Ravi Kapoor, MD, MPH

• Department of Emergency Medicine
• Queens Hospital Center, Mount Sinai School of Medicine
• New York, New York

Marked enhancement of the dissolution velocity of naproxen nanosuspension formulations was achieved compared with pure naproxen erectile dysfunction medications list order levitra with dapoxetine us. Among others impotence and high blood pressure buy levitra with dapoxetine overnight, the authors explained considerable faster dissolution rates of naproxen nanosuspension formulations in comparison to pure drug by the high hydrophilicity of the polymers that bring about aggregation reduction erectile dysfunction medication uk buy 20/60 mg levitra with dapoxetine fast delivery, wettability improvement and local solubilization by the carrier in the diffusion layer erectile dysfunction viagra does not work cost of levitra with dapoxetine, the crystallinity reduction of the nanosuspension erectile dysfunction red 7 order genuine levitra with dapoxetine on line, as well as the reduced particle size and accordingly elevated surface area that could enhance the dissolution rate of naproxen in the formulation which antihypertensive causes erectile dysfunction generic levitra with dapoxetine 20/60 mg fast delivery. Nonetheless, the poor solubility and gastrointestinal side effects, greatly limit the clinical application of meloxicam [99]. Meloxicam displays distinctive characteristics suitable for transdermal delivery, such as low dose, relatively low molecular weight (354. In vitro transdermal permeation was evaluated using a vertical Franz diffusion cell with abdominal skin of Sprague Dawley rats. The skin permeation parameters, including steady-state flux (Jss) and drug deposition per unit skin area (Qr), were calculated. Initially, a steady increase of meloxicam permeated through the skin is observed for all formulations. However, the permeated amount of meloxicam across the skin from nanocrystals increases sharply compared with that from the solution and the suspension. Meloxicam suspensions show higher Qr than the nanosuspension and solution due to the accumulation of crystals inside the hair follicles. The in vivo transdermal delivery of meloxicam from solution, suspension and nanosuspension were followed in Sprague Dawley rats. Similar to the in vitro skin permeation, the suspensions show Qr higher than the other two formulations due to the accumulation of crystals inside the hair follicles. Nonetheless, the accumulated large crystals cannot be dissolved efficiently in this site, providing low but constant concentration gradient. The dissolution experiment results showed both formulations were completely dissolved within 30 min in 0. Due to several drawbacks when given orally, diclofenac acid is preferably administered topically, in spite of its low skin permeability, in long-term treatments, such as in the treatment of local muscle inflammation. The diffusion of diclofenac acid through the mouse skin was investigated ex vivo, while topical antiinflammatory activity was tested in vivo against common inflammatory endpoints: i. When the drug nanosuspension was applied on mouse skin, it produced a higher drug accumulation in the skin compared to both the coarse suspensions and the commercial formulation. Diclofenac acid nanosuspension presented a higher ability, compared to the coarse suspension and Voltaren Emulgel in the reduction of myeloperoxidase activity in the damaged tissue. Controversially diclofenac acid nanosuspension partially suppressed chemically induced edema, which was not statistically distinguishable from Voltaren Emulgel. These advantages have been demonstrated using various routes of administration including oral, parenteral, ocular, transdermal, and others. Moreover, several nanodelivery systems have demonstrated gastrointestinal tract protection against ulceration that is usually associated with conventional formulations. A review of the research results implies a great potential for the use of nanoparticle technology in improving the quality of life for patients taking antiinflammatory drugs for chronic conditions, through reducing drug side effects or frequency of administration. To translate these advances into clinical practice, it is necessary to perform an initial evaluation of novel nanoparticle formulations in extensive in vivo clinical studies. Diclofenac acid nanocrystals as an effective strategy to reduce in vivo skin inflammation by improving dermal drug bioavailability. Innovative formulations for the controlled and site-specific delivery of anti-inflammatory drugs. Etodolac-liquid-filled dispersion into hard gelatin capsules: an approach to improve dissolution and stability of etodolac formulation. Prevention and management of glucocorticoid-induced side effects: a comprehensive review: ocular, cardiovascular, muscular, and psychiatric side effects and issues unique to pediatric patients. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure. Development and physicochemical characterization of dexamethasone-loaded polymeric nanocapsule suspensions. SmartLiu o pids-the third generation of solid submicron lipid particles for dermal delivery of actives. Guidance on the risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain. Physicochemical characterization and stability of the polymeric nanoparticle systems for drug administration. Poly(lactide-co-glycolide)-based micro and nanoparticles for the controlled drug delivery of vitamins. Human skin penetration and distribution of nimesulide from hydrophilic gels containing nanocarriers. Spray-dried indomethacin loaded polyester nanocapsules and nanospheres: development, stability evaluation and nanostructure models. Poly(D,L-lactide) nanocapsules containing nonsteroidal antiinflammatory drugs- gastrointestinal tolerance following intravenous and oral-administration. Elaboration of argan oil nanocapsules containing naproxen for cosmetic and transdermal local application. Elaboration of nanoparticles containing indomethacin: argan oil for transdermal local and cosmetic application. Nanotechnological approaches for delivery of antiinflammatory drugs [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] solvent evaporation technique. Nanoparticle-based topical ophthalmic formulations for sustained celecoxib release. Influence of a polymeric formulation of ketoprofen on its diffusion into cerebrospinal fluid in rats. Comparative study of ibuprofen and indomethacin loaded poly(caprolactone) nanoparticles: physicochemical properties. Chitosan nanoparticles prepared by ionotropic gelation: an overview of recent advances. Chitosan/ alginate nanoparticles as a promising approach for oral delivery of