Strategies for Accelerated Drug Development: An Industry Perspective Based on an IQ Consortium Survey of CMC Considerations.

Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium - Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market.

A New Proposed Combined CT and MRI Staging System for Covid-19-Associated Rhino-Orbito-Cerebral Fungal Infection: A Multi-center Study with Pathological Correlation.

RATIONALE AND OBJECTIVES: To propose a combined computed tomography (CT) and magnetic resonance imaging (MRI) based classification system in the management of COVID-19-associated rhino-orbito-cerebral (C-ROC) fungal infection and to assess the reliability of such proposed staging system. MATERIALS AND METHODS: This was a multi-center prospective study conducted on 122 adults with previously confirmed COVID-19 infection. CT and contrast-enhanced MRI (CE-MRI) were performed for all patients. Three radiologists (with experience of 8, 10, and 14 years) independently assessed all images. Then, each patient was assigned a radiological stage based on the five stages of the proposed system according to the radiological extent of the fungal infection. The intra-class correlation coefficient (ICC) test assessed the inter-rater agreement. Based on the pathological evaluation of post-operative specimens, a diagnosis of fungal infection was documented. RESULTS: The most prevalent severity stage among all raters was stage IV in 29.5-31.1% patients. The overall inter-rater agreement of the proposed staging system was excellent (ICC 0.971, 95% CI;0.960-0.979). Moreover, the most common detected pathogen was Mucormycosis (n = 87, 71.3%). Furthermore, there was a statistically significant association between the patients' outcome and the severity stage (P value 0.001) and there was no statistically significant association between ethmoid and sphenoid sinus affection and cranial extension (P value 0.081). CONCLUSION: Our proposed combined CT and MRI severity staging system has a high inter-rater agreement. Moreover, it can aid in the early detection of the C-ROC fungal infection, improve preoperative planning, and subsequently improve the patient's outcome.

Interplay of LncRNA TUG1 and TGF-ß/P53 Expression in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore the therapeutic targets of CRC. Long non-coding RNA taurine upregulated gene 1 (LncRNA TUG1) was initially discovered as a transcript upregulated by taurine and is observed to be expressed in numerous human cancers. The Study Aim: This article was to explore the correlation between transforming growth factor-beta (TGF-ß)/tumor protein 53 (P53) signaling mechanisms as regulators for LncRNA TUG1 in Egyptian patients with CRC. SUBJECTS AND METHODS: Immunohistochemical (IHC) staining was achieved to study TGF-ß and P53 expression in CRC specimens vs. normal colonic specimens and quantitative real-time PCR (qRT-PCR) was used to analyze LncRNA TUG1, TGF-ß, and P53 relative gene expression in 96 tissue specimens (neoplastic specimens and the corresponding adjacent non-neoplastic specimens). RESULTS: The expressions of LncRNA TUG1, TGF-ß, and P53 were overexpressed significantly in CRC specimens as opposed to the matched neighboring non-neoplastic specimens (P<0.001), also LncRNA TUG1 was significantly positively correlated to the expression of TGF-ß and P53 (r=0.89, 0.91 respectively, P<0.001). CONCLUSION: These findings reveal that LncRNA TUG1 may be a molecular component in the TGF-ß/P53 signaling pathway, and LncRNA TUG1 could function as a CRC possible oncogene. LncRNA TUG1 may serve as a potential oncogene for CRC. The TGF-ß/P53/LncRNA TUG1 interactions may be employed as potential targets for CRC diagnosis, prognostic evaluation, and cure.

Effects of Lactobacilli acidophilus and/or spiramycin as an adjunct in toxoplasmosis infection challenged with diabetes.

