Chas G Newstead BSc FRCP

• Consultant renal physician
• St James? University Hospital
• Honorary senior lecturer
• University of Leeds, Leeds, UK

Vecuronium can be used as an intermittent agent but also as a continuous infusion symptoms stomach flu purchase ritonavir with paypal. There are risks of decreased metabolism and prolonged clearance with vecuronium infusions and many will choose instead to use cisatracurium medicine dictionary prescription drugs ritonavir 250 mg purchase on-line. Cisatracurium is often useful because its elimination is not dependent on renal or hepatic function medicine gif discount 250 mg ritonavir with mastercard. If these drugs are given for more than a day treatment yellow tongue purchase ritonavir without prescription, provision of regular drug holidays should be considered to avoid serum buildup of the drug and prolonged paralysis medications 5113 ritonavir 250 mg buy free shipping. Attempts have been made to develop predictive indices identifying which children can be successfully weaned from mechanical ventilation. These are periods of decreased ventilatory support while the patient is observed for evidence of respiratory distress. It is possible that computerized weaning protocols will further reduce time on mechanical ventilation. Studies indicate a significant percentage of patients being evaluated for weaning are ready for extubation. If we continue mechanical ventilation until we are absolutely certain a patient will not fail, many patients will be ventilated longer than necessary. Overall, the criteria for extubation readiness includes intact airway reflexes, hemodynamic stability, manageable secretions, and an appropriate level of alertness. Extubation failure may be caused by a multitude of reasons but large category is postextubation upper airway obstruction. Croup is a viral infection (parainfluenza, influenza, adenovirus) that causes edema of the tissues in the upper airway, particularly in the immediate subglottic region. There is usually a history of a few days of upper respiratory tract infection symptoms followed by hoarseness, a croupy cough, and possibly stridor. These patients are initially treated with mist and aerosolized racemic epinephrine to reduce swelling of upper airway mucosa. Epiglottitis Epiglottitis is an inflammation of the mucosa of the supraglottic structures that was previously caused by Haemophilus influenzae type B but is now commonly caused by Staphylococcus aureus and streptococcal organisms because immunization against the Haemophilus organism has been so effective. Children with epiglottitis appear toxic and have a fulminant onset of fever and respiratory distress. Tracheal intubation during anesthesia is commonly required until antibiotic therapy (ampicillin and chloramphenicol or ceftriaxone) is initiated and the signs of systemic toxicity subside. The signs and symptoms of this malady are air trapping, wheezing, mild to moderate systemic hypoxemia, increased work of breathing, and increased airway resistance. Apnea is frequently the first sign of decompensation in neonates, which often occurs before significant hypercapnia appears. Treatment is primarily supportive and includes endotracheal intubation and mechanical ventilation for respiratory failure. Cystic Fibrosis Cystic fibrosis is a fatal autosomal recessive disease carried on chromosome 7. Survival of patients with cystic fibrosis has improved dramatically over the past 30 years. Lung transplantation has been performed in patients with chronic respiratory failure with varied success. The cause of this disease is uncertain, but usually patients were premature, had hyaline membrane disease, and required prolonged and aggressive respiratory support with high inflating and distending pressure and high oxygen concentrations. The lungs are hyperinflated, and there are intercostal retractions, nasal flaring, and wheezing. Chest radiographs demonstrate large lung volumes and fibrosis as well as cystic and atelectatic areas. Diuretics and bronchodilators are frequently used and may be associated with electrolyte abnormalities. The latter include central responses to hypercapnia and hypoxia, response to airway irritation, and dynamic phasic contraction of the pharyngeal and hypopharyngeal muscles. Sleep apnea usually occurs when one or more of these protective responses is abnormal. Numerous causes have been postulated, the most attractive of which is immaturity of the medullary chemoreceptors. Lesser breathing disorders may be present during sleep in patients with sudden infant death syndrome. Treatment of sleep apnea consists of respiratory stimulants (theophylline), cardiorespiratory monitoring during sleep, and in some severe cases, tracheotomy and nighttime mechanical ventilation. It may be associated with an identifiable anatomic disorder, such as enlarged tonsils and adenoids, the Pierre Robin syndrome, and tracheal and laryngeal malacia. Signs and symptoms of obstructive sleep apnea include loud snoring, obstructive episodes with frequent arousal, behavior disorders caused by sleep deprivation, and cor pulmonale. In young