curcumin diglutaric acid for cancer treatment. Gastro-intestinal tolerance following oral administration of spray-dried diclofenac-loaded nanocapsules and nanospheres. Ultrafine self nanoemulsifying drug delivery system for transdermal delivery of meloxicam: dependency on the type of surfactants. Hemocompatibility of poly(-caprolactone) lipid core nanocapsules stabilized with polysorbate 80 lecithin and uncoated or coated with chitosan. Positively charged polymeric nanoparticles: application in improving therapeutic efficacy of meloxicam after oral administration. Preparation, characterization, and transport of dexamethasone-loaded polymeric nanoparticles across a human placental in vitro model. Preparation and characterization of nanocapsules for colon-targeted drug delivery system. Influence of benzyl benzoate as oil core on the physicochemical properties of spray-dried powders from polymeric nanocapsules containing indomethacin. Nanoemulsion based gel for transdermal delivery of meloxicam: physicochemical, mechanistic investigation. Penetration and release studies of positively and negatively charged nanoemulsions-is there a benefit of the positive charge Enhancement of antiinflammatory property of aspirin in mice by a nanoemulsion preparation. Modification of palm kernel oil esters nanoemulsions with hydrocolloid gum for enhanced topical delivery of ibuprofen. Nanoemulsion: a review on mechanisms for the transdermal delivery of hydrophobic and hydrophilic drugs. Positively and negatively charged submicron emulsions for enhanced topical delivery of antifungal drugs. Topical delivery of low-molecularweight heparin with surface-charged flexible liposomes. State of the art of u nanocrystals-special features, production, nanotoxicology aspects and intracellular delivery. Improved efficacy in the treatment of contact dermatitis in rats by a dermatological nanomedicine containing clobetasol propionate. Hydrogel containing dexamethasone-loaded nanocapsules for cutaneous administration: preparation, characterization, and in vitro drug release study. Lipid nanoparticles as novel delivery systems for cosmetics and dermal pharmaceuticals. Challenges and solutions for the u delivery of biotech drugs-a review of drug nanocrystal technology and lipid nanoparticles. Development and evaluation of colloidal modified nanolipid carrier: application to topical delivery of tacrolimus. Nanoemulsions as vehicles for topical administration of glycyrrhetic acid: characterization and in vitro and in vivo evaluation. Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process. Nanoemulsions in translational research- opportunities and challenges in targeted cancer therapy. Design, development and evaluation of novel nanoemulsion [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] 226 10. Nanotechnological approaches for delivery of antiinflammatory drugs [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] targeting and stimuli sensitive drug delivery systems. Systematic invesu o tigation of the cavi-precipitation process for the production of ibuprofen nanocrystals. Formulation and process optimization of naproxen nanosuspensions stabilized by hydroxy propyl methyl cellulose. Enhanced anti-inflammatory activity of carbopol loaded meloxicam nanoethosomes gel. Physical characterization of meloxicam-cyclodextrin inclusion complex pellets prepared by a fluid-bed coating method. Flexosomes for transdermal delivery of meloxicam: characterization and anti-inflammatory activity. Enhanced transdermal delivery of meloxicam by nanocrystals: preparation, in vitro and in vivo evaluation. At the time of writing, more than 400 stilbene compounds have been generally identified [3]. Owing to their unique structure, which imparts both antioxidant [4] and antiinflammatory properties [5], they exhibit a wide range of other biological activities, such as neuroprotective and cardioprotective, in addition to cancer prophylaxis [3]. Their widely reported beneficial health effects delineated stilbenoids as "functional foods. This article also provides an overview of technological advantages in nanocarrier development of the same. They were also reported to exhibit antihyperglycemic properties [19, 20], hence they can be useful in the treatment of diabetes. Nanocarriers, which are colloidal particles with size <1000 nm, can be fabricated with diverse types of materials and techniques [27a]. Nanocarriers are a promising means of enhancing the solubility of drugs, since nanomaterials have a large surface area which offers high dissolution and improved bioavailability [27b]. Nano-sized carriers can penetrate living tissue at deep extent owing to their sub-micron size [27c]. Nano-systems can also enhance stability of labile moieties against light or chemical degradation. Moreover, the drug release pattern can also be modulated in order to sustain release or decrease dosing frequency of medication [27d], with the possibility of targeting the required organ. Nanoparticles were also reported as a means of inhibiting the trans to cis isomerization of drugs [7]. For the oral route in particular, nanoparticles were shown to favor the trans-epithelial drug transport in the gastrointestinal tract, and hence to allow for more drug absorption [28]. However, regarding stilbenoid compounds, the oral administration poses a delivery challenge owing to their poor aqueous solubility and extensive metabolism in the intestine and liver into sulfate and glucuronide metabolites, leading to low bioavailability [3]. Bangham discovered liposomes which are biocompatible and biodegradable spherical structures, capable of entrapping both lipophilic and hydrophilic molecules. They are composed of a lipidic bilayer surrounding an aqueous core, and without any further modifications to their structure, they are termed "conventional vesicles. Liposomes have been used to solve problems of natural compounds (either hydrophilic or hydrophobic) such as solubility, stability, and susceptibility to degradation or inactivation. Moreover, liposomes can improve bioavailability of natural compounds and enhance their therapeutic activity [30b]. Similar to liposomes, niosomes are considered promising drug carriers as they increase the therapeutic efficacy of drugs and facilitate their targeted delivery [45]. Transfersomes are another example of modified vesicular generation, in which a surfactant (edge activator) is incorporated within the phospholipid bilayer, conferring flexibility to the vesicles [55, 56]. Lipid nanoparticles could efficiently enhance drug transport through the gut due to the adhesive and absorption enhancing effect of lipids, allowing for a high surface area to release drugs.