The current study assessed the anti-parasitic impact of probiotics on Toxoplasma gondii infection either solely or challenged with diabetes in Swiss albino mice. The study design encompassed group-A (diabetic), group-B (non-diabetic), and healthy controls (C). Each group was divided into infected-untreated (subgroup-1); infected and spiramycin-treated (subgroup-2); infected and probiotic-treated (subgroup-3); infected and spiramycin+ probiotic-treated (subgroup-4). Diabetic-untreated animals exhibited acute toxoplasmosis and higher cerebral parasite load. Overall, various treatments reduced intestinal pathology, improved body weight, and decreased mortalities; nevertheless, probiotic + spiramycin exhibited significant differences. On day 7 post-infection both PD-1 and IL-17A demonstrated higher scores in the intestine of diabetic-untreated mice compared with non-diabetics and healthy control; whereas, claudin-1 revealed worsening expression. Likewise, on day 104 post-infection cerebral PD-1 and IL-17A showed increased expressions in diabetic animals. Overall, treatment modalities revealed lower scores of PD-1 and IL-17A in non-diabetic subgroups compared with diabetics. Intestinal and cerebral expressions of IL-17A and PD-1 demonstrated positive correlations with cerebral parasite load. In conclusion, toxoplasmosis when challenged with diabetes showed massive pathological features and higher parasite load in the cerebral tissues. Probiotics are a promising adjunct to spiramycin by ameliorating IL-17A and PD-1 in the intestinal and cerebral tissues, improving the intestinal expression of claudin-1, and efficiently reducing the cerebral parasite load.

Human protozoa infection and dysplasia in ulcerative colitis: a neglected aspect in a prominent disease.

The chance of getting colorectal cancer (CRC) is higher in people with chronic ulcerative colitis (UC). The impact of parasitic infections on UC is underappreciated. The purpose of this study was to look into the effect of intestinal protozoal infections on the dysplastic changes generated by UC. The research included 152 adult patients with histologically confirmed UC and 152 healthy controls. Fecal samples were examined for the presence of parasites and fecal calprotectin (FC). The enzyme-linked immunosorbent assay measured serum anti-p53 antibodies (p53Abs) and metallothioneins (MTs). The advanced oxidation protein products (AOPPs) and reduced glutathione (GSH) levels were measured by a spectrophotometric method in all subjects. Serum C-reactive protein (CRP) and IL-6 were also measured. In addition, histopathological and immunohistochemical investigations of intestinal tissue were done. Our results exhibited significant increases in FC and CRP, IL-6, AOPPs, MTs, and p53Abs in ulcerative colitis patients with parasitic infections compared to those without parasites. In contrast, GSH levels showed a significant decrease in the same group compared with other groups. Histopathological and immunohistochemical assessments of intestinal tissue signified severe inflammation and strong expression of PD-L1 in patients with parasitic infections compared to others without parasitic infections. Our research indicated a greater frequency of intestinal protozoa in UC patients with elevated inflammatory and dysplastic biomarker levels. This suggests that these parasites may be involved in the etiology of chronic UC and the associated carcinogenetic process. This is the first report of a link between parasitic infections and dysplastic alterations in UC patients.

Breast Milk Mesenchymal Stem Cells and/or Derived Exosomes Mitigated Adenine-Induced Nephropathy via Modulating Renal Autophagy and Fibrotic Signaling Pathways and Their Epigenetic Regulations.

Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in CKD. Eighty adult male Sprague Dawley rats were randomly assigned to one of six groups, including control, nephropathy, nephropathy + conditioned media (CM), nephropathy + Br-MSCs, nephropathy + Br-MSCs derived exosomes (Br-MSCs-EXOs), and nephropathy + Br-MSCs + Br-MSCs-EXOs. Before administration, Br-MSCs and Br-MSCs-EXOs were isolated, identified, and labeled with PKH-26. SOX2, Nanog, and OCT3/4 expression levels in Br-MSCs and miR-29b, miR-181, and Let-7b in both Br-MSCs and Br-MSCs-EXOs were assayed. Twelve weeks after transplantation, renal function tests, oxidative stress, expression of the long non-coding RNA SNHG-7, autophagy, fibrosis, and expression of profibrotic miR-34a and antifibrotic miR-29b, miR-181, and Let-7b were measured in renal tissues. Immunohistochemical analysis for renal Beclin-1, LC3-II, and P62, Masson trichome staining, and histopathological examination of kidney tissues were also performed. The results showed that Br-MSCs expressed SOX2, Nanog, and OCT3/4, while both Br-MSCs and Br-MSCs-EXOs expressed antifibrotic miR-181, miR-29b, and Let-7b, with higher expression levels in exosomes than in Br-MSCs. Interestingly, the administration of Br-MSCs + EXOs, EXOs, and Br-MSCs improved renal function tests, reduced renal oxidative stress, upregulated the renal expression of SNHG-7, AMPK, ULK-1, Beclin-1, LC3, miR-29b, miR-181, Let-7b, and Smad-7, downregulated the renal expression of miR-34a, AKT, mTOR, P62, TGF-ß, Smad-3, and Coli-1, and ameliorated renal pathology. Thus, Br-MSCs and/or their derived exosomes appear to reduce adenine-induced renal damage by secreting antifibrotic microRNAs and potentiate renal autophagy by modulating SNHG-7 expression.