children, an enlarged liver may suggest that the child has pulmonary hypertension. Although tonsillectomy and adenoidectomy may improve the airway, there may still be significant airway obstruction for the first few days after surgery. Foreign Body Aspiration Foreign body aspiration is a relatively common and often catastrophic event in children. Although it can occur at any age, the peak incidence of foreign body aspiration occurs at 6 months to 3 years of age. Vegetable matter (peanuts) and other foodstuff (hot dogs) or coins and small pieces of toys are the most commonly aspirated material. The symptoms of aspiration are related to the location of the foreign body within the airway and the time since the object was aspirated. Acute symptoms may include total airway obstruction, stridor, wheezing, or acute onset of coughing, whereas more chronic symptoms include bloody sputum, chronic coughing, or wheezing. The diagnosis of a foreign body in 79 · Pediatric and Neonatal Critical Care 2553 the airway is made from the history and physical examination and, in some cases, by radiologic imaging. The Heimlich maneuver and back slaps are reserved for acute upper airway obstruction with no air movement. Treatment of less acute or lower airway foreign body aspiration includes bronchoscopy, postural drainage, chest physical therapy, bronchodilators, and surgical removal of the object. Children with meningomyelocele usually have an Arnold-Chiari malformation and may have stridor. This lesion allows caudal displacement of the medulla, stretching of the cranial nerve tracts, and abnormal arterial architecture of the brainstem. Treatment of these brainstem abnormalities includes relief of the hydrocephalus and, if the paralysis persists, cervical decompression of the Arnold-Chiari lesion. Despite these surgical procedures, some children require a tracheotomy and long-term mechanical ventilation. Estimates from the Centers for Disease Control and Prevention placed the percentage of children with asthma at 3. Thankfully, the majority of children with asthma will never require intensive care. However, for the children that do there can be significant morbidity and a risk of mortality. Such factors include allergens, infections (viral > bacterial), changes in the weather, and strong emotions. Inflammation increases irritability of the airway as well as airway hyper responsiveness. The airway lumen is decreased by spasm of the bronchial muscles, edema, and mucus. For laminar airflow, airway resistance is related to the third power of the radius, but with turbulent airflow it is related to the fourth power. Due to the smaller lumen of their airways, children experience much greater changes in airway resistance during asthma attacks than adults. Bronchospasm, edema, or mucus plugging can lead to complete obstruction of small airways. It should be reinforced early that wheezing is caused more things than just asthma and that asthma can occur without wheezing. Wheezing in a toddler of a sudden onset should prompt evaluation for foreign body aspiration. Even the presence of a history of reactive airways or atopy does not rule out aspiration. Intermittently a chest-ray obtained for a child who is wheezing shows cardiomegaly rather than peribronchial cuffing. Asthma is statistically more likely but this can be the presentation of heart failure. With regard to asthma that occurs without wheezing, the movement of air is required to hear wheezing. Patients who present with a quiet chest or limited airflow on auscultation require immediate action. Some children in an effort to increase airway pressure may be breathing out with pursed lips or in smaller children grunting may be noted. Therapy should be started immediately first with supplemental oxygen to address hypoxemia. If the child has moderate or severe respiratory distress, oxygen should be delivered by either face mask or non-rebreather face mask. Inhaled beta agonists such as albuterol are given to relax bronchial smooth muscles. However, the clinical picture alone may provide enough information to guide therapy. A tightly sealed non-rebreather face masks might be able to provide a FiO2 closer to 1. The most commonly used agonists is albuterol, which is a racemic mixture of the active R and inactive S enantiomer. After improvement in air movement with decreased respiratory distress, intermittent doses can be given every 1 to 2 hours. Terbutaline as an inhaled medication is less 2 selective compared with albuterol and therefore is used less commonly. Diastolic hypotension is observed with higher doses of albuterol, although this can be related to decreased intravascular volume and increased intrathoracic pressure. Ipratropium bromide, an inhaled anticholinergic, is sometimes paired with intermittent albuterol doses. Ipratropium bromide has the benefit of promoting bronchodilation without decreasing mucociliary clearance. Systemic steroid use is associated with hyperglycemia, hypertension and occasionally agitation. However, excessive fluids should be avoided as this could lead to pulmonary edema. Fluid boluses may also be