Abdominal complaints and appendiceal changes leading to the diagnosis of cystic fibrosis erectile dysfunction medication cheap levitra with dapoxetine 40/60 mg amex. Liver disease in cystic fibrosis: a prospective study on incidence importance of being earnest order cheapest levitra with dapoxetine and levitra with dapoxetine, risk factors erectile dysfunction age range buy 40/60mg levitra with dapoxetine, and outcome erectile dysfunction treatment prostate cancer quality levitra with dapoxetine 40/60 mg. Atypical cystic fibrosis of the pancreas with normal levels of sweat chloride and minimal pancreatic lesions impotence vs infertile purchase 40/60mg levitra with dapoxetine free shipping. Number and sex of offspring of deltaF508 carriers outside cystic fibrosis families erectile dysfunction treatment cream purchase 20/60mg levitra with dapoxetine. Is there a relationship between sex of cystic fibrosis carriers and sex ratio of their offspring Cystic fibrosis allele frequency, sex ratio anomalies and fertility: a new theory for the dissemination of mutant alleles. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. The genetic advantage hypothesis in cystic fibrosis heterozygotes: a murine study. Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. Characterization of wild-type and deltaF508 cystic fibrosis transmembrane regulator in human respiratory epithelia. Characterization of the promoter region of the cystic fibrosis transmembrane conductance regulator gene. Characterization of the cystic fibrosis transmembrane conductance regulator promoter region. Tissue-specific in vivo transcription start sites of the human and murine cystic fibrosis genes. The cystic fibrosis gene has a "housekeeping"-type promoter and is expressed at low levels in cells of epithelial origin. Basal expression of the cystic fibrosis transmembrane conductance regulator gene is dependent on protein kinase A activity. Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes. In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Multiple mechanisms influence regulation of the cystic fibrosis transmembrane conductance regulator gene promoter. Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia. Mapping of cystic fibrosis transmembrane conductance regulator membrane topology by glycosylation site insertion. Functional roles of the nucleotide-binding folds in the activation of the cystic fibrosis transmembrane conductance regulator. Cystic fibrosis transmembrane conductance regulator: nucleotide binding to a synthetic peptide. Interaction of nucleotides with membrane-associated with cystic fibrosis transmembrane conductance regulator. Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Human cystic fibrosis airway epithelia have reduced Cl- conductance but not increased Na+ conductance. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Ezrin controls the macromolecular complexes formed between an adapter protein Na+/H+ exchanger regulatory factor and the cystic fibrosis transmembrane conductance regulator. Revisiting cystic fibrosis transmembrane conductance regulator structure and function. Expression of the cystic fibrosis gene in non-epithelial invertebrate cells produces a regulated anion conductance. Transmembrane mutations alter the channels characteristics of the cystic fibrosis transmembrane conductance regulator expressed in Xenopus oocytes. Localization of sequences within the C-terminal domain of the cystic fibrosis transmembrane conductance regulator which impact maturation and stability. C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator requires a tyrosine-based signal. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Antisense oligodeoxynucleotide to the cystic fibrosis gene inhibits anion transport in normal cultured sweat duct cells. Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. Osmotic water permeabilities of cultured, well-differentiated normal and cystic fibrosis airway epithelia. Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene. A cystic fibrosis allele encoding missense mutations in both nucleotide binding folds of the cystic fibrosis transmembrane conductance regulator. Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone. Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model. The osmolyte xylitol reduces the salt concentration of airway surface liquid and may enhance bacterial killing. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. Systematic computational identification of variants that activate exonic and intronic cryptic splice sites. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Cystic Fibrosis 321 [268] Cystic Fibrosis Foundation Patient Registry Annual Data Report 1997 (1997). Geographic distribution and regional origin of 272 cystic fibrosis mutations in european populations. Complete detection of mutations in cystic fibrosis patients of Native American origin. Detection of more than 94% cystic fibrosis mutations in a sample of Belgian population and identification of four novel mutations. The origin of the major cystic fibrosis mutation (deltaF508) in European populations. The incidence of different cystic fibrosis mutations in the Scottish population: effects on prenatal diagnosis and genetic counselling. Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians. Mutations of the cystic fibrosis gene locus within the population of North-West England. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. A nonsense mutation in exon 4 of the cystic fibrosis gene frequent among the population of the Reunion Island. Skipping of exon 12 as a consequence of a point mutation (1898+5G->T) in the cystic fibrosis transmembrane conductance regulator gene found in a consanguineous Chinese family. Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. Cystic fibrosis as a disease of misprocessing of the cystic fibrosis transmembrane conductance regulator glycoprotein. Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. Cytoplasmic loop three of cystic fibrosis transmembrane conductance regulator contributes to regulation of chloride channel activity. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. Thirteen cystic fibrosis patients, 12 compound heterozygous and one homozygous for the missense mutation G85E: a pancreatic sufficiency/insufficiency mutation with variable clinical presentation. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. A change in gating mode leading to increased intrinsic Cl- channel activity compensates for defective processing in a cystic fibrosis mutant corresponding to a mild form of the disease. A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis. A mutation in the cystic fibrosis transmembrane conductance regulator generates a novel internalization sequence and enhances endocytic rates. Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W, a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences. Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849+10 kb C->T mutation. Genetic comparisons of patients with cystic fibrosis with or without meconium ileus. Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with severe disease presentation. Genotype/phenotype association in cystic fibrosis: analysis of the deltaF508, R553X, and 3905insT mutations. Mild cystic fibrosis linked to chromosome 7q22 markers with an uncommon haplotype. Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype. L206W mutation of the cystic fibrosis gene, relatively frequent in French Canadians, is associated with atypical presentations of cystic fibrosis. Congenital absence of the vas deferens: a primarily genital form of cystic fibrosis. Cystic fibrosis disease modifiers: complex genetics defines the phenotypic diversity in a monogenic disease. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype. A cystic fibrosis patient homozygous for 621+1G->T mutation has a severe pulmonary disease, mild pancreatic insufficiency and a gastro-esophageal reflux. Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis. Pulmonary outcome in cystic fibrosis is influenced primarily by mucoid Pseudomonas aeruginosa infection and immune status and only modestly by genotype. Linked marker haplotypes and the deltaF508 mutation in adults with mild pulmonary disease and cystic fibrosis. Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function. Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis. Categories of deltaF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings. Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: a review and meta-analysis. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Genetic modifiers play a substantial role in diabetes complicating cystic fibrosis. A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis genetic modifier studies. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.

Due to the difficulty in selecting the training set that shows the variability of spectral response in each class erectile dysfunction drugs recreational use order levitra with dapoxetine with a mastercard, supervised methods become difficult erectile dysfunction zurich purchase levitra with dapoxetine 20/60 mg without prescription. Also erectile dysfunction pills non prescription buy generic levitra with dapoxetine 40/60 mg on line, the data collection process is time consuming and the class to be categorized for data is fixed does kaiser cover erectile dysfunction drugs buy levitra with dapoxetine 20/60mg without prescription. But unsupervised does not have this restriction and multiple dynamic classes can be learned erectile dysfunction home remedies buy on line levitra with dapoxetine. When the training dataset is well prepared and the statistical correlation between the features to the label is high erectile dysfunction in early 30s buy levitra with dapoxetine no prescription, the accuracy of classification in supervised classification is higher than that of unsupervised classification. After analysis, the pixel is mapped to a number of class based on the natural grouping or clusters based on image values. When data in different classes are well separated, the performance of unsupervised classification is higher. The classes that result from the unsupervised classification are spectral classes. A comparison of classified data with some base line reference is needed by the analyst to finalize the identity of the spectral classes. The classes which are separable spectrally are identified by defining the informational utility. Pixels located within the training areas are used to guide the classification algorithms. Based on this information, specific spectral values are matched to appropriate informational class. It uses mathematical regression to learn a hyperplane separating the training data. For the case linearly separable 2D points belonging to one of two classes, the hyperplane is a straight line. The support vector machine provides an optimal hyperplane based on the input training dataset. The constraints are the classification of the entire training sample xi correctly. The problem is similar to that Lagrangian optimization and solved using Lagrange multipliers. Since red and blue bands do not have significant information for exodus detection, they are dropped and the green component in the image is used for analysis. On the segmentation portions, morphological feature extraction is done to extract abnormality features in the fundus image. Images with lesion are classified as abnormal and the images without lesion are classified as normal. Gaussian filter is ideal for removing Gaussian noises compared to salt and pepper and speckle noises from the image. To evaluate the performance of the output result, the following performance measures are calculated: 1. Accuracy To calculate these parameters, the following measurements must be done for N images. The proposed system uses Gaussian filtering for preprocessing and adaptive histogram equalization for contrast enhancement. Gaussian noises are removed by the application of Gaussian filtering on the input fundus image. Adaptive histogram equalization is able to improve the contrast of image better than traditional methods. Fuzzy c-means clustering shows better segments of the lesions in the image compared to other segmentation techniques. Morphological feature extraction is done with dilation and erosion operations for reducing the dimension of the features. The accuracy of the proposed method is more than 94% which is higher than the existing solutions. Gandhi, Detection of retinal hemorrhages in the presence of blood vessels, in: Proceedings of the Ophthalmic Medical Image Analysis First International Workshop. Presented at the Ophthalmic Medical Image Analysis First International Workshop, 2014, pp. Malathi, Automatic detection of blood vessels in digital retinal images using soft computing technique, Mater. Index Note: Page numbers followed by f indicate figures, t indicate tables, and b indicate boxes. The virus can cause substantial economic losses throughout the poultry industry worldwide. It can affect the upper respiratory tract and the reproductive tract, and some strains can cause nephritis (Cavanagh, 1997). Since that initial discovery, many different serotypes, defined by neutralizing antibodies, and genetic types, based on the deduced amino acid sequence (from the nucleic acid sequence) of the spike gene, have been described around the world (El-Houadfi et al. It has a wide geographical distribution and it was found in regions of Africa, Asia, Australia, Europe, and the United States (Khataby et al. However, the variation can sometimes be as high as 50%, which affects the cross-protection toward virus strains (Cavanagh et al. Based on S1 sequence, this variant resembles the Dutch D1466 variant (Lee and Jackwood, 2001). California-type viruses were first isolated in the 1990s and were designated California variant (Moore et al. The molecular analysis of the glycoprotein S1 has shown that the two variants have a unique sequence of the gene S1 (de Wit et al. Later in 1986, the variant Ark emerged, causing devastations to Brazilian poultry (De Wit et al. In Mexico, several different genotypes have now been isolated which include Conn, Mass, and Ark type (Jackwood, 2012). In 1980s the Doorn Institute of the Netherlands isolated four serotypes designated as D207 (also known as D274), D212 (also known as D1466), D3896, and D3128, from Mass isolate-vaccinated flocks (Davelaar et al. It was shown to have a nucleotide sequence in the hypervariable regions of the S1 spike gene quite distinct from Mass and Dutch variant viruses (Cavanagh et al. Italy-02 was found in almost all European countries but in 2004, it was reported to be declining in prevalence in all countries except Spain (Worthington et al. A number of local variants are reported in Africa in addition to the widely known vaccine serotypes such as Mass and 4/91 strains (de Wit et al. These isolates were found closely related to European strains ^ including D274 and 793B (Bourogaa et al. It was confirmed as a variant that showed to be poorly protected by Massachusetts vaccines (Cook et al. However, molecular studies have shown that a new serotype or variant can emerge as a result of only a few changes in the amino acid composition in the S1 part of the virus spike protein, while most of the virus genomes remain unchanged (Cavanagh, 2007). This could be due to immunological pressure caused by the widespread use of vaccines, to recombination as a consequence of mixed infections, or to a reduction of dominant serotypes as a result of vaccination, allowing other field strains to emerge (Lee, 2002; Liu et al. Actually, serotypic determinants have been identified in the first 395 amino acid region of the S1 subunit, which contains three major hypervariable regions. Variants may attain increased virulence, efficient receptor binding, rapid transmission, and persistence in host system causing significant disease in vaccinated flocks of all ages (Wang and Huang, 2000; Dhama et al. And because the clinical signs are not specific, the need for differential diagnostic methods was very important to realize. These methods focus on either isolating or detecting the virus itself as well as detecting serum antibodies to it. Laryngotracheal swabs from live birds or tracheal and lung tissues from fresh carcasses from diseased birds should be collected. After being clarified by low-speed centrifugation and filtration through bacteriological filters, 0. Eggs are candled daily for 7 days with mortality within the first 24 hours being considered nonspecific death. Blind passage into another set of eggs for up to a total of three to four passages is conducted. Also, in situ hybridization can be used to detect viral nucleic acid (Collisson et al. However, nonspecific reactions or lower sensitivity especially in field samples may occur (Benyeda et al. However, extensive passage should be avoided to prevent the reduction in immunogenicity. There is an evidence that some attenuated vaccines showed increase in virulence after back passage in chickens (Hopkins and Yoder, 1986). These vaccines are commercially available for application via drinking water or by coarse spray at 1 day or within the first week of age. Live vaccination of 1-day-old chicks induced a rapid decline in maternally derived antibodies due to binding and partial neutralization of vaccine viruses (Mondal and Naqi, 2001). Given the nature of these live attenuated vaccines, further passage beyond the master seed stock must be kept to a minimum to prevent potential loss of immunogenicity. Most of the commercially available live attenuated vaccines are derived from virulent strains such as Massachusetts-based M41 serotype and the Dutch H52 and H120 strains, although some strains with regional or local impact have been used in different parts of the world (Sasipreeyajan et al. However, it is not clear whether the combination may influence immune response to the combined antigen (Vagnozzi et al. Tissue damage due to live vaccines may lead to pathological disorders or secondary bacterial infections, especially in day-old chick (Tarpey et al. And since inactivated vaccines do not replicate, they are unlikely to revert and cause pathological effects. Being injectable, administration of killed vaccines is either difficult or impracticable in large poultry setting. Likewise, issues of injection-site reactions may also lead to carcass rejection or reduction in value (Cook et al. Though live attenuated vaccines are still common in the field, these vaccines provide only a little or partial cross-protection occurs between vaccine strains and new field which require the development of new vaccines as the recombinant vaccines. S1 gene sequence analysis of a nephropathogenic strain of avian infectious Bronchitis virus