD analysis indicated that the increase in FPF was due to increasing air velocity for the smaller inlet. No significant difference was shown in FPF when the grid voidage was increased, but more drugs deposited in the mouthpiece and throat.

The objective of this study is to investigate the effect of device design of the Aerolizer(®) on the aerosolization of a carrier-based dry powder inhaler formulation (Foradile(®)). The Aerolizer was modified by reducing the air inlet size and mouthpiece length to 1/3 of the original dimensions, or by increasing the grid voidage. Aerosolization of the powder formulation was assessed on a multi-stage liquid impinger at air flow rates of 30, 60, and 100 L/min. Coupled CFD-DEM simulations were performed to investigate the air flow pattern and particle impaction. There was no significant difference in the aerosolization behavior between the original and 1/3 mouthpiece length devices. Significant increases in FPF total and FPF emitted were demonstrated when the inlet size was reduced, and the results were explained by the increases in air velocity and turbulence from the CFD analysis. No significant differences were shown in FPF total and FPF emitted when the grid voidage was increased, but more drugs were found to deposit in induction port and to a lesser extent, the mouthpiece. This was supported by the CFD-DEM analysis which showed the particle-device collisions mainly occurred in the inhaler chamber, and the cross-grid design increased the particle-device collisions on both mouthpiece and induction port. The air inlet size and grid structure of the Aerolizer(®) were found to impact significantly on the aerosolization of the carrier-based powder.

This chapter is dedicated to Mamadou Konté (1945–2007), a laborer-turned-businessman who became one of the most important and influential people in the African music industry. Konté is an illiterate African laborer in France who, in the 1970s, began organizing aid concerts to improve the living conditions of immigrant workers. He is the founder of Africa Fête, a Senegal-based organization dedicated to the promotion of African music and musicians. Established in 1978, Africa Fête has managed numerous African artists, organized international tours and festivals, given exposure to new talent, and provided training in sound engineering, production, and management. As a cultural activist, Konté used music as a medium for furthering economic development and social awareness among Africans both at home and in the diaspora. Throughout his life, Konté used music to raise funds and awareness for important causes, including the HIV/AIDS epidemic.

The growing use of the inhalation route for the delivery of new types of drugs, such as proteins for both local and systemic effects, and the need to manufacture and deliver fine particles to the targeted parts of the respiratory tract have led to more interest in the characterization of not only the size of the aerosol particles, but also their morphology and how they are dispersed by inhaler devices. These devices are most commonly dry powder inhalers. A fractal object, as defined by Mandelbrot, has a dimension greater than the geometric or physical dimension but less than or equal to the embedding dimension in an enclosed space. Characterization of particle surface is important because surface roughness is recognized to affect physicochemical properties of pharmaceutical products and is therefore a crucial factor in the manufacturing process and product performance.

Mannitol particles, produced by spray drying (SD), have been used commercially (Aridol) in bronchial provocation test. In this study, we propose an alternative method to produce inhalable mannitol powders. The elongated mannitol particles (number median length 4.0microm, and axial ratio of 3.5) were prepared using a confined liquid impinging jets (CLIJs) followed by jet milling (JM). Spray dried and jet milled raw mannitol particles were compared in an attempt to assess the performance of the particles produced by the new method. Aerosol performance of the three different powders (CLIJ, SD, and JM) was relatively poor (fine particle fraction or FPF(loaded) below 15%) when dispersed by the Rotahaler. Dispersion through the Aeroliser led to better aerosol performance of the CLIJ mannitol (FPF(loaded) 20.3%), which is worse than the JM (FPF(loaded) 30.3%) and SD mannitol particles (FPF(loaded) 45.7%) at 60 L/min, but comparable (FPF(loaded) 40.0%) with those of the JM (FPF(loaded) 40.7%) and SD (FPF(loaded) 45.5%) powders at 100L/min. Hence, the optimum use of these elongated mannitol particles can be achieved at increased air flow with a more efficient inhaler. In addition to crystallinity, morphology, and particle size distribution, the surface energies of these powders were measured to explain the differences in aerosol performance. A major advantage of using the CLIJ method is that it can be scaled up with a good yield as the precipitate can be largely collected and recovered on a filter, compared with spray drying which has a low collection efficiency for fine particles below 2microm.

The current study aimed to quantify the different degree of particle surface corrugation and correlate it to the aerosol performance of powders.Powders of different degree of surface corrugation were prepared by spray drying under varying conditions. The solid-state properties of the powders including particle size, morphology, crystal form, true density, and moisture content were characterized. The degree of surface corrugation was quantified by the surface fractal dimension (Ds) obtained by light scattering. The aerosol performance was studied by dispersing the powders using the Rotahaler at 60 L/min into a multi-stage liquid impinger. Fine particle fraction (FPF) was expressed as the wt% of BSA particles of sizeor =5 microm in the aerosol.Four powders of increasing degree of particle surface corrugation were prepared, with Ds ranging from 2.06 for the least corrugated to 2.41 for the most corrugated. The powders had a similar size distribution (VMD 3 microm, span 1.4-1.5) and solid-state properties. Increasing the surface corrugation, Ds, slightly from 2.06 to 2.18 enhanced the FPF significantly from 27% to 41%. This was explained by the reduced area of contacts and increased separation distance between the particles. Further increase of corrugation (Dsor = 2.18) did not improve FPF.Powders with varying degrees of corrugation were successfully obtained by spray drying with their surface roughness quantified by fractal analysis. It was shown that only a relatively small degree of surface corrugation was sufficient to accomplish a considerable improvement in the aerosol performance of the powder.

A model to predict fractal dimension from sedimentating fractal aggregates has been successfully developed. This model was developed using the settling rate and size data of fractal aggregates. In order to test the validity of the model, a purpose-built settling rig, equipped with lens with magnification of 1200x, which can capture images of particles/flocs down to 2 microm in diameter was used. The performance and technique of the settling rig were validated by comparing the measured settling rates of 30- and 50.7-microm standard particles with their theoretical settling rates calculated using Stokes' law. The measured settling rates were within 10% agreement with the calculated Stokes' velocities. The settling rates and sizes of the particles/flocs were analyzed using image analysis software called WiT 5.3. The maximum temperature gradient across the settling column was 0.1 degrees C, which effectively eliminated convective currents due to temperature differences in the settling column. A total of 1000 calcium phosphate flocs were analyzed. Calcium phosphate flocs with fractal dimensions varying from 2.3 to 2.8 were generated via orthokinetic aggregation. Measurements of fractal dimensions, using light scattering, were done simultaneously with the settling experiments and they were found to be constant. The fractal dimensions calculated using the model agreed with those obtained by light scattering to within 12%.