needed for children whose respiratory distress progresses require mechanical ventilation. Terbutaline is relatively 2 selective as compared with isoproterenol and epinephrine. There are improved controller medications including the leukotriene inhibitors so fewer children are receiving oral theophylline. The methylxanthines promote bronchial smooth muscle relaxation, but the exact mechanism of action is not known. If the patient has taken oral theophylline in the past 24 hours, the loading dose is reduced by 50% or the aminophylline dosing is adjusted based on a serum theophylline level. In general, an aminophylline loading dose of 1 mg/kg will raise the serum theophylline level by 2 g/mL. Theophylline levels above 20 g/mL are associated with nausea, tachycardia, restlessness, or irritability. The dose for critical asthma and hypomagnesium can be the same 25 to 45 mg/ kg given over 30 minutes. Magnesium toxicity can include muscle weakness, cardiac arrhythmias, decreased reflexes, and respiratory depression. This occurs due to the decreased density of helium as compared with nitrogen (approximately one-seventh). For Helium to be beneficial in small airways, it must occur in a high ration with oxygen. Therefore, hypoxemia and the need for increased supplemental oxygen may limit heliox use. There is data supporting the use of heliox as a method of delivering inhaled 2 agonists. For patients with asthma who are intubated and mechanically ventilated, ketamine may be a good choice for sedation along with a benzodiazepine. Further, there was one pediatric study447 showing an improvement in the PaO2/FiO2 ratio as well as dynamic compliance in mechanically ventilated children with refractory bronchospasm who were receiving a continuous infusion of Ketamine. There has been no study to show whether ketamine used to treat anxiety is beneficial in preventing intubation in patients during an asthma attack. For nonintubated patients, a recent Cochrane Database Review448 did not show significant benefit in severe acute asthma. If a decision is made to use ketamine either for a procedure or a means of sedation, the bolus dose is usually 1 mg/kg, allowing time for effect before repeating. Ketamine is given as a continuous infusion at the dose of 5 to 30 g/kg/min titrated to effect. One of the additional side effects of ketamine can be dysphoria, and as such it is usually given with a benzodiazepine. This should not be used when the level of alertness or ability to protect the airway is diminished. By the time patients with asthma require intubation and mechanical, they are hypoxemic, acidotic, fatigued, and have limited reserve. It is suggested that the most experienced person available perform the intubation.

Syndromes

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• Long duration of the scan
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• Factor II deficiency
• Dress like the opposite sex

Respiratory compromise may occur with peritoneal dialysis because the increased abdominal pressure caused by the dialysate in the abdomen may prevent effective spontaneous ventilation symptoms weight loss order cheap ritonavir. Severe dehydration symptoms vitamin b12 deficiency discount ritonavir 250 mg buy, circulatory collapse treatment 4 toilet infection purchase ritonavir us, and metabolic derangements are other complications of peritoneal dialysis symptoms stomach ulcer cheap 250 mg ritonavir otc. The principles of hemodialysis are essentially the same as those of peritoneal dialysis medicine in spanish buy generic ritonavir 250 mg line, except the blood interfaces with a semipermeable membrane rather than with the peritoneum. Hemodialysis is more appropriate in the acute setting with life-threatening electrolyte disturbances, fluid overload, and toxic ingestions. An ultrafiltrate of plasma is created by hydrostatic pressure exerted across a highly permeable membrane, with simultaneous blood volume replacement with a modified lactated Ringer solution. Furthermore, technical challenges occur in smaller patients due to flow characteristics of smaller dialysis catheters. Hemodialysis can be performed with two separate 5 Fr single lumen catheters, but typically a dual-lumen 7 Fr catheter at a minimum is required. The use of regional anticoagulation with citrate avoids the concerns of systemic anticoagulation and may reduce the risk of systemic bleeding. In general, children do better than adults; in fact, children usually recover completely from a renal insult if the hypoxia or ischemia lasted only a short time and other organ systems are not involved. Children with chronic renal failure require long-term outpatient peritoneal dialysis or hemodialysis until they can undergo renal transplantation. This syndrome is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury. Infections can be spread by person-to-person contact in daycare centers, institutions, and the military. There is also a familial form of the disease that accounts for a small percentage of the total cases. In fact, some investigators consider the two disorders a continuum of the same disease. Toxin-induced