Toxoplasma gondii Suppresses Th2-Induced by Trichinella spiralis Infection and Downregulates Serine Protease Genes Expression: A Critical Role in Vaccine Development.

Background: Toxoplasma gondii coinfection can modify host immune responses and the severity and spread of other parasites. We investigated how T. gondii and Trichinella spiralis infections counter-regulate each other's immune responses. Methods: The parasite burden, the expression of T. gondii rhoptry kinase ROP18 and T. spiralis putative serine protease (TsSP), the IgG1 and IgG2a responses, besides histopathological and immunohistochemical staining with iNOS and arginase were used to evaluate the dynamics of coinfection. Results: Through their effects on host immune responsiveness, coinfection with T. gondii modified the virulence of T. spiralis infection. Coinfected animals with high and low doses of T. gondii demonstrated significant reductions in the T. spiralis burden of 75.2% and 68.2%, respectively. TsSP expression was downregulated in both groups by 96.2% and 86.7%, whereasROP18 expression was downregulated by only 6% and10.6%, respectively. In coinfected mice, elevated levels of T. gondii-specific IgG2a antibodies were detected. Th1 induced by T. gondii inhibits the Th2 response to T. spiralis in coinfected animals with high iNOS expression andlow-arginine1 expression. Conclusion: T. gondii infection induces a shift toward a Th1-type immune response while suppressing a helminth-specific Th2 immune response, paving the way for developing novel vaccines and more efficient control strategies.

COGNITIVE FUNCTIONS IN CHILDREN WITH TYPE I DIABETES.

OBJECTIVE: The aim: To assess the patterns and severity of cognitive impairment in children with type 1 diabetes as well as its association with disease onset and poor glycemic control. PATIENTS AND METHODS: Materials and methods: We assessed higher mental function and screened for psychosocial functioning in 60 children with type 1 DM and 60 age-matched control using the Modified Mini-Mental State examination and Pediatric Symptoms Checklist and its relation with age, gender, socioeconomic status, age at the onset of disease, duration of disease, HbA1c level, frequency of diabetic ketoacidosis and hypoglycemic attacks and type of treatment. RESULTS: Results: Diabetic patients demonstrated a lower Modified Mini-Mental State examination score than controls (25.12±4.58 versus 30.08±2.95) with a highly significant difference. Furthermore, the mean Pediatric symptoms checklist score in patients was 39.08±8.18 which was much lower than that of controls 54.42±6.0 with a highly significant difference. CONCLUSION: Conclusions: There is neurocognitive impairment in diabetic children compared to non-diabetics, and poor glycemic control whether hyper or hypoglycemia could affect their cognition and mental health.

Nutritional status of children and adolescents with Type 1 Diabetes Mellitus in Baghdad: a case-control study.

Diabetes mellitus (DM) is a major life-long non-communicable illness correlated with obesity and chronic undernutrition. It is particularly important to monitor the nutritional status of children with type 1 diabetes mellitus (T1DM), as they are still growing and may be affected by the disease or associated conditions like celiac disease. This study aimed to evaluate the nutritional status of children and adolescents with T1DM in Baghdad city and identify possible risk factors for undernutrition. A single-center, case-control study was conducted in Central Child's Teaching Hospital, Baghdad, Iraq, over 9 months from November 2021 to July 2022. The study included patients with T1DM and healthy controls. Detailed history, clinical examination, and anthropometric measures were performed for all participants in the study. The mean age of the sample was 10.0 ±3.73 years and 8.68±3.1 years in diabetic patients and controls, respectively. Anthropometric measures in patients with type 1 diabetes were significantly lower than those of controls (P<0.001). All patients within the undernourished group were from large-size families compared with 75.76% of the normally nourished group, with a significant difference. The mean age of disease onset in the normal nourished group was 6.61 ± 2.78 years which was significantly earlier than that of the undernourished group (8.83 ± 2.89). Weight-for-age and BMI z-score had a significant negative correlation with HbA1c (r=-0.312, p=0.004, and r=-0.295, p=0.006, respectively). Patients with T1DM had significantly lower anthropometric measures than the normal population. Older children, female gender, large family size, and disease duration are independent predictors of undernutrition in T1DM. BMI and weight-for-age have a significant negative correlation with metabolic control of diabetes represented by HbA1c.