in Egypt. Immunohistochemistry for detection of avian infectious bronchitis virus strain M41 in the proventriculus and nervous system of experimentally infected chicken embryos. Global distributions and strain diversity of avian infectious bronchitis virus: a review. A filterable virus, distinct from that of laryngotracheitis, the cause of a respiratory disease of chicks. Severe acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious bronchitis coronavirus. Location of the amino acid differences in the S1 spike glycoprotein subunit of closely related serotypes of infectious bronchitis virus. Longitudinal field studies of infectious bronchitis virus and avian pneumovirus in broilers using type-specific polymerase chain reactions. Variation in the spike protein of the 793/B type of infectious bronchitis virus, in the field and during alternate passage in chickens and embryonated eggs. Breadth of protection of the respiratory tract provided by different live-attenuated infectious bronchitis vaccines against challenge with infectious bronchitis viruses of heterologous serotypes. Occurrence and significance of infectious bronchitis virus variant strains in egg and broiler production in the Netherlands. Technique for the isolation of infectious bronchitis or Newcastle virus including observations on the use of streptomycin in overcoming bacterial contaminants. In: Proceedings of Northeast Conference of Laboratory Workers in Pullorum Disease Control, vol. Infectious bronchitis virus variants: a review of the history, current situation and control measures. Emergence of avian infectious bronchitis virus and its variants need better diagnosis, prevention and control strategies: a global perspective. Antigenic and molecular characterization of isolates of the Italy 02 infectious bronchitis virus genotype. Characterization of a new genotype and serotype of infectious bronchitis virus in Western Africa. The isolation and characterisation of six avian infectious bronchitis viruses isolated in Morocco. Antigenic and S-1 genomic characterization of the Delaware variant serotype of infectious bronchitis virus. Isolamento e identificacao do virus da bronquite infecciosa das galinhas no Brasil. Antigenic relationship of Australian infectious bronchitis viruses: analysis using polyclonal and monoclonal antibodies.

The pipelines of biologics for pulmonary delivery remain a smaller portion in the market due to the abovementioned challenges erectile dysfunction while drunk purchase cheap levitra with dapoxetine line. Pulmozyme has proved preclinically as well as clinically to have more advantages over traditional inhalants impotence natural generic 20/60 mg levitra with dapoxetine mastercard, such as improved lung deposition impotence cure discount levitra with dapoxetine 20/60 mg visa, decreased rate of administration erectile dysfunction 42 cheap levitra with dapoxetine 20/60 mg without a prescription, and improved stability of the protein erectile dysfunction heart attack purchase levitra with dapoxetine without a prescription. All these advantages could reduce patient compliance impotence herbs buy 20/60mg levitra with dapoxetine with visa, which is usually faced with the traditional inhalants for treating such types of diseases. The delivery route is still in the exploratory phase and requires significant development before it can be considered a standard delivery option for biopharmaceuticals. This route offers several advantages like noninvasiveness and constant delivery of drugs, hence avoiding frequent interventions. The degradation of therapeutic proteins can be avoided as this route has limited proteolytic enzymes which can degrade the proteins compared to other routes, and hence the bioavailability of proteins and peptides can be improved. It is also convenient for patients as it can be self-administered by placing the patch on the skin, which is not painful. Physiologically, it is well known that skin is the largest organ in the body, and it acts as an excellent natural barrier, preventing most drug and foreign particles from entering the body. Therefore, only the small molecules (approximately 500 kDa) that have these physicochemical properties can pass through this limiting barrier, whereas the large macromolecules cannot diffuse through it [40]. The success of transdermal drug delivery is limited to the properties of the skin barrier, mainly the presence of the stratum corneum, which restricts the hydrophilic macromolecules from entering the skin. Considering the challenges faced by macromolecules, many strategies and approaches have been developed to address the problem by various physical and chemical enhancement techniques. Some commonly used physical techniques are microporation, iontophoresis [41, 42], electroporation, and sonophoresis [43, 44]. Similarly, chemical enhancement techniques involve the use of permeation enhancers like alcohols, surfactants, sulfoxides, etc. Although skin has a limited number of proteolytic enzymes when compared to other routes, protease inhibitors are being used for peptide formulations so that the delivery process could be enhanced much more [45]. Most biologic products for transdermal drug delivery are proteins, peptides, and vaccines. Many strategies were tested preclinically using novel peptides for delivering biologics across the skin using various mechanisms. Details of the undergoing clinical trials product for transdermal drug delivery are listed in Table 6. Many of the biologic products used for ocular treatment are monoclonal antibodies, proteins, and peptides. However, the clinical success of these therapeutics is challenged by a higher frequency of injection [51]. In addition, treatment with such types of biologics pose a challenge because of poor permeability across the retinal barriers, poor availability due to their large molecular size, stability, and additionally the dynamic clearance mechanism of the biologics from the eye. There is an unmet medical need for these challenges to improve patient compliance. There has been a growing interest and enormous attention for researchers to overcome these challenges by developing several novel technologies like a sustained drug delivery system using nanotechnology for delivering biologics [52]. Many approaches have been studied on how to overcome the various ocular barriers, and to minimize the clearance mechanism. The nanotechnology at the time of writing is one strategy that could respond to the challenges using both physical and chemical methods. The enhancement of permeation by different nanocarriers like nanoparticles, micelles, and liposomes was shown to have potential by many researchers in delivering drugs to different ocular tissues [51]. Dry eye disease is a condition where the eye lacks moisture and lubrication on the ocular surface, which could lead to visual discomfort, irritation, etc. A few studies have reported that severe dry eye disease results from inflammation due to decreases in tear film nucleases. Additional care has to be taken with the ophthalmic delivery route mainly in terms of skilled injection procedure as well as particle control. Hence, oral drug delivery of biologics remains a "holy grail" at the time of writing. Unfortunately, the success of this route for therapeutics is very poor because of acidic environment and enzymatic degradation due to the presence of intestinal enzymes in the intestinal gut; on the other hand, permeability of these agents is low due to high 138 6. Biologics: Delivery options and formulation strategies molecular weight, which leads to low bioavailability. The high demand for oral delivery of proteins and peptides has led many researchers to put great effort into developing an oral drug delivery system that can overcome these challenges. Different strategies to overcome the challenges of oral drug delivery are: (i) use of mucoadhesive polymers to increase contact time of the drug with the physiological membrane [54]; (ii) compounds that can disrupt the membrane barrier and promote the transient opening of the epithelial tissues [55]; (iii) materials that can inhibit the degrading proteolytic enzymes in the gut [56] and materials that can promote dissociation of protein. All these nanotechnology-based mediated forms of oral delivery have not yet improved beyond the preclinical level. Although various approaches are claimed and being investigated by many researchers, many unaddressed challenges remain to be considered to make oral drug delivery of biologics a reality. Clinically, it has been reported that several biologics are being investigated for oral delivery across the globe. Commercially, there are two peptides which are available in the market: (1) Linzess (Iron Wood Pharmaceuticals) and Trulance (Synergy Pharmaceuticals). In addition, about four vaccines have been approved clinically (against vibrio, cholera, typhoid and rotavirus). The biologics for oral delivery that are undergoing clinical trials are listed in Table 6. Complex molecular structure, lack of welldefined analytical tools, and multiple degradation mechanisms create major problems for the formulation development of biologics and vaccines. Because of the limited availability of drug substance for initial screening and development, formulation scientists perform forced degradation studies using limited analytical techniques, which help in developing optimal formulation and provide insight in understanding degradation pathways of active molecules. Formulation development is one of the most important aspects of drug development, as proper formulation ensures appropriate shelf life and safety to patients. For biologics, the formulation development is generally divided into three interconnected stages: preformulation, formulation, and process development. The preformulation stage involves biochemical analysis, amino acid sequencing, and biophysical characterization of large molecules in the presence of pH, ionic strength, along with development of stability indicating assay. This study also helps researchers to understand degradation pathways and therefore provides an approach to select appropriate excipients of the required characteristics. A thorough understanding of macromolecular behavior can be obtained using high-throughput formulation approaches to explore changes in structure. In the case of liquid formulations, if the initial strategy fails to meet the target product profile, it is recommended to 5 Formulation strategies, degradation routes, and role of excipients 139 develop a lyophilized product using a suitable lyophilization process. Application of quality by design (QbD) in formulation development is also useful to obtain a stable product with the desired target profile. Through extensive stability studies (both real-time and accelerated) and in vivo animal model testing (when applicable), a potential formulation can be selected for preclinical and clinical study. To minimize the cost and complexity of clinical study, it is recommended that process and formulation optimization should occur at an early stage. Peptide, protein, and other biologically derived macromolecules have rapidly emerged as a major class of pharmaceuticals because of their multiple advantages. Excipients have a defined functional role in pharmaceutical products like maintaining pH, osmolality, solubility and bioavailability enhancement, antioxidant effect, emulsifying action, stabilization, etc. The stability of the finished product depends on the selection of the excipients, their concentrations and the interaction between drug-excipients and excipientsexcipients interaction. It is important during the early stage development phase that the excipients are carefully screened and optimized based on the interactions mentioned above. Owing to their clinical and commercial success, biologics are the fastest growing class and have become dominant over other conventional therapy. Protein-based macromolecules now constitute a major proportion of therapeutic imperative for the treatment of various diseases. But due to the fragile nature and complex structure of proteins, it is very challenging to maintain integrity during processing, administration, and distribution of these products. Two types of degradation process are responsible for the instability of protein molecular structure: physical instability and chemical instability (Table 6. Various excipients like buffers, salts, sugars, and surfactants are designed to improve the stability of protein-based