damage to renal endothelial cells, the vasculature, and other organs is directly or indirectly associated with the activation of leukocytes. Patients usually have abdominal cramping, bloody diarrhea, tenesmus, and vomiting. Mildly affected patients exhibit anemia, thrombocytopenia, azotemia, and decreased urine output, and have an uncomplicated course. In severely affected patients, anuria is common, hypertension and seizures may occur, and the duration of illness is prolonged. A small number of children exhibit progressive and permanent renal insufficiency, severe and recurrent hemolysis, thrombocytopenia, and neurologic impairment. Hemolysis often causes hyperbilirubinemia and, despite reticulocytosis, severe anemia with hemoglobin concentrations of 4 to 5 g/dL. Thrombocytopenia is the result of platelet destruction and sequestration in the liver and spleen. Acute renal failure with oliguria or anuria usually lasts less than a week but may linger for more than 10 weeks. Meticulous attention should be paid to volume status, electrolyte and acid-base balance, nutrition, antisepsis, and treatment of hypertension and coagulopathies. Accurate fluid intake and output measurements and frequent assessment of weight and volume status are important for management of these patients. If nephrotoxic drugs must be given, the drug dose should be adjusted and serum concentrations monitored closely. Daily fluids should be restricted to the amounts required to replace insensible losses, urine output, and other ongoing losses. Enteral feedings are preferred, but parenteral feeding may be necessary if ileus develops. Dialysis, improved nutrition, and supportive care have decreased the mortality rate from 100% in the original report to less than 10% in the last 30 years. Congenital adrenal hyperplasia, pheochromocytoma, and iatrogenic chronic adrenal insufficiency will be discussed briefly. Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is an autosomal recessive disorder that is associated with deficiencies in either 21-, 11-, or 17-hydroxylase. This condition is usually manifested in the first few weeks of life as feeding difficulty, vomiting, and failure to thrive. If the deficiency is not diagnosed and treated early in life, affected children may suffer severe cardiovascular collapse. Treatment requires aggressive support of intravascular volume and myocardial function, glucose, and replacement of the deficient hormones. Cortisol can be replaced by oral administration of hydrocortisone at a dose of 25 mg/ m2/day divided into three doses; if the child cannot tolerate oral medication, cortisone acetate can be administered intramuscularly at a dose of 37. For emergency therapy, when the oral route is not possible and perfusion of the muscle is poor, hydrocortisone acetate is used intravenously at a bolus dose of 1. Deficiencies of 11- and 17-hydroxylase do not result in salt wasting; masculinization and hypertension are the common initial signs Pheochromocytoma Less than 5% of pheochromocytomas are diagnosed in childhood. As a rule, these tumors are confined to the adrenal medulla, but they can occur anywhere throughout the sympathetic chain. The clinical signs and symptoms of excessive catecholamines are the same as those in adults. Such use may cause a hypoadrenal state and increase the risk for cardiovascular collapse during a severe illness or stress. Replacement of stress-level steroids (three times the daily replacement dose) is required. Anterior Pituitary Panhypopituitarism is usually secondary to a tumor or to aggressive dissection of a tumor. This syndrome is precipitated by a number of mechanisms, including head trauma, neurosurgery, meningitis, hypoxia, and any major surgical procedure in which there is large-volume fluid shifts and fluid replacement. This syndrome is treated by fluid restriction and, in severe cases, by the infusion of hypertonic or isotonic saline. However, it is uncommon to find a blood glucose level below 40 mg/dL in normal, nourished premature, or term neonates. The usual symptoms of hypoglycemia include tachycardia, diaphoresis, weakness, mental clouding, seizures, and coma. The causes of hypoglycemia can be subdivided into disorders of increased utilization and disorders of decreased production. Transient hypoglycemia of the newborn is caused by decreased or immature hepatic gluconeogenesis and it self-corrects within hours to days. If the hypoglycemia persists, hepatic enzyme deficiencies, endocrine problems, or hyperinsulinism. Other causes of hypoglycemia in the neonatal period include sepsis, hypothermia, hypoxia, and transplacental exposure to maternal hypoglycemic drugs. In older children, hypoglycemia is associated with ketotic hypoglycemia,569 hepatic enzyme abnormalities, hyperinsulinism, hepatic failure, and Reye syndrome, and it is a side effect of certain drugs. Regardless of cause, the initial treatment of hypoglycemia is glucose administration. The second category of patients with hyperglycemia in critically ill children are those who develop elevated glucose during treatment for their underlying disease process, likely