Clinical and laboratory characteristics of children with neurological presentations of COVID-19: a single-center experience.

The study aimed to assess the frequency of neurological presentations of pediatric COVID-19 patients and compare the clinical and laboratory characteristics and the outcomes of those who presented with neurological complaints and those without complaints. A cross-sectional study enrolled 84 children diagnosed with COVID-19 at the emergency department over 12 months. All previously healthy children with a laboratory-confirmed diagnosis of COVID-19 were included in the study. The diagnosis of COVID-19 was made by positive PCR of a nasopharyngeal swab. Patients were divided into 2 groups: group 1 included COVID-19 patients with neurological complaints, and group 2 included COVID-19 patients with non-neurological complaints. Demographical, clinical, and laboratory characteristics were compared among groups. During the study period, 84 children aged 2 months-15years were diagnosed with COVID-19. Only 17 patients (20.2%) presented with new-onset neurological complaints. Seizure was the most common neurological complaint (58.8%), and febrile convulsion was the most frequent diagnosis of COVID-19 patients with neurological presentation (47.1%). C-reactive protein (CRP) and duration of hospitalization were higher in patients with neurological presentations, with P values of 0.002 and 0.001, respectively. All patients with neurological complaints survived the acute illness. Neurological symptoms were present in 20% of the COVID-19 pediatric patients, having higher CRP than patients with non-neurological presentations. CRP can be used as a reliable indicator for neurological symptoms in COVID-19 pediatric patients.

Associations of galectin-3 expression and LGALS-3 (rs4652) gene variant with coronary artery disease risk in diabetics.

BACKGROUND: Galectin-3 protein encoded by lectin galactoside-binding soluble-3 (LGALS-3) gene is an important genetic factor in type 2 diabetes mellitus (T2DM) and its cardiovascular obstacles in various populations. We aimed to elicit the pro-inflammatory effect of galectin-3 as determined by interleukin-6 (IL-6) serum levels and to explore the relationship between galectin-3 (LGALS-3 rs4652) gene variant and its expression levels with coronary artery disease (CAD) risk among T2DM Egyptian patients. METHODS: 112 lean subjects were compared to 100 T2DM without CAD and 84 T2DM with CAD. A tetra-primer amplification refractory mutation system polymerase chain reaction was used to test LGALS-3 (rs4652), and galectin3 expression was tested with a quantitative real-time polymerase chain reaction. Serum IL-6 was measured using an enzyme-linked immunosorbent assay. RESULTS: We found that the prevalence of LGALS-3 (rs4652) AC genotype and galectin-3 gene expression levels in T2DM with CAD were significantly higher than the additional 2 groups and were correlated positively to IL-6 circulating levels. Also, the C allele carriers (AC+CC) had significantly higher relative Galectin-3 expression levels compared to the A allele carriers (AA). CONCLUSIONS: We concluded that galectin-3 expression levels and LGALS-3 (rs4652) AC genotype were coronary artery disease risk factors in people with type two diabetes among an Egyptian sample.

PCSK9 E670G (rs505151) Variant and Coronary Artery Disease Risk Among Diabetics.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme in the family of proprotein convertases implicated in lipid metabolism and is a significant genetic risk factor in cardiovascular diseases among various populations. Aim of the Study: This study explored the correlation between the alleles of the rs505151 (E670G) locus of the PCSK9 gene and its expression levels with coronary artery disease (CAD) risk in Egyptian patients with type 2 diabetes mellitus (T2DM). Subjects and Methods: A case-control study was performed on 112 lean subjects compared to 100 T2DM patients without CAD and 84 T2DM patients with CAD to investigate the relationships among PCSK9 expression levels, the E670G (rs505151) gene variant, lipid concentrations, and CAD risk in an Egyptian diabetic population. A restriction fragment length polymorphism-polymerase chain reaction (PCR) assay was used to assess the gene polymorphism, and PCSK9 mRNA expression was determined by quantitative real-time PCR. Results: The prevalence of the E670G (rs505151) AG genotype in diabetics with CAD was significantly greater than the other two groups. The PCSK9 gene expression levels in diabetics with CAD were significantly greater than the other two groups. G allele carriers (AG+GG) had a higher relative PCSK9 expression than A allele carriers. Conclusion: PCSK9 relative expression levels and the E670G (rs505151) AG genotype are CAD risk factors among Egyptian diabetics and are linked positively to the atherogenic index of plasma.