biologics. These excipients are used to optimize the environment surrounding the protein to maintain its conformational and colloidal stability, reduce interactions with neighboring proteins, and block interactions with container surfaces. This section will provide information about majorly used excipients along with their role and functionality (Table 6. Prevention against these degradation routes requires careful selection of stabilizing excipients. The choice of the excipients is based on the compatibility, functionality, and variability of critical material characteristics within a certain acceptable range for development of a particular drug product. Currently, approximately 1000 excipients of >40 functional categories are used in marketed pharmaceutical products. Conventional excipients are simple in structure, well known, pharmacologically inert, and of natural origin such as sugar, minerals, and wheat, but in recent years, many more novel and highly complex excipients have been developed and evolved for specific usage, especially for novel drug delivery systems like lipids, polymers, dextrans, cyclodextrins, polyethylene glycol, etc. Excipients play a vital role in the formulation development of both small and macromolecule pharmaceutical products. Reaction Deamidation Peptide bond hydrolysis -Elimination Disulfide bond reshuffling Oxidation Thiol-disulfide exchange Racemization Hydrolysis Corresponding amino acid involved Asparagine and glutamine Primarily at aspartic Cystine Cystine Cystine and methionine Cystine and cysteine Aspartic acid and glycine Aspartic acid, serine and threonine route of administration, indication, target population, etc. As per the growing status of protein, peptide therapeutics, and vaccines development, the stabilization of biologics during processing and storage poses a significant challenge for product development scientists. Biologics and vaccines are highly unstable in nature and heavily prone to degradation by physical and chemical (oxidation, hydrolysis, deamination, photo-oxidation, and thiooxidation) mechanisms. Excipients play a significant role in the development of stable biologics product and thereby the selection and use of appropriate excipients is very important at the product development stage. Excipients in biologics products can be used for different functionality, such as: (a) controlling pH and tonicity; (b) enhancing the solubility of the active molecule; (c) preventing its aggregation and degradation; (d) enhancing the process and stability of the active molecule; (e) maintaining its conformation; and (f) other functions like antioxidants, preservatives, bulking agents, etc. The understanding of drug-excipient interactions is also critical in the rational design of formulations to stabilize protein-based therapeutic drugs and vaccines. The complexity of formulation development is often more pronounced for the development of high-concentration antibody formulations due to additional constraints of viscosity, analytical characterization at high concentration, and the desire to formulate an isotonic formulation while maintaining the ratio of excipient to antibody to provide the stability. Commonly used excipients in biologics and vaccine formulation are summarized in Table 6. Regulatory acceptance of excipients is also critical for their selection and inclusion in the final formulation. Regulatory agencies across the globe, maintain information about approved excipients which are already in use with various commercial products. Some biologics products need surfactants to block the particular subregions of the protein or to block the protein-protein interaction that could lead to denaturation. Even in the presence of these surfactants, protein drug stability is often insufficient, particularly because of agitation-induced aggregation. The self-buffering potential of proteins becomes more relevant for high-concentration biologics. Buffer capacity and the possibility of buffer catalysis are crucial characteristics for liquid biologics. Generally, mannitol, lactose sucrose, dextran, trehalose, and glycine are used as bulking agents. Bulking agents always play a dual role as filler and cryoprotectors in lyophilized products. These agents have the potential to turn entire formulations into a crystalline (mannitol and glycine) or amorphous state (sucrose). An appropriate selection of lyoprotector results in better product quality (stability and moisture levels and reconstitution time) and facilitates freezedrying and scaling up to commercial batch. The concentration of bulking agents utilized will determine the rationale use (as stabilizer, eutectic temperature modifier or matrixforming agents). The chemical stability of biologics such as monoclonal antibodies is pH-dependent and slightly acidic conditions are favorable for stability of the formulation. Biologics: Delivery options and formulation strategies Aqueous solution-based biologics may pose stability issues because of hydrolytic degradation of active molecules. Lyophilization is a technique used to stabilize pharmaceutical products by removing water from drug aqueous solution. Lyophilization is the most frequently used strategy to achieve the desired stability of a finished product according to its target product profile. It is also proven to be a superior technique for the stabilization of thermolabile biologics, especially vaccines. Lyophilization consists of three phases: freezing followed by primary and secondary drying under vacuum. During the freezing step, protein denaturation can occur either in the freeze-concentrate state or at frozen surface interfaces. To counter the relevant criticality, the formulation can be designed using salts and buffer, which can minimize protein denaturation during the lyophilization process. Lyoprotectant, along with cryoprotectant, is normally needed for stabilization of biologics. Lyoprotectant plays a vital role in protection of the product during the drying phase while cryoprotectant stabilizes the frozen product during the freezing phase. Bulking agents are also added to lyophilized product to prevent product "blowout" especially in the case of low concentration product (1% solid).

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