due to stress biology. The clinical syndrome includes dehydration and hypovolemic shock from hyperglycemic osmotic diuresis, compensatory hyperventilation (Kussmaul pattern), life-threatening electrolyte depletion, and in cases of severe metabolic imbalance, neurologic obtundation and coma. Adequate intravascular volume is restored with an isotonic glucose-free solution, combined with exogenous insulin administration, commonly referred to as a "two-bag system. Most clinicians continue the insulin infusion until the acidosis is nearly corrected. These children have total-body potassium depletion, but potassium should not be added to any infusion until there is urine output. The need for phosphate may be more theoretical than real, but in most situations, half the potassium is given as a phosphate salt. The severe metabolic acidosis is usually corrected with volume and insulin administration. In an attempt to maintain their normal size, brain cells generate osmotically active idiogenic osmoles. As systemic rehydration and correction of the hyperosmolar state begin, the brain cells may swell until the idiogenic osmoles are metabolized or cleared. Consequently, rapid correction of osmolarity can cause significant brain edema572 and may also worsen the neurologic dysfunction, which may require invasive neuromonitoring. Unfortunately, despite very careful and slow correction of the hyperosmolar and acidotic state, hyperosmolar coma and fulminant brain edema can occur. If the midgut fails to migrate back into the abdominal cavity, an omphalocele occurs. Abnormalities in midgut rotation result in abnormal intraabdominal relationships, the most important being malrotation and volvulus of the intestine. Although the fetus relies on the maternal liver and placenta for detoxification and excretory function in utero, the fetal liver is necessary for both prenatal and postnatal survival. The fetal liver contains approximately three times the amount of glycogen as the adult liver, but the glycogen is nearly completely released within hours of birth to compensate for interruption of the placental supply of nutrients. Congenital Malformations Gross anatomic malformations are usually diagnosed during the first few days of life. Some, such as omphalocele, gastroschisis, diaphragmatic hernia, and imperforate anus, are apparent on the initial physical examination. Others manifest themselves in the first few days of life as failure to feed enterally, intestinal atresia, microcolon, tracheoesophageal fistula, and meconium ileus. Other malformations present difficult diagnostic and therapeutic dilemmas after the neonatal period. Malrotation of the intestine is caused by incomplete rotation of the fetal midgut when the gut migrates into the abdominal cavity. This abnormal rotation can cause partial or complete duodenal obstruction by peritoneal (Ladd) bands or, more importantly, midgut volvulus. The midgut (duodenum to transverse colon) and its vascular supply hang on a single pedicle; if the pedicle twists, the entire midgut may infarct. Infants with omphalocele almost invariably have associated malrotation of the gut. Symptomatic infants and children have signs of high intestinal obstruction (bilious vomiting) or signs of an acute abdomen, intestinal perforation, and sepsis. Treatment is surgical reduction and fixation of the volvulus and resection of nonviable bowel. Postoperative respiratory support and total parenteral nutrition are often necessary in infants who were severely compromised before surgery. The bleeding site is due to ulceration of the bowel mucosa caused by secretion of gastric acid. Structural and Functional Development of the Intestine Knowledge of fetal midgut development makes it easier to understand a number of severe congenital anomalies. The lumen is later reconstituted when vacuoles within the epithelial cells coalesce. Some of the neonatal intestinal atresias are the result of abnormalities of this recanalization process. The technetium pertechnetate isotope scan demonstrates gastric mucosa in the diverticulum. Therapy is supportive, but particular attention must be paid to blood replacement. Hirschsprung disease (congenital aganglionic megacolon) is characterized by the absence of parasympathetic ganglion cells in the rectum and colon and occasionally in the small bowel. The clinical symptoms can be relatively minor, with abdominal distention and stool retention, or severe, with toxic megacolon, peritonitis, and intestinal perforation. Toxic megacolon is usually manifested in younger children; reported mortality rates are as high as 75% with toxic megacolon. The diagnosis of Hirschsprung disease is occasionally made by the history and physical examination. A barium enema reveals a narrowed segment with ballooning of the proximal part of the bowel. The definitive diagnosis is made by finding no ganglion cells on rectal or colon biopsy (or both). Treatment of toxic megacolon is both supportive (volume re-expansion and antibiotic administration) and definitive (surgical decompression via colostomy). Intestinal disorders can cause bleeding, obstruction, or