Eco-friendly polyurethane acrylate (PUA)/natural filler-based composite as an antifouling product for marine coating.

In the current study, the polyurethane acrylate (PUA) polymer was synthesized by the addition reaction between an isophorone diisocyanate (IPDI) and 2-hydroxyethyl acrylate and cured by polyol. Different properties of the synthesized PUA were determined through diverse analysis methods. The polyurethane acrylate (PUA)/natural filler-based composite (rhizome water extract of Costus speciosus) was prepared as an antifouling agent. The results revealed that the lowest weight loss percentages were detected at 2 wt% PUA/natural filler composite loadings with Escherichia coli (ATCC 23,282) and Pseudomonas aeruginosa (ATCC 10,145). The decreased weight loss percentage may be attributed to the well dispersed natural composite resulting in a slippery surface that can prevent fouling adhesion. It was concluded that the PUA/natural filler composite might be considered an eco-friendly and economical solution to the biofouling problem. KEY POINTS: • A novel strategy for anti-biofouling. • A new composite reduced Gram-negative bacteria.

Risk factors in children with febrile seizures and their iron status.

OBJECTIVE: To determine the risk factors for patients with febrile convulsions and to assess their iron status. METHODS: The case-control study was conducted at the Central Child Teaching Hospital, Baghdad, Iraq, from May 1 to August 31, 2017, and comprised febrile patients aged 6-72 months admitted after presenting with axillary temperature ≥38oC. Those who got fits along with fever were declared the cases, while those with just fever were considered the controls. Venous blood samples were taken for complete blood count, biochemical tests, and for serum ferritin, serum iron and total iron binding capacity. Data was analysed using SPSS 23. RESULTS: Of the 80 patients, 40(50%) were in each of the two groups. Respiratory tract infection was the commonest cause of fever in 29(58%) cases and 21(42%) controls (p>0.05). The cases were significantly younger in age (p<0.05). Also, there was significantly low haemoglobin level, low packed cell volume, low serum iron, higher total iron binding capacity and low serum ferritin in the case group (p<0.05). Iron deficiency anaemia was found in 17(73.9%) of the cases compared to 6(26.1%) among the controls. The mean serum ferritin of the cases was lower compared to the controls (p=0.001). CONCLUSIONS: The risk of febrile seizure in iron-deficient children increased in the presence of risk factors.

Stabilization of a hyaluronate-associated gene delivery system using calcium ions.

A "DPH" ternary complex consisting of plasmid DNA (pDNA), intracellularly degradable polyethyleneimine, and hyaluronic acid (HA) is a promising non-viral gene carrier with low toxicity and good gene transfection efficiency. HA plays a key role in providing an optimal balance between DNA protection and release, but it causes aggregation due to the entanglement of HA chains of neighbouring DPH particles. Here we report that the addition of an optimal level of Ca2+ successfully prevents particle aggregation and maintains a relatively small size. The Ca-stabilized DPH is comparable to DPH in cytotoxicity and gene transfection efficiency. MW monitoring and conductometric titration suggest that such size stabilization effect is partly mediated by the complexation between HA and Ca2+, which enables intra- and intermolecular interactions of HAs.

Peripheral refraction in myopia corrected with spectacles versus contact lenses.

PURPOSE: Previous studies suggest that the refractive status of the peripheral retina can influence the development and progression of myopia. Our aim was to compare peripheral refractions in the same cohort of human eyes corrected with spectacle lenses vs soft contact lenses. METHODS: Ten young adults with moderate to high myopia (-5.00 D to -8.00 D) were investigated. Open-field autorefraction was used to measure on- and off-axis refractions with the eyes in primary gaze, when uncorrected, and when corrected with spectacles and contact lenses. Measures were made every 5° out to 30° horizontally in nasal and temporal retina and analysed as power vectors (M, J(0) , and J(45)). Partial coherence interferometry measures of eye size were also made on-axis and off-axis at 10º and 20º in nasal and temporal retina. RESULTS: Subjects (mean age 24; range 19-29 years) had an average on-axis mean-sphere refraction of -6.33 ± 0.31 D (mean ± 1 S.E.) and an average axial eye length of 25.99 ± 0.20 mm. The average relative peripheral refraction (RPR) for all subjects across all eccentricities was hyperopic when uncorrected (+0.90 ± 0.14 D) and also when corrected with spectacles (+1.01 ± 0.13 D) but changed to a myopic RPR when corrected with contact lenses (-1.84 ± 0.61 D). There was a highly significant effect of correction on peripheral refraction (p < 0.0001). Peripheral J(0) astigmatism also became significantly more negative (less with-the-rule) on correction with contact lenses (p = 0.015), whereas J(45) astigmatism remained unchanged. On- and off- axis eye length measures indicated a relatively prolate eye shape. CONCLUSIONS: Correcting the on-axis refractive error in moderate to high myopia with conventional spherical spectacle lenses results in hyperopic defocus in the peripheral retina. Correcting the same eyes with conventional spherical soft contact lenses results in significant myopic defocus in the peripheral retina. These results corroborate the general findings of earlier studies and the predictions of optical modelling by others. If the refractive status of the peripheral retina does influence myopia progression, then these results suggest that myopia progression should be slower with conventional contact lens wear than with conventional spectacle wear. However, previous studies comparing myopia progression with conventional spectacles and conventional contact lenses have reported no such difference.

A strategy to deliver genes to cystic fibrosis lungs: a battle with environment.

Cystic fibrosis (CF) sputum, a tenacious biopolymer network accumulating in the airways, critically interferes with the effectiveness of pulmonary gene delivery. To overcome this challenge, nanoparticulate ternary gene-polymer complexes were encapsulated in inhalable dry microparticles containing mannitol. When applied on a layer of artificial sputum, which comprised major components of CF sputum such as DNA and mucin, mannitol microparticles rapidly dissolved in it and enhanced transport of nanoparticles across the sputum layer. Despite the improvement of nanoparticle transport in the artificial sputum, the gene-polymer complex passing the sputum did not show gene transfection because of the significant inactivation by DNA and, to a lesser extent, mucin. Particle size measurement suggested that aggregation of the gene transfer agents was mainly responsible for the activity loss. These results indicate that the delivery of gene transfer agent across CF sputum depended not only on the ability to penetrate the sputum but also on preservation of the activity during and/or after the transport.

Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease.

INTRODUCTION: Cystic fibrosis (CF) is a multisystem genetic disorder, which usually results in significant respiratory dysfunction. At present there is no cure for CF, but advances in pharmacotherapy have gradually increased the life expectancy of CF patients. As many drugs used in the therapy of CF are delivered by inhalation, the demand for effective and convenient inhalational CF drug formulations will grow as CF patients live longer. Knowledge of the current limitations in inhalational CF drug delivery is critical in identifying new opportunities and designing rational delivery strategies. AREAS COVERED: This review discusses current and emerging therapeutic agents for CF therapy, selected physiological challenges to effective inhalational medication delivery, and various approaches to overcoming these challenges. The reader will find an integrated view of the known inhalational drug delivery challenges and the rationales for recent investigational inhalational drug formulations. EXPERT OPINION: An ideal drug/gene delivery system to CF airways should overcome the tenacious sputum, which presents physical, chemical and biological barriers to effective transport of therapeutic agents to the targets and various cellular challenges.

Development of inhalable dry powder formulation of basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is a promising agent for therapy of asthma or chronic obstructive pulmonary disease. We aim to develop an inhalable powder formulation of bFGF, which may provide a safe, effective, and convenient way of delivering bFGF to the disease-ridden lungs. Development of a bFGF dry powder formulation is constrained by the poor stability of bFGF and the uncertainty in compatibility of the protein with carrier excipients. With these constraints in mind, we prepared dry powders containing bFGF in combinations of albumin, phospholipid, lactose, and/or leucine, by spray drying, and evaluated the aerodynamic properties of the powders and the stability of bFGF loaded in the powders. While an ethanolic solution of phospholipid, albumin, and lactose produced dispersible powder, bFGF was unstable in ethanol. The stability of bFGF was preserved when spray-dried with lactose in an aqueous solution. Leucine was required to obtain dry powder with good dispersibility; however, increase in the leucine content more than 50% (w/w) negatively influenced the bFGF stability with no additional benefit to the aerodynamic properties of the powders. Dry powders containing 20% (w/w) leucine provided desirable aerodynamic properties (fine particle fraction of 25.2+/-5.4% and mass median aerodynamic diameter of 4.7+/-0.9 microm) and 98.1+/-7% recovery of bioactive bFGF. This result warrants further investigation of the biological activity of the inhaled bFGF in a disease model.