inflammation, and there can be secondary problems such as malabsorption and bowel perforation. Although ulcer disease is an uncommon initial complaint in pediatric patients, stress gastritis or stress ulcers occur in critically ill children. Bowel obstruction can be caused by intussusception, twisting of the bowel around congenital or postsurgical bands, and twisting of the bowel on itself (volvulus). Intussusception is relatively common in the pediatric age group and usually occurs in the distal part of the ileum. In only a few cases can a leading point, such as a polyp or localized edema (as seen in HenochSchönlein purpura), be identified. Treatment of intussusception can be surgical or, in patients with no evidence of necrotic bowel, with barium, air, or saline enema. These patients often have diarrhea, malabsorption (especially lactose intolerance), and bloody diarrhea. It is probably due to a combination of intestinal ischemia, oral feeding, and pathogenic organisms. The most common initial signs are feeding intolerance, abdominal distention, and bloody stools. Peritoneal drainage may be helpful for very-lowbirth-weight babies and for those in extremis. Chronic liver failure can be caused by biliary atresia, inborn errors of metabolism (tyrosinosis, Wilson disease, galactosemia, cystic fibrosis), or chronic inflammatory hepatitis. Children with chronic disease often have signs and symptoms of synthetic dysfunction (malnutrition, hypoalbuminemia, abnormal coagulation), degradation dysfunction (icterus and hyperammonemia), and portal hypertension (hypersplenism and varices).

For example medicine rising appalachia lyrics buy ritonavir with visa, one study described the production of enteric-coated caplets by printing a methacrylic polymer-based shell surrounding a drug core treatment shingles ritonavir 250 mg buy online. Moreover medications ok for dogs discount ritonavir online visa, novel strategies such as four-dimensional (4D) printing could provide excellent promise within the pharmaceutical sector medications japan generic 250 mg ritonavir mastercard, especially for the advancement of modified drug delivery 5 medications purchase ritonavir with paypal. As the goal of 4D printed objects is to alter their shape and size from external stimulation, the printed material (otherwise known as smart material) used is required to be responsive to stimuli varying from heat, pH, magnetic field or light. Investigation of the effect of tablet surface area/volume on drug release from hydroxypropylmethylcellulose controlled-release matrix tablets. Formulation aspects in the development of osmotically controlled oral drug delivery systems. Formulation and evaluation of orodispersible tablet of taste masked doxylamine succinate using ion exchange resin. A quantitative review and meta-models of the variability and factors affecting oral drug absorption-part I: gastrointestinal pH. Formulation and development of lenalidomide loaded delayed release mini tablets in capsules. A paradigm shift in enteric coating: achieving rapid release in the proximal small intestine of man. Contribution of scintigraphy to verify the reliability of different preparation processes for enteric coated capsules. Absorption of acetylsalicylic acid from enteric-coated tablets in relation to gastric emptying and in-vivo disintegration. A novel concept in enteric coating: a double-coating system providing rapid drug release in the proximal small intestine. Predicting the gastrointestinal behaviour of modifiedrelease products: utility of a novel dynamic dissolution test apparatus involving the use of bicarbonate buffers. Gastroretentive drug delivery technologies: current approaches and future potential. Helicobacter pylori: past, current and future treatment strategies with gastroretentive drug delivery systems. Decades of research in drug targeting to the upper gastrointestinal tract using gastroretention technologies: where do we stand Design and evaluation of an innovative floating and bioadhesive multiparticulate drug delivery system based on hollow structure. Oral, ultra­long-lasting drug delivery: application toward malaria elimination goals. A pH-dependent colon targeted oral drug delivery system using c methacrylic acid copolymers: I. Manipulation of drug release using Eudragit L100-55 and Eudragit S100 combinations. A novel double-coating approach for improved pH-triggered delivery to the ileo-colonic region of the gastrointestinal tract. All disease begins in the gut: influence of gastrointestinal disorders and surgery on oral drug performance. Variations in concentrations of bacterial metabolites, enzyme activities, moisture, pH and bacterial composition between and within individuals in faeces of seven healthy adults. Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption. Targeted delivery of probiotics to enhance gastrointestinal stability and intestinal colonisation. A new concept in colonic drug targeting: a combined pH-responsive and bacterially-triggered drug delivery technology. Modified drug release 197 ´ [50] Goyanes A, Fernandez-Ferreiro A, Majeed A, et al. Oral disintegrating patient-tailored tablets of warfarin sodium produced by 3D printing. Channelled tablets: an innovative approach to accelerating drug release from 3D printed tablets. Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing. Roque Saenz Pen Chaco, Argentina ~a, c Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Haifa, Israel Katia P. Introduction Oral delivery remains the preferred route of drug administration due to its non-invasive nature and improved patient compliance. The absorption of any chemical entity administered by the oral route is a complex process that is influenced by various factors and events related both to the organism and the drug. This percentage increases for new chemical entities under different stages of development. In these cases, the aqueous solubility and membrane permeability are the limiting step and hinder the oral absorption and bioavailability of the drug [9]. Therefore, the oral administration of such compounds requires effective drug delivery systems to achieve improved bioavailability and successful use in humans. The design of these systems requires an understanding of intestinal physiology and the mucosal microenvironment [2]. To overcome this barrier, one of the factors that must be taken into account is the surface charge of the drug carriers. Therefore, uncharged and negatively-charged carriers can move across the mucus, but positively-charged ones usually cannot permeate through it, as they become immobilized by ionic interactions. However, when negatively-charged carriers reach the intestinal epithelium, cell uptake via endocytosis is less pronounced than for positively-charged counterparts. Thus, a strategy to overcome this obstacle could be the development of drug carriers that can change their zetapotential from negative to positive as they permeate mucus [23, 24]. Other strategies based on the breakdown of the mucus could be problematic, as this layer has a protective function. Therefore, other strategies have emerged, including the use of carrier systems at nanometric scale capable of permeating the mucus without destroying it or only to a very limited extent and transiently. Oppositely, active systems interact with the mucus by means of chemical reactions. These systems are based on carriers bearing free thiol groups and on proteolytic enzymes that are able to cleave disulfide bonds and peptide bonds of mucus glycoproteins, respectively [30]. In addition, active systems based on thiolated polymers (coined as Thiomers) [31, 32] and zeta-potential change [33, 34] that avoid a back-diffusion of the particles out of the mucus layer are also a promising strategy [30]. Most licensed vaccines are injectable despite the majority of human pathogens infecting the body through mucosal sites. This is due to the fact that oral vaccines face many hurdles, such as the harsh gastric conditions. Davitt and Lavelle [36] reviewed the opportunities, challenges and potential delivery solutions to facilitate the development of improved Delivery platforms for oral drug administration 201 oral vaccines for infectious enteric diseases. Moreover, capsid viruses are a useful model for developing nanocarriers used as mucosal drug delivery systems, as they can diffuse through mucus as rapidly as through water, and penetrate across the epithelium, since they have a smaller size than the mucus mesh spacing and surfaces that do not stick to the mucus [38]. Several pH-sensitive nanocarriers have been designed to increase efficacy and reduce toxicity associated with off-target drug exposure [39]. One of the most promising methods for targeted delivery to cancer tissues of anticancer drugs or genes is based on receptor-mediated endocytosis of nanocarriers [42]. Cancer cells overexpress on their surfaces many tumor-specific receptor that exhibit high binding affinity towards specific ligands. For example, biotin (vitamin H or B7) is an essential vitamin for cell division and an important growth promoter for tumors. Biotin receptors are overexpressed in various tumor cell types more than other vitamin receptors. Therefore, biotin receptors can be used as biomarkers to design cytotoxic oral delivery systems modified on their surface with tumor-targeting ligands [43, 44]. Neonatal Fc receptor (FcRn) is related to the major histocompatibility complex Class I and interacts with antibodies of the immunoglobulin G (IgG) class. FcRn is expressed in several organs and tissues, in which it may have a role in IgG transport and protect IgG from degradation, extending its half-life in serum. Therefore, the conjugation of the IgG Fc portion to a nanocarrier can enhance the intestinal absorption and extend the half-life in the serum, improving the oral bioavailability and increasing tissue accumulation of the therapeutic antibody [45­47]. In this context, the administration frequency or dosage requirements could be reduced [48]. Sockolosky and Szoka [49] reviewed the therapeutic opportunities and challenges of targeting FcRn for drug delivery. Recently, FcRnmediated transcytosis has been proposed as a strategy to increase the transport of drugs across the intestinal epithelium [50]. Delivery platforms for oral administration of (bio)pharmaceuticals Different types of drug carriers have emerged as an effective strategy for mucosa delivery. One of the greatest challenges, however, is their ability to penetrate quickly through the mucus layer and this limits their success [51]. This is one drug among the statins that is widely used to inhibit cholesterol synthesis. Results of short-term stability studies showed no significant change in the particle size of both formulations storage at 4 °C during 5 days. These results suggest that particle size plays an important role not only in blood bioavailability, but also in the pharmacological response [54, 55]. Small particles (about 50 nm) can easily go through epithelia by the paracellular pathway. Nevertheless, very small particles (<20­30 nm) will be eliminated by renal excretion. With some exceptions, 200 nm (50­300 nm) is considered the ideal particle size to cross the endothelial barrier [56]. However, there is no general rule and drug delivery systems for oral administration have to be individually designed based on the target organ to avoid or minimize accumulation in off-target organs [57]. Anticancer drug formulations are generally developed for administration via parenteral route. Nanoparticulate drug delivery systems can be used by oral route in cancer treatment when particle size is adjusted. For this, polystyrene sphere-, rod- and disc-shaped particles were prepared from polystyrene spherical particles using the film-stretching procedure. Fluorescent spheres (200 nm) with free carboxyl terminus were suspended in a 10% poly(vinyl alcohol) solution containing 204 Nanotechnology for oral drug delivery 2% glycerol. Subsequently, the films were stretched at 120 °C in an oil bath, in one or two directions, using a custom-made stretching apparatus. Then, these films were cooled and cut into small pieces which were dissolved at 65 °C in water. Gut epithelial cells, including Caco-2 cells, show expression of the biotin receptors on their surface [60]. The particles have negative charge due to the presence of carboxyl terminus residues. Conjugation of biotin to particles greatly reduced their charge, which suggests successful conjugation. A triple co-culture model of intestinal cells involved in absorption and transportation of the drugs across the intestine was used in this study. Results showed that the transport across the Caco-2 monolayer was minimal and did not depend on the size. In the triple co-culture, particles of 50 and 200 nm showed significantly higher transport (>20%) at 5 h compared to particles of 500 and 1000 nm (15% and 8%, respectively). In Caco-2 cells, the uptake of rods and discs was significantly higher than that of spheres, but there was no difference in the uptake between rods and discs. Regarding the effect of particle shape on their transport across intestinal cells, no significant difference was evidenced on the transport of spheres, rods or discs in the Caco-2 monolayers. In Caco-2/Raji-B co-culture, the transport of Delivery platforms for oral drug administration 205 both rods and discs increased up to 20%, while that of spheres increased to a lesser extent (14%) after the same incubation time. A maximum transport of about 1% was observed for spheres, but not significantly different from that of rods and discs after 5 h. Discs showed the highest transport (18%) at the end of the assay, but not significantly different from that of rods ($15%). On the other hand, spheres showed less transport capacity than that of rods and discs (11%). In summary, this study indicated that rods and discs are transported to a greater extent compared to spheres across intestinal cells. Confocal images of transwell membranes using the triple co-culture model at the end of the transport experiment were consistent with this observation. On the other hand, results of the transport across monolayers showed that the transport of conjugated particles was higher across Caco-2/Raji-B cells. Rods were transported to the highest extent ($27%), followed by discs ($23%) and spheres ($13%) after 5 h. In the triple co-culture model, by the end of the study, conjugated discs were transported to the highest extent (21%), followed by rods (18%) and spheres (12%). The percentage of transport of biotin-conjugated particles was similar to that of unconjugated particles, with the exception of conjugated rods that showed significantly higher transport across the triple co-culture compared to unconjugated rods. The nanocarrier shape has emerged as an additional feature that can have a significant effect on drug dissolution, absorption and oral bioavailability and efficacy [61, 62]. Most of the bacteria as Helicobacter pylori and Vibrio cholera have rodlike shape, which confers high mobility in mucus [63]. Generally, carriers with negative charge are more slippery because they avoid ionic interactions with the mucus layer, which has a net negative charge and therefore, permeate through this layer more easily.

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